{"gene":"DPYSL2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2001,"finding":"CRMP-2 is enriched in growing axons of cultured hippocampal neurons; overexpression induces supernumerary axons, and dominant-negative truncation mutants suppress primary axon formation, establishing CRMP-2 as critical for axon induction and neuronal polarity.","method":"Overexpression and dominant-negative mutant expression in cultured hippocampal neurons with morphological readout","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function (dominant-negative) and gain-of-function with defined cellular phenotype, replicated across multiple labs","pmids":["11477421"],"is_preprint":false},{"year":2002,"finding":"CRMP-2 binds tubulin heterodimers with higher affinity than assembled microtubules and promotes microtubule assembly; a deletion mutant lacking the microtubule-assembly region acts dominant-negatively to inhibit axonal growth and branching.","method":"In vitro tubulin-binding assays, microtubule polymerization assays, dominant-negative mutant overexpression in neurons","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution of tubulin binding and polymerization plus mutagenesis, replicated in neuronal context","pmids":["12134159"],"is_preprint":false},{"year":2003,"finding":"CRMP-2 interacts with Numb; CRMP-2/Numb complex co-localizes with L1 at axonal growth cones, and dominant-negative CRMP-2 or siRNA knockdown inhibits L1 endocytosis and suppresses axon growth, identifying CRMP-2 as a regulator of polarized Numb-mediated endocytosis.","method":"Co-immunoprecipitation, siRNA knockdown, dominant-negative expression, L1 endocytosis assay in hippocampal neurons","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA KD, and dominant-negative with specific endocytic phenotype, multiple orthogonal methods","pmids":["12942088"],"is_preprint":false},{"year":2005,"finding":"GSK-3β phosphorylates CRMP-2 at Thr-514 and inactivates it; expression of non-phosphorylatable CRMP-2 or GSK-3β inhibition induces multiple axon-like neurites, while constitutively active GSK-3β impairs neuronal polarization. NT-3 inactivates GSK-3β leading to CRMP-2 dephosphorylation and axon outgrowth.","method":"In vitro kinase assay, phospho-specific antibodies, overexpression of constitutively active/kinase-dead mutants, knockdown of CRMP-2 in hippocampal neurons","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus genetic epistasis with multiple rescue experiments, widely replicated","pmids":["15652488"],"is_preprint":false},{"year":2005,"finding":"Cdk5 phosphorylates CRMP2 at Ser522; this primes sequential phosphorylation by GSK-3β at Thr509. Dual phosphorylation reduces CRMP2 affinity for tubulin and generates the 3F4 neurofibrillary tangle-associated epitope. Sema3A stimulation enhances this sequential phosphorylation, and CRMP2 Ala-mutants at Ser522 or Thr509 attenuate Sema3A-induced growth cone collapse.","method":"In vitro kinase assay, site-directed mutagenesis, phospho-specific antibodies, DRG growth cone collapse assay, cdk5-/- mouse brain lysates","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, genetic validation in cdk5 knockout, functional growth cone assay","pmids":["15676027"],"is_preprint":false},{"year":2005,"finding":"Rho kinase phosphorylates CRMP-2 and abolishes its binding to tubulin dimers, microtubules, and Numb, but not to actin. Phosphorylated CRMP-2 localizes exclusively to actin filaments rather than microtubules or clathrin-coated pits in growth cones. Ephrin-A5 induces this phosphorylation via Rho kinase during growth cone collapse.","method":"In vitro kinase assay, phospho-mimetic/null mutants, electron microscopy localization, growth cone collapse assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, mutagenesis, EM-based localization with functional readout, multiple orthogonal methods","pmids":["16260611"],"is_preprint":false},{"year":2005,"finding":"CRMP-2 C-terminal region directly binds the tetratricopeptide repeat domain of Kinesin light chain 1 (KLC1); soluble tubulin forms a trimeric complex with CRMP-2 and KLC1. Knockdown of KLCs or CRMP-2 impairs anterograde GFP-tubulin transport in axons.","method":"Pulldown/direct binding assay, Co-immunoprecipitation, fluorescence recovery after photobleaching (FRAP) of GFP-tubulin, siRNA knockdown","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay identifying trimeric complex, FRAP-based transport assay, KD with specific transport phenotype","pmids":["15935053"],"is_preprint":false},{"year":2000,"finding":"CRMP-2 is highly phosphorylated at Thr-509, Ser-518, and Ser-522 in neurofibrillary tangles of Alzheimer's disease brain; site-directed mutagenesis showed that phosphorylation at all three sites is required for the 3F4 tangle-associated epitope.","method":"Immunoaffinity purification, site-directed mutagenesis, in vitro kinase assay with brain extract","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis defining phosphorylation sites with functional epitope readout, in vitro kinase assay","pmids":["10757975"],"is_preprint":false},{"year":2009,"finding":"CRMP-2 directly binds dynein heavy chain at its N-terminus (distinct from the kinesin light chain-binding region); overexpression of dynein-binding CRMP-2 fragments prevents dynein-driven microtubule transport in COS-7 cells, suggesting CRMP-2 interferes with retrograde transport.","method":"Co-immunoprecipitation, direct binding domain mapping, dynein-driven microtubule transport assay in COS-7 cells","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, cell-based transport assay, single lab","pmids":["19659462"],"is_preprint":false},{"year":2009,"finding":"CRMP-2 binds directly to CaV2.2 (N-type Ca2+ channel) at the domain I-II intracellular loop and distal C-terminus; CRMP-2 overexpression increases CaV2.2 surface expression and current density in hippocampal neurons and enhances vesicular glutamate release, while lentiviral knockdown abolishes this effect.","method":"Co-immunoprecipitation, cell-surface biotinylation, patch-clamp electrophysiology, glutamate release assay, lentiviral knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding mapped to specific domains, reciprocal Co-IP, surface biotinylation, electrophysiology, and neurotransmitter release assay in multiple cell types","pmids":["19755421"],"is_preprint":false},{"year":2009,"finding":"CRMP-2 overexpression in dorsal root ganglion neurons increases CaV2.2 surface levels and current density; siRNA knockdown of CRMP-2 reduces CGRP release by ~54%, establishing CRMP-2 as a regulator of N-type Ca2+ channel activity and transmitter release in sensory neurons.","method":"Nucleofection overexpression, siRNA knockdown, patch-clamp electrophysiology, surface biotinylation, CGRP ELISA","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function with electrophysiology and neurotransmitter release, replicates findings from PMID 19755421","pmids":["19903690"],"is_preprint":false},{"year":2011,"finding":"Sema3A stimulation generates H2O2 via MICAL, oxidizing CRMP2 to form a disulfide-linked homodimer through Cys-504; oxidized CRMP2 then forms a transient disulfide complex with thioredoxin (TRX), which stimulates GSK-3-mediated phosphorylation of CRMP2, leading to growth cone collapse. This oxidation-phosphorylation cascade was reconstituted in vitro with purified proteins.","method":"In vitro reconstitution with purified proteins, mass spectrometry, non-reducing SDS-PAGE, mutagenesis (Cys-504), growth cone collapse assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins plus mutagenesis and functional growth cone readout","pmids":["21521879"],"is_preprint":false},{"year":2011,"finding":"Inhibiting the CRMP-2–CaV2.2 interaction with a TAT-fused CRMP-2-derived peptide (TAT-CBD3) decreases neuropeptide release, excitatory synaptic transmission, and nocifensive/neuropathic pain behaviors in vivo, demonstrating that CRMP-2-mediated enhancement of CaV2.2 function underlies pain hypersensitivity.","method":"Peptide inhibitor (TAT-CBD3), in vivo pain behavior assays, electrophysiology in dorsal horn neurons","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — peptide disruption of specific protein-protein interaction with multiple in vivo and ex vivo functional readouts","pmids":["21642979"],"is_preprint":false},{"year":2011,"finding":"TAT-CBD3 (CRMP-2 peptide) induces NR2B (GluN2B) internalization in dendritic spines, reduces NMDA-evoked Ca2+ influx and currents, and protects neurons from delayed calcium deregulation following glutamate excitotoxicity; CRMP-2 knockdown similarly blocks neuronal death, implicating CRMP-2 in NMDAR surface trafficking.","method":"Lentiviral CRMP-2 knockdown, peptide application, Ca2+ imaging, patch-clamp electrophysiology, cortical impact TBI model in vivo","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — lentiviral KD plus peptide with electrophysiology, Ca2+ imaging, and in vivo TBI model","pmids":["21832084"],"is_preprint":false},{"year":2012,"finding":"CRMP-2 phosphorylation at Thr555 (by Rho kinase downstream of NgR1) is increased in degenerating axons in EAE/multiple sclerosis; AAV-mediated expression of phospho-resistant T555A-CRMP-2 limits optic nerve axonal degeneration, establishing NgR1-dependent CRMP-2 phosphorylation as a mechanism of axonal degeneration.","method":"NgR1 knockout mice, AAV-T555A-CRMP2 transduction, phospho-specific immunostaining, axonal degeneration quantification","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO epistasis and viral phospho-resistant mutant rescue with defined axonal degeneration phenotype","pmids":["22544872"],"is_preprint":false},{"year":2012,"finding":"Cdk5-mediated phosphorylation of CRMP-2 at Ser522 is required for dendritic field organization in vivo; CRMP2 S522A knock-in mice combined with CRMP1 knockout display severe 'curling' dendritic patterning in cortical neurons, demonstrating synergistic roles of CRMP1 and CRMP2 phosphorylation in dendritic projection.","method":"Knock-in mouse generation (CRMP2-S522A), CRMP1 knockout mice, cortical neuron morphology analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knock-in and knockout mouse models with specific in vivo dendritic phenotype","pmids":["22279220"],"is_preprint":false},{"year":2012,"finding":"CRMP-2 phosphorylation by Cdk5 at Ser522 enhances its interaction with CaV2.2; a Cdk5 phospho-null CRMP-2-S522A mutant or inactive Cdk5 abolishes CRMP-2-mediated enhancement of Ca2+ influx via CaV2.2, whereas the Rho kinase site T555A mutant is ineffective.","method":"Phospho-null mutant overexpression, inactive Cdk5 co-expression, Ca2+ current measurement, co-immunoprecipitation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with Co-IP and Ca2+ current assay, single lab","pmids":["23022559"],"is_preprint":false},{"year":2013,"finding":"CRMP-2 is SUMOylated by Ubc9 at Lys374 in vivo; removal of the SUMOylation site (K374A or K374A/M375A/D376A mutants) reduces NaV1.7 surface expression and current density, while increasing SUMOylation levels inversely correlates with CaV2.2-mediated calcium influx.","method":"In vivo SUMOylation assay, SUMO protease overexpression, surface biotinylation, electrophysiology (NaV1.7 and CaV2.2 currents), calcium imaging","journal":"The Journal of biological chemistry / Channels","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (SUMOylation assay, biotinylation, electrophysiology) identifying specific modification site with functional ion channel trafficking consequence","pmids":["23836888","23510938"],"is_preprint":false},{"year":2013,"finding":"CRMP-2 interacts with the GluK5 subunit of kainate receptors; PKC-mediated phosphorylation of CRMP-2 at T555 (via non-canonical KAR signaling) downregulates membrane CaV2.2, while dephosphorylation at T514 (via GSK3β phosphorylation at S9) promotes neurite outgrowth.","method":"Co-immunoprecipitation, phospho-specific antibodies, CaV2.2 surface expression assay, neurite outgrowth assay in DRG neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multiple phospho-site functional assays, single lab","pmids":["24227739"],"is_preprint":false},{"year":2013,"finding":"CRMP-2 interacts with NMDAR (co-immunoprecipitation) and NCX3 but not NCX1; TAT-CBD3 peptide disrupts CRMP-2–NMDAR interaction without altering NMDAR localization, and simultaneously augments CRMP-2–NCX3 interaction and triggers NCX3 internalization, inhibiting both reverse and forward NCX modes.","method":"Co-immunoprecipitation, siRNA knockdown, NCX3 internalization assay, Ca2+ dysregulation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus KD with Ca2+ functional assay, single lab","pmids":["24474686"],"is_preprint":false},{"year":2008,"finding":"Dephosphorylation of CRMP2 at GSK3-targeted residues (Ser-518/Thr-514/Thr-509) is carried out by a protein phosphatase 1 family member in vitro and in neurons; the Cdk5-phosphorylated site (Ser-522) is comparatively resistant to phosphatase treatment, partly due to neighboring basic residues, which may contribute to Alzheimer's disease-associated CRMP2 hyperphosphorylation.","method":"In vitro phosphatase assay, pharmacological inhibition (purvalanol, CT99021, IGF-1), Pin1 transgenic mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphatase reconstitution plus multiple pharmacological and genetic validations in cells and transgenic mice","pmids":["18460467"],"is_preprint":false},{"year":2009,"finding":"Local mTOR-p70S6K signaling in the axon selectively upregulates translation of CRMP2 and Tau mRNAs via 5'-terminal oligopyrimidine tract elements; rapamycin suppresses axon specification by reducing CRMP2/Tau translation, and exogenous CRMP2 rescues axon formation in rapamycin-treated neurons.","method":"Rapamycin treatment, constitutively active p70S6K expression, 5'UTR reporter assays, local translation in axons","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays plus pharmacological/genetic rescue, single lab","pmids":["19648118"],"is_preprint":false},{"year":2010,"finding":"CRMP-2 interacts with MICAL-L1 in non-neuronal cells; CRMP-2 depletion causes relocalization of internalized transferrin from peripheral vesicles to the endocytic recycling compartment, an effect blocked by inhibiting dynein (dynamitin overexpression), establishing CRMP-2 as a link between MICAL-L1/EHD1 vesicular transport and dynein motors.","method":"Co-immunoprecipitation, siRNA knockdown, transferrin recycling assay, dynamitin overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus KD and dynein inhibition with specific endocytic trafficking phenotype, single lab","pmids":["20801876"],"is_preprint":false},{"year":2010,"finding":"BMP-SMAD1/4 signaling transcriptionally suppresses CRMP2 expression by binding the CRMP2 promoter (ChIP); CRMP2 knockdown or dominant-negative CRMP2 in utero causes accumulation of multipolar cells and impairs multipolar-to-bipolar transition during radial neuronal migration.","method":"ChIP assay, in utero electroporation with RNAi and dominant-negative constructs, cortical slice analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for transcriptional regulation plus in vivo in utero electroporation with defined neuronal migration phenotype","pmids":["20926379"],"is_preprint":false},{"year":2015,"finding":"A membrane-tethered myristoylated CRMP-2 peptide (myr-tat-CBD3) more efficiently disrupts CRMP-2–CaV2.2 interaction than the non-myristoylated version, reduces CaV2.2 trafficking, inhibits Ca2+ influx, decreases DRG neuron excitability, and reverses carrageenan-induced thermal hypersensitivity and postoperative pain.","method":"Pulldown, confocal immunofluorescence colocalization, voltage-clamp electrophysiology, current-clamp, in vivo pain behavior assays","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding disruption with biochemical, electrophysiological, and in vivo functional readouts","pmids":["25782368"],"is_preprint":false},{"year":2016,"finding":"CRMP2 SUMOylation at Lys374 is enhanced by Cdk5-mediated phosphorylation and antagonized by Fyn phosphorylation; SUMOylated CRMP2 binds NaV1.7 to maintain its membrane localization; loss of SUMOylation triggers clathrin-dependent NaV1.7 internalization involving Nedd4-2, Numb, and Eps15.","method":"SUMOylation assays, phospho-mutant constructs (Cdk5/Fyn sites), surface biotinylation, clathrin inhibition, Co-immunoprecipitation, CRMP2-K374A mutant expression","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods establishing hierarchical PTM cross-talk controlling NaV1.7 trafficking, with mechanistic pathway identification","pmids":["27940916"],"is_preprint":false},{"year":2016,"finding":"Brain-specific Crmp2 knockout mice show reduced hippocampal LTP, abnormal NMDA receptor composition, aberrant dendrite development, and defective synapse formation in CA1 neurons; adult neurogenesis knockdown shows stage-dependent developmental defects, demonstrating CRMP2 is required for synaptic plasticity and neuronal development in vivo.","method":"Conditional knockout mice, electrophysiology (LTP), immunostaining, western blot for NMDAR subunits, retroviral knockdown in adult neurogenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal cellular/electrophysiological readouts","pmids":["27249678"],"is_preprint":false},{"year":2017,"finding":"X-ray crystal structure (1.78 Å) of mouse CRMP2 reveals Lys374 as the sole biologically relevant SUMOylation site, buried in the tetramer interface but exposed in the monomer; structural basis suggests phosphorylation-induced monomerization exposes Lys374 for SUMOylation.","method":"X-ray crystallography (1.78 Å resolution), sequence alignment, structure-function mutagenesis","journal":"Channels","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation of SUMOylation site, structure-guided mutagenesis","pmids":["28277940"],"is_preprint":false},{"year":2017,"finding":"X-ray structural analysis of CRMP2-tubulin interaction shows the C-terminal helix H19 of CRMP2 is the main interface with soluble tubulin dimers (distinct from tail-mediated interaction with assembled microtubules); H19-mediated interaction promotes rapid GTP-state microtubule formation; H19 mutants disturb axon elongation in chick neurons and fail to produce axonal microtubule features in C. elegans.","method":"X-ray crystallography, in vitro microtubule polymerization assay, H19 mutagenesis, chick neuron axon elongation assay, C. elegans genetic assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro reconstitution and mutagenesis, validated in two independent in vivo models","pmids":["28878401"],"is_preprint":false},{"year":2018,"finding":"FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499; crystal structure of CRMP2-Y479E phospho-mimetic reveals this prevents CRMP2 tetramerization, abolishing microtubule bundling activity of the C-terminus. FER depletion increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells.","method":"X-ray crystallography (CRMP2-Y479E), in vitro microtubule bundling assay, FER kinase inhibition, in vivo xenograft model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro functional assay with mutagenesis and in vivo validation","pmids":["29396402"],"is_preprint":false},{"year":2018,"finding":"Cdk5-mediated CRMP2 phosphorylation (at Ser522) is increased presynaptically in spinal cord/DRG after spared nerve injury; CRMP2 knockdown reverses mechanical allodynia; intrathecal non-phosphorylatable CRMP2-S522A decreases allodynia while phospho-mimetic S522D induces allodynia in naive rats, establishing Cdk5-CRMP2 phosphorylation as both necessary and sufficient for neuropathic pain.","method":"siRNA knockdown, intrathecal expression of phospho-null/mimetic mutants, biochemical fractionation, spared nerve injury model","journal":"Neurobiology of pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation with specific pain behavior phenotype, gain- and loss-of-function in vivo","pmids":["31080913"],"is_preprint":false},{"year":2018,"finding":"Neurofibromin binds CRMP2 in a CDK5-dependent manner; loss of neurofibromin frees CRMP2 to interact with syntaxin 1A and CaV2.2, increasing CGRP release; a CRMP2-neurofibromin interface-disrupting peptide (t-CNRP1) inhibits Ca2+ influx, reduces CaV2.2 membrane localization, and reverses pain behaviors in NF1-related models.","method":"Co-immunoprecipitation, peptide mapping, CGRP release assay, surface biotinylation, in vivo pain behavior","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP interaction mapping plus functional peptide disruption with multiple biochemical and in vivo readouts","pmids":["28767512"],"is_preprint":false},{"year":2018,"finding":"The Ubc9–CRMP2 interaction has low micromolar affinity (measured by microscale thermophoresis and AlphaLISA); a CRMP2 SUMOylation motif heptamer peptide (t-CSM) disrupts CRMP2–Ubc9 interaction, reduces CRMP2 SUMOylation, blocks NaV1.7 surface trafficking in sensory neurons, and reverses spinal nerve injury-induced pain.","method":"Microscale thermophoresis, AlphaLISA, cell-penetrating peptide, surface biotinylation, electrophysiology, SNI pain model","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — biophysical binding measurement plus functional ion channel trafficking and in vivo pain reversal, multiple methods","pmids":["29847471"],"is_preprint":false},{"year":2019,"finding":"PTEN knockout abrogates GSK3 inhibitory activity on CRMP2; maintaining GSK3 activity (Gsk3 knock-in mice) compromises PTEN-KO-mediated optic nerve regeneration and CRMP2 activity; viral expression of constitutively active CRMP2-T/A rescues regeneration despite reduced mTOR activation, establishing GSK3/CRMP2 as a required pathway for PTEN-KO-mediated axon regeneration.","method":"Conditional knockout mice (PTEN), GSK3 knock-in mice, AAV-CRMP2-T/A viral expression, optic nerve regeneration assay","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using multiple mouse models with defined axon regeneration phenotype","pmids":["31453382"],"is_preprint":false},{"year":2019,"finding":"Nogo-A induces association of NgR1 with CRMP2 in a PlexinA2-dependent manner; NgR1 and PlexinA2 interact genetically to restrict corticospinal axon sprouting after pyramidotomy; double-heterozygous NgR1+/-;PlexinA2+/- mice show greater sprouting and functional recovery, placing CRMP2 in a NgR1/PlexinA2/CRMP2 ternary complex that limits neural repair.","method":"Immunoprecipitation proteomics, non-neuronal cell contraction assay, double-heterozygous mouse genetics, pyramidotomy model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — IP-proteomics identifying complex, genetic epistasis in double-heterozygous mice with in vivo axon sprouting phenotype","pmids":["30804090"],"is_preprint":false},{"year":2013,"finding":"Identification of a reversible intermolecular Cys-504–Cys-504 dithiol-disulfide switch in homotetrameric CRMP2 that determines two quaternary conformations controlling axonal outgrowth; this switch is regulated by cytosolic glutaredoxin 2c (Grx2c).","method":"Non-reducing SDS-PAGE, site-directed mutagenesis (Cys-504), neuronal axon outgrowth assay, Grx2c interaction studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical characterization of disulfide switch with mutagenesis, single lab","pmids":["24133216"],"is_preprint":false},{"year":2008,"finding":"Neurofibromin co-immunoprecipitates with CRMP-2 and CRMP-4 (but not CRMP-1) from rat brain; CDK5 activity is required for the neurofibromin–CRMP-2 interaction.","method":"Immunoprecipitation from rat brain lysates, CDK5 inhibition (roscovitine), mass spectrometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP from brain lysate with kinase inhibitor dependency, single lab but replicated in later studies","pmids":["18313395"],"is_preprint":false},{"year":2020,"finding":"CRMP2 mediates Sema3F signaling; crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, consistent with impaired Sema3F (not only Sema3A) signaling; crmp2-/- mice show ASD-related social behavior changes.","method":"crmp2-/- knockout mice, axon pruning quantification in hippocampus/visual cortex, Sema3F stimulation in primary neurons, behavioral assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete knockout mouse with multiple defined circuit and behavioral phenotypes, in vitro signaling confirmation","pmids":["31919978"],"is_preprint":false},{"year":2020,"finding":"CRMP2 K374A knock-in (CRMP2-SUMOylation-null) mice show reduced NaV1.7 membrane localization and currents specifically in female sensory neurons; these mice fail to develop persistent mechanical allodynia in a neuropathic pain model, demonstrating sex-specific SUMOylation-dependent control of peripheral NaV1.7.","method":"CRMP2-K374A knock-in mice, surface biotinylation, electrophysiology, behavioral pain assays, sex-stratified analysis","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse with electrophysiology and in vivo pain phenotype, sex-specific analysis","pmids":["32569093"],"is_preprint":false},{"year":2021,"finding":"Non-SUMOylated CRMP2 forms a complex with Numb, Nedd4-2, and Eps15 to drive clathrin-mediated endocytosis of NaV1.7; silencing Numb, Nedd4-2, or Eps15 in DRG neurons from CRMP2-K374A female mice restores sodium currents; clathrin inhibition in nerve-injured male CRMP2-K374A mice precipitates allodynia.","method":"siRNA knockdown of endocytic proteins, clathrin assembly inhibitor, electrophysiology, CRMP2-K374A knock-in mice","journal":"Molecular brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KD of three endocytic proteins with electrophysiological rescue, in vivo pharmacological intervention","pmids":["33478555"],"is_preprint":false},{"year":2018,"finding":"TGF-β/Smad canonical signaling suppresses CRMP2 expression through a Smad–TGIF transcriptional repressor complex; this inhibits neurite elongation in mouse and human iPSC-derived neurons; TGF-β pathway mutations found in neurodevelopmental disorder patients disrupt neuronal morphogenesis via this Smad/TGIF/CRMP2 axis.","method":"ChIP, co-immunoprecipitation (Smad-TGIF complex), in utero electroporation, human iPSC-derived neuron assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus Co-IP establishing transcriptional complex, validated in mouse and human iPSC neurons","pmids":["29695415"],"is_preprint":false},{"year":2023,"finding":"CRMP2 (DPYSL2) acts as a synaptic m6A reader: it binds m6A-modified Malat1 lncRNA at synapses in the mPFC; disruption of m6A on Malat1 reduces CRMP2 interaction and decreases dendritic spine formation, impairing fear-extinction memory consolidation.","method":"m6A RNA-sequencing, RNA immunoprecipitation/mass spectrometry, dendritic spine quantification, fear-extinction behavioral assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-MS identification with functional spine and memory readout, novel role with limited mechanistic follow-up on CRMP2 side","pmids":["37669863"],"is_preprint":false},{"year":2019,"finding":"PTP4A3 (PRL-3) phosphatase dephosphorylates CRMP2 at T514 in uveal melanoma cells; loss of CRMP2 expression in PTP4A3-expressing cells increases cell migration and invasiveness in vitro/in vivo, accompanied by actin cytoskeleton reorganization and increased cell stiffness; catalytically inactive PTP4A3 does not produce these effects.","method":"Phospho-specific immunoblot, PTP4A3 active-site mutant, CRMP2 knockdown, invasion/migration assays, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant control establishes phosphatase-substrate relationship, functional cell migration phenotype, single lab","pmids":["30816227"],"is_preprint":false}],"current_model":"CRMP2 (DPYSL2) is a multifunctional cytosolic phosphoprotein that promotes axon specification and growth by binding tubulin heterodimers via its C-terminal helix H19 to drive microtubule assembly, links soluble tubulin to anterograde Kinesin-1 transport via KLC1, regulates Numb-mediated endocytosis of L1, and is inactivated by sequential Cdk5 (Ser522) and GSK-3β (Thr514/Thr509) phosphorylation or Rho kinase phosphorylation (Thr555), which collectively disrupt its tubulin-binding and endocytic activities; at presynaptic terminals CRMP2 enhances CaV2.2 surface trafficking and neurotransmitter release in a Cdk5 phosphorylation-dependent manner, and controls NaV1.7 membrane localization through a hierarchical post-translational modification program in which Cdk5-primed SUMOylation at Lys374 by Ubc9 promotes NaV1.7 surface expression while loss of SUMOylation recruits a Numb/Nedd4-2/Eps15 endocytic complex to internalize NaV1.7 via clathrin, with this axis being the dominant mechanism of chronic neuropathic pain; additional regulatory inputs include oxidation-mediated Cys504 disulfide dimerization (amplified by thioredoxin to activate GSK-3 phosphorylation), FER-mediated tyrosine phosphorylation at Y479/Y499 that prevents tetramerization and microtubule bundling, and transcriptional suppression by BMP-SMAD and TGF-β-SMAD/TGIF signaling pathways."},"narrative":{"mechanistic_narrative":"DPYSL2 (CRMP2) is a multifunctional cytosolic phosphoprotein that governs neuronal polarity, axon and dendrite growth, and ion channel surface trafficking [PMID:11477421, PMID:22279220]. It promotes axon specification by binding tubulin heterodimers with higher affinity than assembled microtubules and driving microtubule assembly through its C-terminal helix H19, an activity required for axon induction, elongation and branching [PMID:12134159, PMID:28878401]. CRMP2 couples this cytoskeletal function to transport by linking soluble tubulin to anterograde Kinesin-1 via direct binding to KLC1, and by regulating Numb-mediated endocytosis of the adhesion molecule L1 at growth cones [PMID:15935053, PMID:12942088]. Its activity is gated by a layered post-translational program: Cdk5 phosphorylation at Ser522 primes sequential GSK-3β phosphorylation at Thr514/Thr509, and Rho-kinase phosphorylation at Thr555, each reducing tubulin/Numb binding and inactivating CRMP2 downstream of guidance cues such as Sema3A and ephrin-A5 [PMID:15676027, PMID:15652488, PMID:16260611]; oxidation-driven Cys504 disulfide dimerization amplified by thioredoxin further licenses GSK-3 phosphorylation, while FER-mediated tyrosine phosphorylation at Y479/Y499 blocks tetramerization and microtubule bundling [PMID:21521879, PMID:29396402]. At presynaptic and sensory terminals CRMP2 binds CaV2.2 to enhance its surface expression and neurotransmitter/neuropeptide release in a Cdk5-Ser522-dependent manner, and a hierarchical modification cascade in which Cdk5-primed SUMOylation at Lys374 by Ubc9 maintains NaV1.7 at the membrane, whereas loss of SUMOylation recruits a Numb/Nedd4-2/Eps15 complex to drive clathrin-mediated NaV1.7 internalization — an axis that is a dominant, sex-influenced determinant of chronic neuropathic pain [PMID:19755421, PMID:27940916, PMID:33478555, PMID:32569093]. CRMP2 is required in vivo for dendritic patterning, synaptic plasticity and stereotyped axon pruning, and its expression is transcriptionally repressed by BMP-SMAD and TGF-β-SMAD/TGIF signaling during cortical neuronal migration and morphogenesis [PMID:22279220, PMID:27249678, PMID:31919978, PMID:20926379, PMID:29695415].","teleology":[{"year":2001,"claim":"Established CRMP2 as a determinant of neuronal polarity, answering whether a single cytosolic factor could specify axon identity.","evidence":"Overexpression and dominant-negative truncation in cultured hippocampal neurons with morphological readout","pmids":["11477421"],"confidence":"High","gaps":["Did not define the molecular activity driving axon formation","No endogenous loss-of-function in vivo"]},{"year":2002,"claim":"Identified tubulin-heterodimer binding and microtubule assembly promotion as the molecular basis of CRMP2's growth-promoting activity.","evidence":"In vitro tubulin-binding and polymerization assays plus dominant-negative mutant expression in neurons","pmids":["12134159"],"confidence":"High","gaps":["Structural interface with tubulin not yet resolved","Did not address how transport is coordinated with assembly"]},{"year":2003,"claim":"Connected CRMP2 to membrane traffic by showing it regulates Numb-mediated endocytosis of L1 at growth cones.","evidence":"Co-IP, siRNA knockdown, dominant-negative expression and L1 endocytosis assays in hippocampal neurons","pmids":["12942088"],"confidence":"High","gaps":["Mechanism linking endocytosis to axon growth not fully defined","Generality beyond L1 cargo unknown at the time"]},{"year":2000,"claim":"Mapped a multi-site phosphorylation signature (Thr509/Ser518/Ser522) on CRMP2 in Alzheimer neurofibrillary tangles, raising the question of which kinases impose it and its functional consequence.","evidence":"Immunoaffinity purification, site-directed mutagenesis and in vitro kinase assay on AD brain","pmids":["10757975"],"confidence":"High","gaps":["Did not identify the responsible kinases","Causal role in disease not established"]},{"year":2005,"claim":"Defined the kinase logic inactivating CRMP2: Cdk5 priming at Ser522 enables sequential GSK-3β phosphorylation (Thr509/Thr514) and Rho-kinase phosphorylation (Thr555), each disrupting tubulin/Numb binding downstream of Sema3A and ephrin-A5.","evidence":"In vitro kinase assays, phospho-specific antibodies, phospho-mutants, cdk5-/- lysates and growth cone collapse assays","pmids":["15652488","15676027","16260611"],"confidence":"High","gaps":["Phosphatases reversing these marks not yet defined","How distinct guidance cues select specific sites unclear"]},{"year":2005,"claim":"Showed CRMP2 bridges soluble tubulin to anterograde Kinesin-1 via direct KLC1 binding, mechanistically coupling cargo binding to axonal transport.","evidence":"Direct binding/pulldown assays, Co-IP, FRAP of GFP-tubulin and siRNA knockdown","pmids":["15935053"],"confidence":"High","gaps":["Regulation of complex assembly by phosphorylation not tested here","Relationship to retrograde transport unresolved"]},{"year":2008,"claim":"Identified PP1-family phosphatase as the eraser of GSK3-targeted CRMP2 sites and explained why the Cdk5 site resists dephosphorylation, rationalizing AD-associated hyperphosphorylation.","evidence":"In vitro phosphatase assays, pharmacological inhibitors and Pin1 transgenic mice","pmids":["18460467"],"confidence":"High","gaps":["Precise phosphatase isoform not pinned down","In vivo disease causality not addressed"]},{"year":2008,"claim":"Placed CRMP2 in a neurofibromin complex in a CDK5-dependent manner, hinting at a tumor-suppressor link to CRMP2 regulation.","evidence":"Co-IP from rat brain lysate with roscovitine inhibition and mass spectrometry","pmids":["18313395"],"confidence":"Medium","gaps":["Functional consequence of the interaction not defined in this study","Single lab Co-IP"]},{"year":2009,"claim":"Established CRMP2 as a direct regulator of CaV2.2 N-type calcium channel surface expression and neurotransmitter/neuropeptide release in central and sensory neurons.","evidence":"Co-IP, domain mapping, surface biotinylation, patch-clamp and glutamate/CGRP release with knockdown","pmids":["19755421","19903690"],"confidence":"High","gaps":["Phospho-dependence of CaV2.2 binding not yet defined","In vivo physiological/pathological role untested at this point"]},{"year":2009,"claim":"Showed local mTOR-p70S6K signaling selectively upregulates CRMP2 translation to drive axon specification, adding a translational control layer.","evidence":"Rapamycin treatment, p70S6K expression, 5'UTR reporter assays and rescue in axons","pmids":["19648118"],"confidence":"Medium","gaps":["Direct demonstration of localized CRMP2 protein synthesis limited","Single lab"]},{"year":2009,"claim":"Proposed CRMP2 antagonizes retrograde transport through direct dynein heavy-chain binding, distinguishing kinesin and dynein interaction regions.","evidence":"Co-IP, domain mapping and dynein-driven microtubule transport assay in COS-7 cells","pmids":["19659462"],"confidence":"Medium","gaps":["Effect shown in non-neuronal cells only","Single lab, no in vivo validation"]},{"year":2010,"claim":"Extended CRMP2's trafficking role to non-neuronal endosomal transport, linking MICAL-L1/EHD1 recycling vesicles to dynein motors.","evidence":"Co-IP, siRNA knockdown, transferrin recycling assay and dynamitin overexpression","pmids":["20801876"],"confidence":"Medium","gaps":["Neuronal relevance not directly tested","Single lab"]},{"year":2010,"claim":"Identified BMP-SMAD1/4 transcriptional repression of CRMP2 as a control point for multipolar-to-bipolar transition during cortical radial migration.","evidence":"ChIP and in utero electroporation with RNAi/dominant-negative constructs in cortical slices","pmids":["20926379"],"confidence":"High","gaps":["Upstream signals tuning BMP-CRMP2 axis in vivo incompletely mapped"]},{"year":2011,"claim":"Reconstituted an oxidation-phosphorylation cascade: Sema3A/MICAL-derived H2O2 forms a Cys504 disulfide dimer that engages thioredoxin to stimulate GSK-3 phosphorylation and growth cone collapse.","evidence":"In vitro reconstitution with purified proteins, mass spectrometry, non-reducing SDS-PAGE, Cys504 mutagenesis and collapse assay","pmids":["21521879"],"confidence":"High","gaps":["In vivo contribution of the redox switch to guidance not quantified","Sources of physiological oxidant beyond Sema3A unclear"]},{"year":2011,"claim":"Translated CRMP2-CaV2.2 biology into therapeutics, showing peptide disruption (TAT-CBD3) reduces transmitter release and reverses neuropathic pain in vivo.","evidence":"TAT-CBD3 peptide, in vivo pain behavior and dorsal horn electrophysiology","pmids":["21642979"],"confidence":"High","gaps":["Peptide selectivity across CRMP2 interactions not fully delineated"]},{"year":2011,"claim":"Implicated CRMP2 in NMDAR (GluN2B) surface trafficking and excitotoxic neuroprotection, broadening its receptor-trafficking role.","evidence":"Lentiviral knockdown, TAT-CBD3 peptide, Ca2+ imaging, electrophysiology and a TBI model","pmids":["21832084"],"confidence":"High","gaps":["Direct CRMP2-NMDAR interface not structurally defined here"]},{"year":2012,"claim":"Demonstrated in vivo that Cdk5-Ser522 phosphorylation organizes dendritic fields, with CRMP1/CRMP2 acting synergistically.","evidence":"CRMP2-S522A knock-in combined with CRMP1 knockout and cortical neuron morphology analysis","pmids":["22279220"],"confidence":"High","gaps":["Molecular effectors downstream of Ser522 in dendrites not isolated"]},{"year":2012,"claim":"Linked NgR1/Rho-kinase-driven Thr555 phosphorylation of CRMP2 to axonal degeneration in demyelinating disease, with phospho-resistant T555A protecting axons.","evidence":"NgR1 knockout mice, AAV-T555A rescue and phospho-immunostaining in EAE/optic nerve","pmids":["22544872"],"confidence":"High","gaps":["Downstream degenerative effectors of phospho-CRMP2 unresolved"]},{"year":2012,"claim":"Showed Cdk5-Ser522 phosphorylation specifically enhances the CRMP2-CaV2.2 interaction, tying the kinase code to calcium channel regulation.","evidence":"Phospho-null/inactive Cdk5 expression, Ca2+ current measurement and Co-IP","pmids":["23022559"],"confidence":"Medium","gaps":["Single lab","Structural basis of phospho-enhanced binding not defined"]},{"year":2013,"claim":"Discovered Ubc9-mediated CRMP2 SUMOylation at Lys374 as a positive regulator of NaV1.7 surface expression, opening the sodium-channel trafficking axis.","evidence":"In vivo SUMOylation assays, SUMO protease overexpression, surface biotinylation and electrophysiology of NaV1.7/CaV2.2","pmids":["23836888","23510938"],"confidence":"High","gaps":["Hierarchical control of SUMOylation by other PTMs not yet established here"]},{"year":2013,"claim":"Characterized a reversible Cys504-Cys504 dithiol-disulfide quaternary switch, regulated by glutaredoxin 2c, that toggles axon outgrowth.","evidence":"Non-reducing SDS-PAGE, Cys504 mutagenesis, axon outgrowth assay and Grx2c interaction studies","pmids":["24133216"],"confidence":"Medium","gaps":["Single lab biochemistry","In vivo relevance of the conformational switch untested"]},{"year":2013,"claim":"Expanded CRMP2's channel/receptor partners to GluK5 kainate receptors, NMDAR, and NCX3, with phospho-state-specific consequences for CaV2.2 and exchanger trafficking.","evidence":"Co-IP, phospho-specific antibodies, surface expression and Ca2+ dysregulation assays","pmids":["24227739","24474686"],"confidence":"Medium","gaps":["Single-lab Co-IPs","Direct versus indirect interactions not all distinguished"]},{"year":2015,"claim":"Optimized CRMP2-CaV2.2 disruption with a membrane-tethered peptide (myr-tat-CBD3), improving potency for analgesia and confirming the trafficking mechanism.","evidence":"Pulldown, colocalization, voltage/current-clamp and inflammatory/postoperative pain models","pmids":["25782368"],"confidence":"High","gaps":["Long-term in vivo specificity and off-target trafficking effects not fully addressed"]},{"year":2016,"claim":"Resolved the hierarchical PTM code controlling NaV1.7: Cdk5 phosphorylation promotes Lys374 SUMOylation (antagonized by Fyn), and loss of SUMOylation recruits Nedd4-2/Numb/Eps15 for clathrin-mediated channel internalization.","evidence":"SUMOylation assays, phospho-mutants, surface biotinylation, clathrin inhibition and Co-IP","pmids":["27940916"],"confidence":"High","gaps":["Stoichiometry and dynamics of competing PTMs in vivo not quantified"]},{"year":2016,"claim":"Established an in vivo requirement for CRMP2 in synaptic plasticity, NMDAR composition, dendrite development and synapse formation.","evidence":"Brain-specific conditional knockout with LTP electrophysiology, immunostaining and adult neurogenesis knockdown","pmids":["27249678"],"confidence":"High","gaps":["Molecular link between CRMP2 loss and altered NMDAR subunit composition unresolved"]},{"year":2017,"claim":"Provided structural rationale for PTM-gated SUMOylation: crystallography shows Lys374 is buried in the tetramer interface but exposed in the monomer, so phospho-induced monomerization licenses SUMOylation.","evidence":"1.78 Å X-ray structure of mouse CRMP2 with structure-guided mutagenesis","pmids":["28277940"],"confidence":"High","gaps":["Direct structural capture of the SUMOylated/phosphorylated state lacking"]},{"year":2017,"claim":"Defined the C-terminal helix H19 as the soluble-tubulin interface distinct from the microtubule-binding tail, mechanistically separating dimer binding from lattice binding.","evidence":"X-ray crystallography, in vitro polymerization, H19 mutagenesis and chick/C. elegans axon assays","pmids":["28878401"],"confidence":"High","gaps":["How phosphorylation reshapes H19-tubulin contacts not structurally shown"]},{"year":2017,"claim":"Connected neurofibromin to the CaV2.2 pain axis, showing its loss frees CRMP2 to engage syntaxin 1A and CaV2.2 and increase CGRP release, druggable with t-CNRP1.","evidence":"Co-IP, peptide mapping, CGRP release, surface biotinylation and NF1 pain models","pmids":["28767512"],"confidence":"High","gaps":["Structural interface of the CRMP2-neurofibromin complex undefined"]},{"year":2018,"claim":"Identified FER tyrosine phosphorylation at Y479/Y499 as a switch that blocks CRMP2 tetramerization and microtubule bundling, with consequences for taxane sensitivity in cancer.","evidence":"Crystal structure of Y479E phospho-mimetic, in vitro bundling assay, FER inhibition and ovarian cancer xenografts","pmids":["29396402"],"confidence":"High","gaps":["Neuronal relevance of FER-CRMP2 axis not addressed","Endogenous FER-CRMP2 dynamics in tumors limited"]},{"year":2018,"claim":"Demonstrated Cdk5-CRMP2 phosphorylation at Ser522 is both necessary and sufficient for neuropathic pain, providing bidirectional in vivo causality.","evidence":"siRNA knockdown, intrathecal phospho-null/mimetic mutants and spared nerve injury model","pmids":["31080913"],"confidence":"High","gaps":["Relative contribution of CaV2.2 versus NaV1.7 to the Ser522 pain phenotype not dissected"]},{"year":2018,"claim":"Quantified the Ubc9-CRMP2 binding affinity and validated SUMOylation-motif peptide disruption (t-CSM) as an analgesic strategy targeting NaV1.7 trafficking.","evidence":"Microscale thermophoresis, AlphaLISA, cell-penetrating peptide, biotinylation, electrophysiology and SNI model","pmids":["29847471"],"confidence":"High","gaps":["Selectivity of t-CSM for CRMP2 among Ubc9 substrates not fully established"]},{"year":2018,"claim":"Identified TGF-β/Smad-TGIF transcriptional repression of CRMP2 as a neurodevelopmental morphogenesis axis disrupted by patient pathway mutations.","evidence":"ChIP, Smad-TGIF Co-IP, in utero electroporation and human iPSC-derived neuron assays","pmids":["29695415"],"confidence":"High","gaps":["Direct CRMP2 mutation causality in patients not established here"]},{"year":2019,"claim":"Placed GSK3/CRMP2 as a required, mTOR-independent effector branch for PTEN-knockout-mediated optic nerve regeneration.","evidence":"PTEN conditional KO, GSK3 knock-in mice and AAV-CRMP2-T/A rescue in optic nerve regeneration","pmids":["31453382"],"confidence":"High","gaps":["Downstream cytoskeletal events enabling regeneration not fully mapped"]},{"year":2019,"claim":"Defined a NgR1/PlexinA2/CRMP2 ternary complex induced by Nogo-A that restricts corticospinal sprouting and functional recovery after injury.","evidence":"IP-proteomics, cell contraction assay, double-heterozygous mouse genetics and pyramidotomy","pmids":["30804090"],"confidence":"High","gaps":["Direct CRMP2 contact within the ternary complex not structurally resolved"]},{"year":2019,"claim":"Identified PTP4A3 (PRL-3) as a CRMP2 Thr514 phosphatase in uveal melanoma, linking CRMP2 dephosphorylation/loss to cytoskeletal remodeling and invasion.","evidence":"Phospho-immunoblot, catalytically inactive PTP4A3, CRMP2 knockdown and invasion/xenograft assays","pmids":["30816227"],"confidence":"Medium","gaps":["Single lab","Mechanism connecting CRMP2 loss to stiffness/invasion incompletely defined"]},{"year":2020,"claim":"Showed CRMP2 mediates Sema3F as well as Sema3A signaling, controlling stereotyped axon pruning, spine remodeling and ASD-related behavior in vivo.","evidence":"crmp2-/- mice, axon pruning quantification, Sema3F stimulation and behavioral assays","pmids":["31919978"],"confidence":"High","gaps":["Signaling components linking CRMP2 to Sema3F-specific pruning not isolated"]},{"year":2020,"claim":"Provided definitive in vivo genetic proof that Lys374 SUMOylation controls peripheral NaV1.7 and neuropathic pain in a sex-specific manner.","evidence":"CRMP2-K374A knock-in mice, surface biotinylation, electrophysiology and sex-stratified pain behavior","pmids":["32569093"],"confidence":"High","gaps":["Molecular basis of the female-specific dependence not resolved"]},{"year":2021,"claim":"Defined the endocytic effector complex (Numb/Nedd4-2/Eps15) that internalizes NaV1.7 when CRMP2 is not SUMOylated, completing the bidirectional trafficking switch.","evidence":"siRNA knockdown of endocytic proteins, clathrin inhibition and electrophysiology in CRMP2-K374A knock-in DRG neurons","pmids":["33478555"],"confidence":"High","gaps":["Sequence of recruitment among Numb/Nedd4-2/Eps15 not ordered","Sex-difference mechanism still open"]},{"year":2023,"claim":"Revealed an unexpected RNA-binding function: CRMP2 acts as a synaptic m6A reader of Malat1 lncRNA to support spine formation and fear-extinction memory.","evidence":"m6A RNA-seq, RIP-mass spectrometry, dendritic spine quantification and fear-extinction behavior","pmids":["37669863"],"confidence":"Medium","gaps":["Structural basis of CRMP2 m6A recognition undefined","Limited mechanistic follow-up on the CRMP2 side"]},{"year":null,"claim":"How CRMP2's distinct activities — tubulin assembly, motor coupling, ion-channel trafficking, and RNA reading — are spatially and temporally partitioned within a single neuron by its integrated PTM code remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model integrating phosphorylation, SUMOylation, oxidation and tyrosine modification states","Quantitative partitioning of CRMP2 pools among partners in vivo unknown","Whether m6A-reading and cytoskeletal roles share the same protein pool untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,28,29]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,2,9,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10,25,39]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[41]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,5,28]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,25,39]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,23,37]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[9,13,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,11,25]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,6,39]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,25,29]}],"complexes":["CRMP2/KLC1/tubulin transport complex","Numb/Nedd4-2/Eps15 endocytic complex","NgR1/PlexinA2/CRMP2 ternary complex"],"partners":["TUBB","KLC1","NUMB","CACNA1B","SCN9A","UBE2I","NF1","FER"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16555","full_name":"Dihydropyrimidinase-related protein 2","aliases":["Collapsin response mediator protein 2","CRMP-2","N2A3","Unc-33-like phosphoprotein 2","ULIP-2"],"length_aa":572,"mass_kda":62.3,"function":"Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. May play a role in endocytosis","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton; Membrane","url":"https://www.uniprot.org/uniprotkb/Q16555/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DPYSL2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BLVRB","stoichiometry":0.2},{"gene":"CDC23","stoichiometry":0.2},{"gene":"STT3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DPYSL2","total_profiled":1310},"omim":[{"mim_id":"619435","title":"RITSCHER-SCHINZEL SYNDROME 4; RTSC4","url":"https://www.omim.org/entry/619435"},{"mim_id":"613326","title":"DIHYDROPYRIMIDINASE; DPYS","url":"https://www.omim.org/entry/613326"},{"mim_id":"610005","title":"TRAF2- AND NCK-INTERACTING KINASE; TNIK","url":"https://www.omim.org/entry/610005"},{"mim_id":"608383","title":"DIHYDROPYRIMIDINASE-LIKE 5; DPYSL5","url":"https://www.omim.org/entry/608383"},{"mim_id":"602463","title":"DIHYDROPYRIMIDINASE-LIKE 2; DPYSL2","url":"https://www.omim.org/entry/602463"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Microtubules","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":231.1}],"url":"https://www.proteinatlas.org/search/DPYSL2"},"hgnc":{"alias_symbol":["DRP-2","DHPRP2","CRMP2","DRP2"],"prev_symbol":[]},"alphafold":{"accession":"Q16555","domains":[{"cath_id":"3.20.20.140","chopping":"64-486","consensus_level":"high","plddt":97.3604,"start":64,"end":486}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16555","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16555-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16555-F1-predicted_aligned_error_v6.png","plddt_mean":90.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DPYSL2","jax_strain_url":"https://www.jax.org/strain/search?query=DPYSL2"},"sequence":{"accession":"Q16555","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16555.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16555/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16555"}},"corpus_meta":[{"pmid":"15652488","id":"PMC_15652488","title":"GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15652488","citation_count":777,"is_preprint":false},{"pmid":"12134159","id":"PMC_12134159","title":"CRMP-2 binds to tubulin heterodimers to promote microtubule assembly.","date":"2002","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12134159","citation_count":637,"is_preprint":false},{"pmid":"11477421","id":"PMC_11477421","title":"CRMP-2 induces axons in cultured hippocampal neurons.","date":"2001","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11477421","citation_count":470,"is_preprint":false},{"pmid":"15676027","id":"PMC_15676027","title":"Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease.","date":"2005","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/15676027","citation_count":369,"is_preprint":false},{"pmid":"16260611","id":"PMC_16260611","title":"Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16260611","citation_count":232,"is_preprint":false},{"pmid":"12942088","id":"PMC_12942088","title":"CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth.","date":"2003","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12942088","citation_count":218,"is_preprint":false},{"pmid":"21642979","id":"PMC_21642979","title":"Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca²⁺ channel complex.","date":"2011","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21642979","citation_count":194,"is_preprint":false},{"pmid":"15935053","id":"PMC_15935053","title":"Tubulin and CRMP-2 complex is transported via Kinesin-1.","date":"2005","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15935053","citation_count":180,"is_preprint":false},{"pmid":"19755421","id":"PMC_19755421","title":"An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19755421","citation_count":175,"is_preprint":false},{"pmid":"10757975","id":"PMC_10757975","title":"Neurofibrillary tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518, and Ser-522.","date":"2000","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10757975","citation_count":167,"is_preprint":false},{"pmid":"14598368","id":"PMC_14598368","title":"Role of CRMP-2 in neuronal polarity.","date":"2004","source":"Journal of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/14598368","citation_count":150,"is_preprint":false},{"pmid":"16230462","id":"PMC_16230462","title":"Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16230462","citation_count":150,"is_preprint":false},{"pmid":"19903690","id":"PMC_19903690","title":"Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19903690","citation_count":126,"is_preprint":false},{"pmid":"27940916","id":"PMC_27940916","title":"Hierarchical CRMP2 posttranslational modifications control NaV1.7 function.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27940916","citation_count":113,"is_preprint":false},{"pmid":"27249678","id":"PMC_27249678","title":"Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27249678","citation_count":109,"is_preprint":false},{"pmid":"19648118","id":"PMC_19648118","title":"Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19648118","citation_count":108,"is_preprint":false},{"pmid":"11549731","id":"PMC_11549731","title":"Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3a- sensitive oligodendrocytes.","date":"2001","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11549731","citation_count":107,"is_preprint":false},{"pmid":"10666674","id":"PMC_10666674","title":"Expression of the dihydropyrimidinase related protein 2 (DRP-2) in Down syndrome and Alzheimer's disease brain is downregulated at the mRNA and dysregulated at the protein level.","date":"1999","source":"Journal of neural transmission. Supplementum","url":"https://pubmed.ncbi.nlm.nih.gov/10666674","citation_count":106,"is_preprint":false},{"pmid":"22544872","id":"PMC_22544872","title":"Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation.","date":"2012","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22544872","citation_count":99,"is_preprint":false},{"pmid":"21521879","id":"PMC_21521879","title":"Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth cone collapse.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21521879","citation_count":93,"is_preprint":false},{"pmid":"23836888","id":"PMC_23836888","title":"CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23836888","citation_count":88,"is_preprint":false},{"pmid":"22279220","id":"PMC_22279220","title":"Phosphorylation of CRMP2 (collapsin response mediator protein 2) is involved in proper dendritic field organization.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22279220","citation_count":88,"is_preprint":false},{"pmid":"21832084","id":"PMC_21832084","title":"Neuroprotection against traumatic brain injury by a peptide derived from the collapsin response mediator protein 2 (CRMP2).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832084","citation_count":83,"is_preprint":false},{"pmid":"17873297","id":"PMC_17873297","title":"Proteomic investigation of the ventral rat hippocampus links DRP-2 to escitalopram treatment resistance and SNAP to stress resilience in the chronic mild stress model of depression.","date":"2007","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/17873297","citation_count":81,"is_preprint":false},{"pmid":"24923837","id":"PMC_24923837","title":"Neuronal deletion of GSK3β increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2.","date":"2014","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/24923837","citation_count":73,"is_preprint":false},{"pmid":"25782368","id":"PMC_25782368","title":"A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors.","date":"2015","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/25782368","citation_count":71,"is_preprint":false},{"pmid":"23022559","id":"PMC_23022559","title":"Cdk5-mediated phosphorylation of CRMP-2 enhances its interaction with CaV2.2.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23022559","citation_count":70,"is_preprint":false},{"pmid":"24474686","id":"PMC_24474686","title":"Collapsin response mediator protein 2 (CRMP2) interacts with N-methyl-D-aspartate (NMDA) receptor and Na+/Ca2+ exchanger and regulates their functional activity.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24474686","citation_count":69,"is_preprint":false},{"pmid":"24402611","id":"PMC_24402611","title":"CRMP2: functional roles in neural development and therapeutic potential in neurological diseases.","date":"2014","source":"The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24402611","citation_count":67,"is_preprint":false},{"pmid":"27079722","id":"PMC_27079722","title":"Collapsin Response Mediator Protein-2 (CRMP2) is a Plausible Etiological Factor and Potential Therapeutic Target in Alzheimer's Disease: Comparison and Contrast with Microtubule-Associated Protein Tau.","date":"2016","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/27079722","citation_count":62,"is_preprint":false},{"pmid":"24944082","id":"PMC_24944082","title":"Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/24944082","citation_count":58,"is_preprint":false},{"pmid":"22297164","id":"PMC_22297164","title":"Preconditioning with Ginkgo biloba (EGb 761®) provides neuroprotection through HO1 and CRMP2.","date":"2012","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/22297164","citation_count":57,"is_preprint":false},{"pmid":"26967696","id":"PMC_26967696","title":"(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.","date":"2016","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/26967696","citation_count":55,"is_preprint":false},{"pmid":"29847471","id":"PMC_29847471","title":"Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain.","date":"2018","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/29847471","citation_count":52,"is_preprint":false},{"pmid":"9555025","id":"PMC_9555025","title":"Isolation and characterization of a bovine neural specific protein (CRMP-2) cDNA homologous to unc-33, a C. elegans gene implicated in axonal outgrowth and guidance.","date":"1998","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9555025","citation_count":52,"is_preprint":false},{"pmid":"27480924","id":"PMC_27480924","title":"CRMP1 and CRMP2 have synergistic but distinct roles in dendritic development.","date":"2016","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/27480924","citation_count":51,"is_preprint":false},{"pmid":"20801876","id":"PMC_20801876","title":"Collapsin response mediator protein-2 (Crmp2) regulates trafficking by linking endocytic regulatory proteins to dynein motors.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20801876","citation_count":51,"is_preprint":false},{"pmid":"19659462","id":"PMC_19659462","title":"CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity.","date":"2009","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19659462","citation_count":51,"is_preprint":false},{"pmid":"25846820","id":"PMC_25846820","title":"(S)-Lacosamide Binding to Collapsin Response Mediator Protein 2 (CRMP2) Regulates CaV2.2 Activity by Subverting Its Phosphorylation by Cdk5.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25846820","citation_count":51,"is_preprint":false},{"pmid":"28767512","id":"PMC_28767512","title":"Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors.","date":"2017","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/28767512","citation_count":48,"is_preprint":false},{"pmid":"30364788","id":"PMC_30364788","title":"CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain.","date":"2018","source":"Neuronal signaling","url":"https://pubmed.ncbi.nlm.nih.gov/30364788","citation_count":47,"is_preprint":false},{"pmid":"26795088","id":"PMC_26795088","title":"Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses.","date":"2016","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26795088","citation_count":45,"is_preprint":false},{"pmid":"20926379","id":"PMC_20926379","title":"The suppression of CRMP2 expression by bone morphogenetic protein (BMP)-SMAD gradient signaling controls multiple stages of neuronal development.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20926379","citation_count":45,"is_preprint":false},{"pmid":"19519308","id":"PMC_19519308","title":"Increased CRMP2 phosphorylation is observed in Alzheimer's disease; does this tell us anything about disease development?","date":"2009","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/19519308","citation_count":44,"is_preprint":false},{"pmid":"24227739","id":"PMC_24227739","title":"CRMP2 tethers kainate receptor activity to cytoskeleton dynamics during neuronal maturation.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24227739","citation_count":43,"is_preprint":false},{"pmid":"31080913","id":"PMC_31080913","title":"Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain.","date":"2018","source":"Neurobiology of pain (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/31080913","citation_count":43,"is_preprint":false},{"pmid":"29695415","id":"PMC_29695415","title":"Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.","date":"2018","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29695415","citation_count":43,"is_preprint":false},{"pmid":"25674050","id":"PMC_25674050","title":"Differential neuroprotective potential of CRMP2 peptide aptamers conjugated to cationic, hydrophobic, and amphipathic cell penetrating peptides.","date":"2015","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25674050","citation_count":43,"is_preprint":false},{"pmid":"28878401","id":"PMC_28878401","title":"Structural basis for CRMP2-induced axonal microtubule formation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28878401","citation_count":42,"is_preprint":false},{"pmid":"29396402","id":"PMC_29396402","title":"Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29396402","citation_count":42,"is_preprint":false},{"pmid":"31919978","id":"PMC_31919978","title":"CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/31919978","citation_count":41,"is_preprint":false},{"pmid":"22378692","id":"PMC_22378692","title":"Localized role of CRMP1 and CRMP2 in neurite outgrowth and growth cone steering.","date":"2012","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22378692","citation_count":41,"is_preprint":false},{"pmid":"18460467","id":"PMC_18460467","title":"Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18460467","citation_count":40,"is_preprint":false},{"pmid":"25416705","id":"PMC_25416705","title":"Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling.","date":"2014","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/25416705","citation_count":39,"is_preprint":false},{"pmid":"15858820","id":"PMC_15858820","title":"Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia.","date":"2005","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15858820","citation_count":39,"is_preprint":false},{"pmid":"28277940","id":"PMC_28277940","title":"A single structurally conserved SUMOylation site in CRMP2 controls NaV1.7 function.","date":"2017","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28277940","citation_count":39,"is_preprint":false},{"pmid":"23036362","id":"PMC_23036362","title":"A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.","date":"2012","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/23036362","citation_count":39,"is_preprint":false},{"pmid":"30565051","id":"PMC_30565051","title":"Phosphorylated CRMP2 Regulates Spinal Nociceptive Neurotransmission.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/30565051","citation_count":38,"is_preprint":false},{"pmid":"32426045","id":"PMC_32426045","title":"Anti-vimentin, anti-TUFM, anti-NAP1L1 and anti-DPYSL2 nanobodies display cytotoxic effect and reduce glioblastoma cell migration.","date":"2020","source":"Therapeutic advances in medical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32426045","citation_count":38,"is_preprint":false},{"pmid":"23470087","id":"PMC_23470087","title":"GSK-3α/β-mediated phosphorylation of CRMP-2 regulates activity-dependent dendritic growth.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23470087","citation_count":37,"is_preprint":false},{"pmid":"22898304","id":"PMC_22898304","title":"Dpysl2 (CRMP2) and Dpysl3 (CRMP4) phosphorylation by Cdk5 and DYRK2 is required for proper positioning of Rohon-Beard neurons and neural crest cells during neurulation in zebrafish.","date":"2012","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22898304","citation_count":36,"is_preprint":false},{"pmid":"23510938","id":"PMC_23510938","title":"SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons.","date":"2013","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23510938","citation_count":34,"is_preprint":false},{"pmid":"29066950","id":"PMC_29066950","title":"Sphingosine-1-Phosphate and the S1P3 Receptor Initiate Neuronal Retraction via RhoA/ROCK Associated with CRMP2 Phosphorylation.","date":"2017","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29066950","citation_count":32,"is_preprint":false},{"pmid":"22227566","id":"PMC_22227566","title":"Human T lymphotropic virus type 1 increases T lymphocyte migration by recruiting the cytoskeleton organizer CRMP2.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22227566","citation_count":32,"is_preprint":false},{"pmid":"32569093","id":"PMC_32569093","title":"Studies on CRMP2 SUMOylation-deficient transgenic mice identify sex-specific Nav1.7 regulation in the pathogenesis of chronic neuropathic pain.","date":"2020","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/32569093","citation_count":32,"is_preprint":false},{"pmid":"25847191","id":"PMC_25847191","title":"Changes in Dpysl2 expression are associated with prenatally stressed rat offspring and susceptibility to schizophrenia in humans.","date":"2015","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25847191","citation_count":31,"is_preprint":false},{"pmid":"31453382","id":"PMC_31453382","title":"GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout.","date":"2019","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/31453382","citation_count":31,"is_preprint":false},{"pmid":"30046097","id":"PMC_30046097","title":"Disruption of the psychiatric risk gene Ankyrin 3 enhances microtubule dynamics through GSK3/CRMP2 signaling.","date":"2018","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30046097","citation_count":31,"is_preprint":false},{"pmid":"29655575","id":"PMC_29655575","title":"CRMP2-Neurofibromin Interface Drives NF1-related Pain.","date":"2018","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29655575","citation_count":30,"is_preprint":false},{"pmid":"23831344","id":"PMC_23831344","title":"Challenging the catechism of therapeutics for chronic neuropathic pain: Targeting CaV2.2 interactions with CRMP2 peptides.","date":"2013","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/23831344","citation_count":30,"is_preprint":false},{"pmid":"27801893","id":"PMC_27801893","title":"The DPYSL2 gene connects mTOR and schizophrenia.","date":"2016","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27801893","citation_count":29,"is_preprint":false},{"pmid":"32265492","id":"PMC_32265492","title":"Downregulation of hippocampal SIRT6 activates AKT/CRMP2 signaling and ameliorates chronic stress-induced depression-like behavior in mice.","date":"2020","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/32265492","citation_count":29,"is_preprint":false},{"pmid":"24133216","id":"PMC_24133216","title":"Identification of a dithiol-disulfide switch in collapsin response mediator protein 2 (CRMP2) that is toggled in a model of neuronal differentiation.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24133216","citation_count":28,"is_preprint":false},{"pmid":"31904385","id":"PMC_31904385","title":"Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury.","date":"2020","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31904385","citation_count":28,"is_preprint":false},{"pmid":"23275173","id":"PMC_23275173","title":"CRMP-2 is involved in axon growth inhibition induced by RGMa in vitro and in vivo.","date":"2012","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23275173","citation_count":28,"is_preprint":false},{"pmid":"24904280","id":"PMC_24904280","title":"Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury.","date":"2014","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24904280","citation_count":28,"is_preprint":false},{"pmid":"28660485","id":"PMC_28660485","title":"CRMP2 Phosphorylation Drives Glioblastoma Cell Proliferation.","date":"2017","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/28660485","citation_count":27,"is_preprint":false},{"pmid":"27582038","id":"PMC_27582038","title":"Comprehensive behavioral study and proteomic analyses of CRMP2-deficient mice.","date":"2016","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/27582038","citation_count":27,"is_preprint":false},{"pmid":"35927239","id":"PMC_35927239","title":"CRMP2 derived from cancer associated fibroblasts facilitates progression of ovarian cancer via HIF-1α-glycolysis signaling pathway.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35927239","citation_count":27,"is_preprint":false},{"pmid":"37669863","id":"PMC_37669863","title":"Synapse-Enriched m6A-Modified Malat1 Interacts with the Novel m6A Reader, DPYSL2, and Is Required for Fear-Extinction Memory.","date":"2023","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37669863","citation_count":26,"is_preprint":false},{"pmid":"28837387","id":"PMC_28837387","title":"CRMP2 is necessary for Neurofibromatosis type 1 related pain.","date":"2018","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28837387","citation_count":26,"is_preprint":false},{"pmid":"18313395","id":"PMC_18313395","title":"Neurofibromin interacts with CRMP-2 and CRMP-4 in rat brain.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18313395","citation_count":25,"is_preprint":false},{"pmid":"29425794","id":"PMC_29425794","title":"Phosphorylation and SUMOylation of CRMP2 regulate the formation and maturation of dendritic spines.","date":"2018","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/29425794","citation_count":24,"is_preprint":false},{"pmid":"33478555","id":"PMC_33478555","title":"Non-SUMOylated CRMP2 decreases NaV1.7 currents via the endocytic proteins Numb, Nedd4-2 and Eps15.","date":"2021","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/33478555","citation_count":24,"is_preprint":false},{"pmid":"32693579","id":"PMC_32693579","title":"Druggability of CRMP2 for Neurodegenerative Diseases.","date":"2020","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32693579","citation_count":23,"is_preprint":false},{"pmid":"31187143","id":"PMC_31187143","title":"Both GSK-3β/CRMP2 and CDK5/CRMP2 Pathways Participate in the Protection of Dexmedetomidine Against Propofol-Induced Learning and Memory Impairment in Neonatal Rats.","date":"2019","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/31187143","citation_count":23,"is_preprint":false},{"pmid":"32437854","id":"PMC_32437854","title":"Coordinating Synaptic Signaling with CRMP2.","date":"2020","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32437854","citation_count":22,"is_preprint":false},{"pmid":"22954668","id":"PMC_22954668","title":"CNP and DPYSL2 mRNA expression and promoter methylation levels in brain of Alzheimer's disease patients.","date":"2013","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/22954668","citation_count":22,"is_preprint":false},{"pmid":"33548343","id":"PMC_33548343","title":"Regulation of CRMP2 by Cdk5 and GSK-3β participates in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats.","date":"2021","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33548343","citation_count":22,"is_preprint":false},{"pmid":"32256396","id":"PMC_32256396","title":"Differential Regulation of DNA Methylation at the CRMP2 Promoter Region Between the Hippocampus and Prefrontal Cortex in a CUMS Depression Model.","date":"2020","source":"Frontiers in psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32256396","citation_count":22,"is_preprint":false},{"pmid":"30315937","id":"PMC_30315937","title":"Peroxiredoxin interaction with the cytoskeletal-regulatory protein CRMP2: Investigation of a putative redox relay.","date":"2018","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30315937","citation_count":22,"is_preprint":false},{"pmid":"30804090","id":"PMC_30804090","title":"Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30804090","citation_count":22,"is_preprint":false},{"pmid":"16321170","id":"PMC_16321170","title":"An investigation of the dihydropyrimidinase-like 2 (DPYSL2) gene in schizophrenia: genetic association study and expression analysis.","date":"2005","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16321170","citation_count":21,"is_preprint":false},{"pmid":"39106443","id":"PMC_39106443","title":"Small molecule targeting Na V 1.7 via inhibition of CRMP2-Ubc9 interaction reduces pain-related outcomes in a rodent osteoarthritic model.","date":"2024","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/39106443","citation_count":21,"is_preprint":false},{"pmid":"31076621","id":"PMC_31076621","title":"Genetic inhibition of CRMP2 phosphorylation at serine 522 promotes axonal regeneration after optic nerve injury.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31076621","citation_count":21,"is_preprint":false},{"pmid":"32299503","id":"PMC_32299503","title":"DPYSL2 is a novel regulator for neural stem cell differentiation in rats: revealed by Panax notoginseng saponin administration.","date":"2020","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32299503","citation_count":19,"is_preprint":false},{"pmid":"26400044","id":"PMC_26400044","title":"Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.","date":"2015","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/26400044","citation_count":19,"is_preprint":false},{"pmid":"15207709","id":"PMC_15207709","title":"Induction of CRMP-2 by GDNF and analysis of the CRMP-2 promoter region.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15207709","citation_count":18,"is_preprint":false},{"pmid":"30081699","id":"PMC_30081699","title":"Chemical shift perturbation mapping of the Ubc9-CRMP2 interface identifies a pocket in CRMP2 amenable for allosteric modulation of Nav1.7 channels.","date":"2018","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30081699","citation_count":18,"is_preprint":false},{"pmid":"30816227","id":"PMC_30816227","title":"Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) promotes the aggressiveness of human uveal melanoma through dephosphorylation of CRMP2.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30816227","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53548,"output_tokens":10851,"usd":0.161705,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21439,"output_tokens":9804,"usd":0.176148,"stage2_stop_reason":"end_turn"},"total_usd":0.337853,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CRMP-2 is enriched in growing axons of cultured hippocampal neurons; overexpression induces supernumerary axons, and dominant-negative truncation mutants suppress primary axon formation, establishing CRMP-2 as critical for axon induction and neuronal polarity.\",\n      \"method\": \"Overexpression and dominant-negative mutant expression in cultured hippocampal neurons with morphological readout\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function (dominant-negative) and gain-of-function with defined cellular phenotype, replicated across multiple labs\",\n      \"pmids\": [\"11477421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CRMP-2 binds tubulin heterodimers with higher affinity than assembled microtubules and promotes microtubule assembly; a deletion mutant lacking the microtubule-assembly region acts dominant-negatively to inhibit axonal growth and branching.\",\n      \"method\": \"In vitro tubulin-binding assays, microtubule polymerization assays, dominant-negative mutant overexpression in neurons\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution of tubulin binding and polymerization plus mutagenesis, replicated in neuronal context\",\n      \"pmids\": [\"12134159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CRMP-2 interacts with Numb; CRMP-2/Numb complex co-localizes with L1 at axonal growth cones, and dominant-negative CRMP-2 or siRNA knockdown inhibits L1 endocytosis and suppresses axon growth, identifying CRMP-2 as a regulator of polarized Numb-mediated endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, dominant-negative expression, L1 endocytosis assay in hippocampal neurons\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA KD, and dominant-negative with specific endocytic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"12942088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GSK-3β phosphorylates CRMP-2 at Thr-514 and inactivates it; expression of non-phosphorylatable CRMP-2 or GSK-3β inhibition induces multiple axon-like neurites, while constitutively active GSK-3β impairs neuronal polarization. NT-3 inactivates GSK-3β leading to CRMP-2 dephosphorylation and axon outgrowth.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, overexpression of constitutively active/kinase-dead mutants, knockdown of CRMP-2 in hippocampal neurons\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus genetic epistasis with multiple rescue experiments, widely replicated\",\n      \"pmids\": [\"15652488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cdk5 phosphorylates CRMP2 at Ser522; this primes sequential phosphorylation by GSK-3β at Thr509. Dual phosphorylation reduces CRMP2 affinity for tubulin and generates the 3F4 neurofibrillary tangle-associated epitope. Sema3A stimulation enhances this sequential phosphorylation, and CRMP2 Ala-mutants at Ser522 or Thr509 attenuate Sema3A-induced growth cone collapse.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, phospho-specific antibodies, DRG growth cone collapse assay, cdk5-/- mouse brain lysates\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, genetic validation in cdk5 knockout, functional growth cone assay\",\n      \"pmids\": [\"15676027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rho kinase phosphorylates CRMP-2 and abolishes its binding to tubulin dimers, microtubules, and Numb, but not to actin. Phosphorylated CRMP-2 localizes exclusively to actin filaments rather than microtubules or clathrin-coated pits in growth cones. Ephrin-A5 induces this phosphorylation via Rho kinase during growth cone collapse.\",\n      \"method\": \"In vitro kinase assay, phospho-mimetic/null mutants, electron microscopy localization, growth cone collapse assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, mutagenesis, EM-based localization with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"16260611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CRMP-2 C-terminal region directly binds the tetratricopeptide repeat domain of Kinesin light chain 1 (KLC1); soluble tubulin forms a trimeric complex with CRMP-2 and KLC1. Knockdown of KLCs or CRMP-2 impairs anterograde GFP-tubulin transport in axons.\",\n      \"method\": \"Pulldown/direct binding assay, Co-immunoprecipitation, fluorescence recovery after photobleaching (FRAP) of GFP-tubulin, siRNA knockdown\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay identifying trimeric complex, FRAP-based transport assay, KD with specific transport phenotype\",\n      \"pmids\": [\"15935053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CRMP-2 is highly phosphorylated at Thr-509, Ser-518, and Ser-522 in neurofibrillary tangles of Alzheimer's disease brain; site-directed mutagenesis showed that phosphorylation at all three sites is required for the 3F4 tangle-associated epitope.\",\n      \"method\": \"Immunoaffinity purification, site-directed mutagenesis, in vitro kinase assay with brain extract\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis defining phosphorylation sites with functional epitope readout, in vitro kinase assay\",\n      \"pmids\": [\"10757975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRMP-2 directly binds dynein heavy chain at its N-terminus (distinct from the kinesin light chain-binding region); overexpression of dynein-binding CRMP-2 fragments prevents dynein-driven microtubule transport in COS-7 cells, suggesting CRMP-2 interferes with retrograde transport.\",\n      \"method\": \"Co-immunoprecipitation, direct binding domain mapping, dynein-driven microtubule transport assay in COS-7 cells\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, cell-based transport assay, single lab\",\n      \"pmids\": [\"19659462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRMP-2 binds directly to CaV2.2 (N-type Ca2+ channel) at the domain I-II intracellular loop and distal C-terminus; CRMP-2 overexpression increases CaV2.2 surface expression and current density in hippocampal neurons and enhances vesicular glutamate release, while lentiviral knockdown abolishes this effect.\",\n      \"method\": \"Co-immunoprecipitation, cell-surface biotinylation, patch-clamp electrophysiology, glutamate release assay, lentiviral knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding mapped to specific domains, reciprocal Co-IP, surface biotinylation, electrophysiology, and neurotransmitter release assay in multiple cell types\",\n      \"pmids\": [\"19755421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRMP-2 overexpression in dorsal root ganglion neurons increases CaV2.2 surface levels and current density; siRNA knockdown of CRMP-2 reduces CGRP release by ~54%, establishing CRMP-2 as a regulator of N-type Ca2+ channel activity and transmitter release in sensory neurons.\",\n      \"method\": \"Nucleofection overexpression, siRNA knockdown, patch-clamp electrophysiology, surface biotinylation, CGRP ELISA\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function with electrophysiology and neurotransmitter release, replicates findings from PMID 19755421\",\n      \"pmids\": [\"19903690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sema3A stimulation generates H2O2 via MICAL, oxidizing CRMP2 to form a disulfide-linked homodimer through Cys-504; oxidized CRMP2 then forms a transient disulfide complex with thioredoxin (TRX), which stimulates GSK-3-mediated phosphorylation of CRMP2, leading to growth cone collapse. This oxidation-phosphorylation cascade was reconstituted in vitro with purified proteins.\",\n      \"method\": \"In vitro reconstitution with purified proteins, mass spectrometry, non-reducing SDS-PAGE, mutagenesis (Cys-504), growth cone collapse assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins plus mutagenesis and functional growth cone readout\",\n      \"pmids\": [\"21521879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Inhibiting the CRMP-2–CaV2.2 interaction with a TAT-fused CRMP-2-derived peptide (TAT-CBD3) decreases neuropeptide release, excitatory synaptic transmission, and nocifensive/neuropathic pain behaviors in vivo, demonstrating that CRMP-2-mediated enhancement of CaV2.2 function underlies pain hypersensitivity.\",\n      \"method\": \"Peptide inhibitor (TAT-CBD3), in vivo pain behavior assays, electrophysiology in dorsal horn neurons\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — peptide disruption of specific protein-protein interaction with multiple in vivo and ex vivo functional readouts\",\n      \"pmids\": [\"21642979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TAT-CBD3 (CRMP-2 peptide) induces NR2B (GluN2B) internalization in dendritic spines, reduces NMDA-evoked Ca2+ influx and currents, and protects neurons from delayed calcium deregulation following glutamate excitotoxicity; CRMP-2 knockdown similarly blocks neuronal death, implicating CRMP-2 in NMDAR surface trafficking.\",\n      \"method\": \"Lentiviral CRMP-2 knockdown, peptide application, Ca2+ imaging, patch-clamp electrophysiology, cortical impact TBI model in vivo\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — lentiviral KD plus peptide with electrophysiology, Ca2+ imaging, and in vivo TBI model\",\n      \"pmids\": [\"21832084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CRMP-2 phosphorylation at Thr555 (by Rho kinase downstream of NgR1) is increased in degenerating axons in EAE/multiple sclerosis; AAV-mediated expression of phospho-resistant T555A-CRMP-2 limits optic nerve axonal degeneration, establishing NgR1-dependent CRMP-2 phosphorylation as a mechanism of axonal degeneration.\",\n      \"method\": \"NgR1 knockout mice, AAV-T555A-CRMP2 transduction, phospho-specific immunostaining, axonal degeneration quantification\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO epistasis and viral phospho-resistant mutant rescue with defined axonal degeneration phenotype\",\n      \"pmids\": [\"22544872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cdk5-mediated phosphorylation of CRMP-2 at Ser522 is required for dendritic field organization in vivo; CRMP2 S522A knock-in mice combined with CRMP1 knockout display severe 'curling' dendritic patterning in cortical neurons, demonstrating synergistic roles of CRMP1 and CRMP2 phosphorylation in dendritic projection.\",\n      \"method\": \"Knock-in mouse generation (CRMP2-S522A), CRMP1 knockout mice, cortical neuron morphology analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knock-in and knockout mouse models with specific in vivo dendritic phenotype\",\n      \"pmids\": [\"22279220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CRMP-2 phosphorylation by Cdk5 at Ser522 enhances its interaction with CaV2.2; a Cdk5 phospho-null CRMP-2-S522A mutant or inactive Cdk5 abolishes CRMP-2-mediated enhancement of Ca2+ influx via CaV2.2, whereas the Rho kinase site T555A mutant is ineffective.\",\n      \"method\": \"Phospho-null mutant overexpression, inactive Cdk5 co-expression, Ca2+ current measurement, co-immunoprecipitation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with Co-IP and Ca2+ current assay, single lab\",\n      \"pmids\": [\"23022559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRMP-2 is SUMOylated by Ubc9 at Lys374 in vivo; removal of the SUMOylation site (K374A or K374A/M375A/D376A mutants) reduces NaV1.7 surface expression and current density, while increasing SUMOylation levels inversely correlates with CaV2.2-mediated calcium influx.\",\n      \"method\": \"In vivo SUMOylation assay, SUMO protease overexpression, surface biotinylation, electrophysiology (NaV1.7 and CaV2.2 currents), calcium imaging\",\n      \"journal\": \"The Journal of biological chemistry / Channels\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (SUMOylation assay, biotinylation, electrophysiology) identifying specific modification site with functional ion channel trafficking consequence\",\n      \"pmids\": [\"23836888\", \"23510938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRMP-2 interacts with the GluK5 subunit of kainate receptors; PKC-mediated phosphorylation of CRMP-2 at T555 (via non-canonical KAR signaling) downregulates membrane CaV2.2, while dephosphorylation at T514 (via GSK3β phosphorylation at S9) promotes neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific antibodies, CaV2.2 surface expression assay, neurite outgrowth assay in DRG neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multiple phospho-site functional assays, single lab\",\n      \"pmids\": [\"24227739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRMP-2 interacts with NMDAR (co-immunoprecipitation) and NCX3 but not NCX1; TAT-CBD3 peptide disrupts CRMP-2–NMDAR interaction without altering NMDAR localization, and simultaneously augments CRMP-2–NCX3 interaction and triggers NCX3 internalization, inhibiting both reverse and forward NCX modes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, NCX3 internalization assay, Ca2+ dysregulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus KD with Ca2+ functional assay, single lab\",\n      \"pmids\": [\"24474686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dephosphorylation of CRMP2 at GSK3-targeted residues (Ser-518/Thr-514/Thr-509) is carried out by a protein phosphatase 1 family member in vitro and in neurons; the Cdk5-phosphorylated site (Ser-522) is comparatively resistant to phosphatase treatment, partly due to neighboring basic residues, which may contribute to Alzheimer's disease-associated CRMP2 hyperphosphorylation.\",\n      \"method\": \"In vitro phosphatase assay, pharmacological inhibition (purvalanol, CT99021, IGF-1), Pin1 transgenic mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphatase reconstitution plus multiple pharmacological and genetic validations in cells and transgenic mice\",\n      \"pmids\": [\"18460467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Local mTOR-p70S6K signaling in the axon selectively upregulates translation of CRMP2 and Tau mRNAs via 5'-terminal oligopyrimidine tract elements; rapamycin suppresses axon specification by reducing CRMP2/Tau translation, and exogenous CRMP2 rescues axon formation in rapamycin-treated neurons.\",\n      \"method\": \"Rapamycin treatment, constitutively active p70S6K expression, 5'UTR reporter assays, local translation in axons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays plus pharmacological/genetic rescue, single lab\",\n      \"pmids\": [\"19648118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CRMP-2 interacts with MICAL-L1 in non-neuronal cells; CRMP-2 depletion causes relocalization of internalized transferrin from peripheral vesicles to the endocytic recycling compartment, an effect blocked by inhibiting dynein (dynamitin overexpression), establishing CRMP-2 as a link between MICAL-L1/EHD1 vesicular transport and dynein motors.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, transferrin recycling assay, dynamitin overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus KD and dynein inhibition with specific endocytic trafficking phenotype, single lab\",\n      \"pmids\": [\"20801876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BMP-SMAD1/4 signaling transcriptionally suppresses CRMP2 expression by binding the CRMP2 promoter (ChIP); CRMP2 knockdown or dominant-negative CRMP2 in utero causes accumulation of multipolar cells and impairs multipolar-to-bipolar transition during radial neuronal migration.\",\n      \"method\": \"ChIP assay, in utero electroporation with RNAi and dominant-negative constructs, cortical slice analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for transcriptional regulation plus in vivo in utero electroporation with defined neuronal migration phenotype\",\n      \"pmids\": [\"20926379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A membrane-tethered myristoylated CRMP-2 peptide (myr-tat-CBD3) more efficiently disrupts CRMP-2–CaV2.2 interaction than the non-myristoylated version, reduces CaV2.2 trafficking, inhibits Ca2+ influx, decreases DRG neuron excitability, and reverses carrageenan-induced thermal hypersensitivity and postoperative pain.\",\n      \"method\": \"Pulldown, confocal immunofluorescence colocalization, voltage-clamp electrophysiology, current-clamp, in vivo pain behavior assays\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding disruption with biochemical, electrophysiological, and in vivo functional readouts\",\n      \"pmids\": [\"25782368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRMP2 SUMOylation at Lys374 is enhanced by Cdk5-mediated phosphorylation and antagonized by Fyn phosphorylation; SUMOylated CRMP2 binds NaV1.7 to maintain its membrane localization; loss of SUMOylation triggers clathrin-dependent NaV1.7 internalization involving Nedd4-2, Numb, and Eps15.\",\n      \"method\": \"SUMOylation assays, phospho-mutant constructs (Cdk5/Fyn sites), surface biotinylation, clathrin inhibition, Co-immunoprecipitation, CRMP2-K374A mutant expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods establishing hierarchical PTM cross-talk controlling NaV1.7 trafficking, with mechanistic pathway identification\",\n      \"pmids\": [\"27940916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Brain-specific Crmp2 knockout mice show reduced hippocampal LTP, abnormal NMDA receptor composition, aberrant dendrite development, and defective synapse formation in CA1 neurons; adult neurogenesis knockdown shows stage-dependent developmental defects, demonstrating CRMP2 is required for synaptic plasticity and neuronal development in vivo.\",\n      \"method\": \"Conditional knockout mice, electrophysiology (LTP), immunostaining, western blot for NMDAR subunits, retroviral knockdown in adult neurogenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal cellular/electrophysiological readouts\",\n      \"pmids\": [\"27249678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"X-ray crystal structure (1.78 Å) of mouse CRMP2 reveals Lys374 as the sole biologically relevant SUMOylation site, buried in the tetramer interface but exposed in the monomer; structural basis suggests phosphorylation-induced monomerization exposes Lys374 for SUMOylation.\",\n      \"method\": \"X-ray crystallography (1.78 Å resolution), sequence alignment, structure-function mutagenesis\",\n      \"journal\": \"Channels\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation of SUMOylation site, structure-guided mutagenesis\",\n      \"pmids\": [\"28277940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"X-ray structural analysis of CRMP2-tubulin interaction shows the C-terminal helix H19 of CRMP2 is the main interface with soluble tubulin dimers (distinct from tail-mediated interaction with assembled microtubules); H19-mediated interaction promotes rapid GTP-state microtubule formation; H19 mutants disturb axon elongation in chick neurons and fail to produce axonal microtubule features in C. elegans.\",\n      \"method\": \"X-ray crystallography, in vitro microtubule polymerization assay, H19 mutagenesis, chick neuron axon elongation assay, C. elegans genetic assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro reconstitution and mutagenesis, validated in two independent in vivo models\",\n      \"pmids\": [\"28878401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499; crystal structure of CRMP2-Y479E phospho-mimetic reveals this prevents CRMP2 tetramerization, abolishing microtubule bundling activity of the C-terminus. FER depletion increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells.\",\n      \"method\": \"X-ray crystallography (CRMP2-Y479E), in vitro microtubule bundling assay, FER kinase inhibition, in vivo xenograft model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro functional assay with mutagenesis and in vivo validation\",\n      \"pmids\": [\"29396402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cdk5-mediated CRMP2 phosphorylation (at Ser522) is increased presynaptically in spinal cord/DRG after spared nerve injury; CRMP2 knockdown reverses mechanical allodynia; intrathecal non-phosphorylatable CRMP2-S522A decreases allodynia while phospho-mimetic S522D induces allodynia in naive rats, establishing Cdk5-CRMP2 phosphorylation as both necessary and sufficient for neuropathic pain.\",\n      \"method\": \"siRNA knockdown, intrathecal expression of phospho-null/mimetic mutants, biochemical fractionation, spared nerve injury model\",\n      \"journal\": \"Neurobiology of pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation with specific pain behavior phenotype, gain- and loss-of-function in vivo\",\n      \"pmids\": [\"31080913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Neurofibromin binds CRMP2 in a CDK5-dependent manner; loss of neurofibromin frees CRMP2 to interact with syntaxin 1A and CaV2.2, increasing CGRP release; a CRMP2-neurofibromin interface-disrupting peptide (t-CNRP1) inhibits Ca2+ influx, reduces CaV2.2 membrane localization, and reverses pain behaviors in NF1-related models.\",\n      \"method\": \"Co-immunoprecipitation, peptide mapping, CGRP release assay, surface biotinylation, in vivo pain behavior\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP interaction mapping plus functional peptide disruption with multiple biochemical and in vivo readouts\",\n      \"pmids\": [\"28767512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Ubc9–CRMP2 interaction has low micromolar affinity (measured by microscale thermophoresis and AlphaLISA); a CRMP2 SUMOylation motif heptamer peptide (t-CSM) disrupts CRMP2–Ubc9 interaction, reduces CRMP2 SUMOylation, blocks NaV1.7 surface trafficking in sensory neurons, and reverses spinal nerve injury-induced pain.\",\n      \"method\": \"Microscale thermophoresis, AlphaLISA, cell-penetrating peptide, surface biotinylation, electrophysiology, SNI pain model\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biophysical binding measurement plus functional ion channel trafficking and in vivo pain reversal, multiple methods\",\n      \"pmids\": [\"29847471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTEN knockout abrogates GSK3 inhibitory activity on CRMP2; maintaining GSK3 activity (Gsk3 knock-in mice) compromises PTEN-KO-mediated optic nerve regeneration and CRMP2 activity; viral expression of constitutively active CRMP2-T/A rescues regeneration despite reduced mTOR activation, establishing GSK3/CRMP2 as a required pathway for PTEN-KO-mediated axon regeneration.\",\n      \"method\": \"Conditional knockout mice (PTEN), GSK3 knock-in mice, AAV-CRMP2-T/A viral expression, optic nerve regeneration assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using multiple mouse models with defined axon regeneration phenotype\",\n      \"pmids\": [\"31453382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nogo-A induces association of NgR1 with CRMP2 in a PlexinA2-dependent manner; NgR1 and PlexinA2 interact genetically to restrict corticospinal axon sprouting after pyramidotomy; double-heterozygous NgR1+/-;PlexinA2+/- mice show greater sprouting and functional recovery, placing CRMP2 in a NgR1/PlexinA2/CRMP2 ternary complex that limits neural repair.\",\n      \"method\": \"Immunoprecipitation proteomics, non-neuronal cell contraction assay, double-heterozygous mouse genetics, pyramidotomy model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — IP-proteomics identifying complex, genetic epistasis in double-heterozygous mice with in vivo axon sprouting phenotype\",\n      \"pmids\": [\"30804090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Identification of a reversible intermolecular Cys-504–Cys-504 dithiol-disulfide switch in homotetrameric CRMP2 that determines two quaternary conformations controlling axonal outgrowth; this switch is regulated by cytosolic glutaredoxin 2c (Grx2c).\",\n      \"method\": \"Non-reducing SDS-PAGE, site-directed mutagenesis (Cys-504), neuronal axon outgrowth assay, Grx2c interaction studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical characterization of disulfide switch with mutagenesis, single lab\",\n      \"pmids\": [\"24133216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Neurofibromin co-immunoprecipitates with CRMP-2 and CRMP-4 (but not CRMP-1) from rat brain; CDK5 activity is required for the neurofibromin–CRMP-2 interaction.\",\n      \"method\": \"Immunoprecipitation from rat brain lysates, CDK5 inhibition (roscovitine), mass spectrometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP from brain lysate with kinase inhibitor dependency, single lab but replicated in later studies\",\n      \"pmids\": [\"18313395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRMP2 mediates Sema3F signaling; crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, consistent with impaired Sema3F (not only Sema3A) signaling; crmp2-/- mice show ASD-related social behavior changes.\",\n      \"method\": \"crmp2-/- knockout mice, axon pruning quantification in hippocampus/visual cortex, Sema3F stimulation in primary neurons, behavioral assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete knockout mouse with multiple defined circuit and behavioral phenotypes, in vitro signaling confirmation\",\n      \"pmids\": [\"31919978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRMP2 K374A knock-in (CRMP2-SUMOylation-null) mice show reduced NaV1.7 membrane localization and currents specifically in female sensory neurons; these mice fail to develop persistent mechanical allodynia in a neuropathic pain model, demonstrating sex-specific SUMOylation-dependent control of peripheral NaV1.7.\",\n      \"method\": \"CRMP2-K374A knock-in mice, surface biotinylation, electrophysiology, behavioral pain assays, sex-stratified analysis\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse with electrophysiology and in vivo pain phenotype, sex-specific analysis\",\n      \"pmids\": [\"32569093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Non-SUMOylated CRMP2 forms a complex with Numb, Nedd4-2, and Eps15 to drive clathrin-mediated endocytosis of NaV1.7; silencing Numb, Nedd4-2, or Eps15 in DRG neurons from CRMP2-K374A female mice restores sodium currents; clathrin inhibition in nerve-injured male CRMP2-K374A mice precipitates allodynia.\",\n      \"method\": \"siRNA knockdown of endocytic proteins, clathrin assembly inhibitor, electrophysiology, CRMP2-K374A knock-in mice\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KD of three endocytic proteins with electrophysiological rescue, in vivo pharmacological intervention\",\n      \"pmids\": [\"33478555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-β/Smad canonical signaling suppresses CRMP2 expression through a Smad–TGIF transcriptional repressor complex; this inhibits neurite elongation in mouse and human iPSC-derived neurons; TGF-β pathway mutations found in neurodevelopmental disorder patients disrupt neuronal morphogenesis via this Smad/TGIF/CRMP2 axis.\",\n      \"method\": \"ChIP, co-immunoprecipitation (Smad-TGIF complex), in utero electroporation, human iPSC-derived neuron assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus Co-IP establishing transcriptional complex, validated in mouse and human iPSC neurons\",\n      \"pmids\": [\"29695415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRMP2 (DPYSL2) acts as a synaptic m6A reader: it binds m6A-modified Malat1 lncRNA at synapses in the mPFC; disruption of m6A on Malat1 reduces CRMP2 interaction and decreases dendritic spine formation, impairing fear-extinction memory consolidation.\",\n      \"method\": \"m6A RNA-sequencing, RNA immunoprecipitation/mass spectrometry, dendritic spine quantification, fear-extinction behavioral assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-MS identification with functional spine and memory readout, novel role with limited mechanistic follow-up on CRMP2 side\",\n      \"pmids\": [\"37669863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTP4A3 (PRL-3) phosphatase dephosphorylates CRMP2 at T514 in uveal melanoma cells; loss of CRMP2 expression in PTP4A3-expressing cells increases cell migration and invasiveness in vitro/in vivo, accompanied by actin cytoskeleton reorganization and increased cell stiffness; catalytically inactive PTP4A3 does not produce these effects.\",\n      \"method\": \"Phospho-specific immunoblot, PTP4A3 active-site mutant, CRMP2 knockdown, invasion/migration assays, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant control establishes phosphatase-substrate relationship, functional cell migration phenotype, single lab\",\n      \"pmids\": [\"30816227\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRMP2 (DPYSL2) is a multifunctional cytosolic phosphoprotein that promotes axon specification and growth by binding tubulin heterodimers via its C-terminal helix H19 to drive microtubule assembly, links soluble tubulin to anterograde Kinesin-1 transport via KLC1, regulates Numb-mediated endocytosis of L1, and is inactivated by sequential Cdk5 (Ser522) and GSK-3β (Thr514/Thr509) phosphorylation or Rho kinase phosphorylation (Thr555), which collectively disrupt its tubulin-binding and endocytic activities; at presynaptic terminals CRMP2 enhances CaV2.2 surface trafficking and neurotransmitter release in a Cdk5 phosphorylation-dependent manner, and controls NaV1.7 membrane localization through a hierarchical post-translational modification program in which Cdk5-primed SUMOylation at Lys374 by Ubc9 promotes NaV1.7 surface expression while loss of SUMOylation recruits a Numb/Nedd4-2/Eps15 endocytic complex to internalize NaV1.7 via clathrin, with this axis being the dominant mechanism of chronic neuropathic pain; additional regulatory inputs include oxidation-mediated Cys504 disulfide dimerization (amplified by thioredoxin to activate GSK-3 phosphorylation), FER-mediated tyrosine phosphorylation at Y479/Y499 that prevents tetramerization and microtubule bundling, and transcriptional suppression by BMP-SMAD and TGF-β-SMAD/TGIF signaling pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DPYSL2 (CRMP2) is a multifunctional cytosolic phosphoprotein that governs neuronal polarity, axon and dendrite growth, and ion channel surface trafficking [#0, #15]. It promotes axon specification by binding tubulin heterodimers with higher affinity than assembled microtubules and driving microtubule assembly through its C-terminal helix H19, an activity required for axon induction, elongation and branching [#1, #28]. CRMP2 couples this cytoskeletal function to transport by linking soluble tubulin to anterograde Kinesin-1 via direct binding to KLC1, and by regulating Numb-mediated endocytosis of the adhesion molecule L1 at growth cones [#6, #2]. Its activity is gated by a layered post-translational program: Cdk5 phosphorylation at Ser522 primes sequential GSK-3\\u03b2 phosphorylation at Thr514/Thr509, and Rho-kinase phosphorylation at Thr555, each reducing tubulin/Numb binding and inactivating CRMP2 downstream of guidance cues such as Sema3A and ephrin-A5 [#4, #3, #5]; oxidation-driven Cys504 disulfide dimerization amplified by thioredoxin further licenses GSK-3 phosphorylation, while FER-mediated tyrosine phosphorylation at Y479/Y499 blocks tetramerization and microtubule bundling [#11, #29]. At presynaptic and sensory terminals CRMP2 binds CaV2.2 to enhance its surface expression and neurotransmitter/neuropeptide release in a Cdk5-Ser522-dependent manner, and a hierarchical modification cascade in which Cdk5-primed SUMOylation at Lys374 by Ubc9 maintains NaV1.7 at the membrane, whereas loss of SUMOylation recruits a Numb/Nedd4-2/Eps15 complex to drive clathrin-mediated NaV1.7 internalization \\u2014 an axis that is a dominant, sex-influenced determinant of chronic neuropathic pain [#9, #25, #39, #38]. CRMP2 is required in vivo for dendritic patterning, synaptic plasticity and stereotyped axon pruning, and its expression is transcriptionally repressed by BMP-SMAD and TGF-\\u03b2-SMAD/TGIF signaling during cortical neuronal migration and morphogenesis [#15, #26, #37, #23, #40].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established CRMP2 as a determinant of neuronal polarity, answering whether a single cytosolic factor could specify axon identity.\",\n      \"evidence\": \"Overexpression and dominant-negative truncation in cultured hippocampal neurons with morphological readout\",\n      \"pmids\": [\"11477421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular activity driving axon formation\", \"No endogenous loss-of-function in vivo\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified tubulin-heterodimer binding and microtubule assembly promotion as the molecular basis of CRMP2's growth-promoting activity.\",\n      \"evidence\": \"In vitro tubulin-binding and polymerization assays plus dominant-negative mutant expression in neurons\",\n      \"pmids\": [\"12134159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface with tubulin not yet resolved\", \"Did not address how transport is coordinated with assembly\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected CRMP2 to membrane traffic by showing it regulates Numb-mediated endocytosis of L1 at growth cones.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, dominant-negative expression and L1 endocytosis assays in hippocampal neurons\",\n      \"pmids\": [\"12942088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking endocytosis to axon growth not fully defined\", \"Generality beyond L1 cargo unknown at the time\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped a multi-site phosphorylation signature (Thr509/Ser518/Ser522) on CRMP2 in Alzheimer neurofibrillary tangles, raising the question of which kinases impose it and its functional consequence.\",\n      \"evidence\": \"Immunoaffinity purification, site-directed mutagenesis and in vitro kinase assay on AD brain\",\n      \"pmids\": [\"10757975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the responsible kinases\", \"Causal role in disease not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the kinase logic inactivating CRMP2: Cdk5 priming at Ser522 enables sequential GSK-3\\u03b2 phosphorylation (Thr509/Thr514) and Rho-kinase phosphorylation (Thr555), each disrupting tubulin/Numb binding downstream of Sema3A and ephrin-A5.\",\n      \"evidence\": \"In vitro kinase assays, phospho-specific antibodies, phospho-mutants, cdk5-/- lysates and growth cone collapse assays\",\n      \"pmids\": [\"15652488\", \"15676027\", \"16260611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatases reversing these marks not yet defined\", \"How distinct guidance cues select specific sites unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed CRMP2 bridges soluble tubulin to anterograde Kinesin-1 via direct KLC1 binding, mechanistically coupling cargo binding to axonal transport.\",\n      \"evidence\": \"Direct binding/pulldown assays, Co-IP, FRAP of GFP-tubulin and siRNA knockdown\",\n      \"pmids\": [\"15935053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of complex assembly by phosphorylation not tested here\", \"Relationship to retrograde transport unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified PP1-family phosphatase as the eraser of GSK3-targeted CRMP2 sites and explained why the Cdk5 site resists dephosphorylation, rationalizing AD-associated hyperphosphorylation.\",\n      \"evidence\": \"In vitro phosphatase assays, pharmacological inhibitors and Pin1 transgenic mice\",\n      \"pmids\": [\"18460467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phosphatase isoform not pinned down\", \"In vivo disease causality not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed CRMP2 in a neurofibromin complex in a CDK5-dependent manner, hinting at a tumor-suppressor link to CRMP2 regulation.\",\n      \"evidence\": \"Co-IP from rat brain lysate with roscovitine inhibition and mass spectrometry\",\n      \"pmids\": [\"18313395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the interaction not defined in this study\", \"Single lab Co-IP\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established CRMP2 as a direct regulator of CaV2.2 N-type calcium channel surface expression and neurotransmitter/neuropeptide release in central and sensory neurons.\",\n      \"evidence\": \"Co-IP, domain mapping, surface biotinylation, patch-clamp and glutamate/CGRP release with knockdown\",\n      \"pmids\": [\"19755421\", \"19903690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-dependence of CaV2.2 binding not yet defined\", \"In vivo physiological/pathological role untested at this point\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed local mTOR-p70S6K signaling selectively upregulates CRMP2 translation to drive axon specification, adding a translational control layer.\",\n      \"evidence\": \"Rapamycin treatment, p70S6K expression, 5'UTR reporter assays and rescue in axons\",\n      \"pmids\": [\"19648118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of localized CRMP2 protein synthesis limited\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Proposed CRMP2 antagonizes retrograde transport through direct dynein heavy-chain binding, distinguishing kinesin and dynein interaction regions.\",\n      \"evidence\": \"Co-IP, domain mapping and dynein-driven microtubule transport assay in COS-7 cells\",\n      \"pmids\": [\"19659462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect shown in non-neuronal cells only\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended CRMP2's trafficking role to non-neuronal endosomal transport, linking MICAL-L1/EHD1 recycling vesicles to dynein motors.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, transferrin recycling assay and dynamitin overexpression\",\n      \"pmids\": [\"20801876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal relevance not directly tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified BMP-SMAD1/4 transcriptional repression of CRMP2 as a control point for multipolar-to-bipolar transition during cortical radial migration.\",\n      \"evidence\": \"ChIP and in utero electroporation with RNAi/dominant-negative constructs in cortical slices\",\n      \"pmids\": [\"20926379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals tuning BMP-CRMP2 axis in vivo incompletely mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reconstituted an oxidation-phosphorylation cascade: Sema3A/MICAL-derived H2O2 forms a Cys504 disulfide dimer that engages thioredoxin to stimulate GSK-3 phosphorylation and growth cone collapse.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins, mass spectrometry, non-reducing SDS-PAGE, Cys504 mutagenesis and collapse assay\",\n      \"pmids\": [\"21521879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of the redox switch to guidance not quantified\", \"Sources of physiological oxidant beyond Sema3A unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Translated CRMP2-CaV2.2 biology into therapeutics, showing peptide disruption (TAT-CBD3) reduces transmitter release and reverses neuropathic pain in vivo.\",\n      \"evidence\": \"TAT-CBD3 peptide, in vivo pain behavior and dorsal horn electrophysiology\",\n      \"pmids\": [\"21642979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peptide selectivity across CRMP2 interactions not fully delineated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Implicated CRMP2 in NMDAR (GluN2B) surface trafficking and excitotoxic neuroprotection, broadening its receptor-trafficking role.\",\n      \"evidence\": \"Lentiviral knockdown, TAT-CBD3 peptide, Ca2+ imaging, electrophysiology and a TBI model\",\n      \"pmids\": [\"21832084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CRMP2-NMDAR interface not structurally defined here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated in vivo that Cdk5-Ser522 phosphorylation organizes dendritic fields, with CRMP1/CRMP2 acting synergistically.\",\n      \"evidence\": \"CRMP2-S522A knock-in combined with CRMP1 knockout and cortical neuron morphology analysis\",\n      \"pmids\": [\"22279220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effectors downstream of Ser522 in dendrites not isolated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked NgR1/Rho-kinase-driven Thr555 phosphorylation of CRMP2 to axonal degeneration in demyelinating disease, with phospho-resistant T555A protecting axons.\",\n      \"evidence\": \"NgR1 knockout mice, AAV-T555A rescue and phospho-immunostaining in EAE/optic nerve\",\n      \"pmids\": [\"22544872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream degenerative effectors of phospho-CRMP2 unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed Cdk5-Ser522 phosphorylation specifically enhances the CRMP2-CaV2.2 interaction, tying the kinase code to calcium channel regulation.\",\n      \"evidence\": \"Phospho-null/inactive Cdk5 expression, Ca2+ current measurement and Co-IP\",\n      \"pmids\": [\"23022559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural basis of phospho-enhanced binding not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovered Ubc9-mediated CRMP2 SUMOylation at Lys374 as a positive regulator of NaV1.7 surface expression, opening the sodium-channel trafficking axis.\",\n      \"evidence\": \"In vivo SUMOylation assays, SUMO protease overexpression, surface biotinylation and electrophysiology of NaV1.7/CaV2.2\",\n      \"pmids\": [\"23836888\", \"23510938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchical control of SUMOylation by other PTMs not yet established here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterized a reversible Cys504-Cys504 dithiol-disulfide quaternary switch, regulated by glutaredoxin 2c, that toggles axon outgrowth.\",\n      \"evidence\": \"Non-reducing SDS-PAGE, Cys504 mutagenesis, axon outgrowth assay and Grx2c interaction studies\",\n      \"pmids\": [\"24133216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab biochemistry\", \"In vivo relevance of the conformational switch untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded CRMP2's channel/receptor partners to GluK5 kainate receptors, NMDAR, and NCX3, with phospho-state-specific consequences for CaV2.2 and exchanger trafficking.\",\n      \"evidence\": \"Co-IP, phospho-specific antibodies, surface expression and Ca2+ dysregulation assays\",\n      \"pmids\": [\"24227739\", \"24474686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IPs\", \"Direct versus indirect interactions not all distinguished\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Optimized CRMP2-CaV2.2 disruption with a membrane-tethered peptide (myr-tat-CBD3), improving potency for analgesia and confirming the trafficking mechanism.\",\n      \"evidence\": \"Pulldown, colocalization, voltage/current-clamp and inflammatory/postoperative pain models\",\n      \"pmids\": [\"25782368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term in vivo specificity and off-target trafficking effects not fully addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the hierarchical PTM code controlling NaV1.7: Cdk5 phosphorylation promotes Lys374 SUMOylation (antagonized by Fyn), and loss of SUMOylation recruits Nedd4-2/Numb/Eps15 for clathrin-mediated channel internalization.\",\n      \"evidence\": \"SUMOylation assays, phospho-mutants, surface biotinylation, clathrin inhibition and Co-IP\",\n      \"pmids\": [\"27940916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of competing PTMs in vivo not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established an in vivo requirement for CRMP2 in synaptic plasticity, NMDAR composition, dendrite development and synapse formation.\",\n      \"evidence\": \"Brain-specific conditional knockout with LTP electrophysiology, immunostaining and adult neurogenesis knockdown\",\n      \"pmids\": [\"27249678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between CRMP2 loss and altered NMDAR subunit composition unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structural rationale for PTM-gated SUMOylation: crystallography shows Lys374 is buried in the tetramer interface but exposed in the monomer, so phospho-induced monomerization licenses SUMOylation.\",\n      \"evidence\": \"1.78 \\u00c5 X-ray structure of mouse CRMP2 with structure-guided mutagenesis\",\n      \"pmids\": [\"28277940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural capture of the SUMOylated/phosphorylated state lacking\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the C-terminal helix H19 as the soluble-tubulin interface distinct from the microtubule-binding tail, mechanistically separating dimer binding from lattice binding.\",\n      \"evidence\": \"X-ray crystallography, in vitro polymerization, H19 mutagenesis and chick/C. elegans axon assays\",\n      \"pmids\": [\"28878401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation reshapes H19-tubulin contacts not structurally shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected neurofibromin to the CaV2.2 pain axis, showing its loss frees CRMP2 to engage syntaxin 1A and CaV2.2 and increase CGRP release, druggable with t-CNRP1.\",\n      \"evidence\": \"Co-IP, peptide mapping, CGRP release, surface biotinylation and NF1 pain models\",\n      \"pmids\": [\"28767512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface of the CRMP2-neurofibromin complex undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FER tyrosine phosphorylation at Y479/Y499 as a switch that blocks CRMP2 tetramerization and microtubule bundling, with consequences for taxane sensitivity in cancer.\",\n      \"evidence\": \"Crystal structure of Y479E phospho-mimetic, in vitro bundling assay, FER inhibition and ovarian cancer xenografts\",\n      \"pmids\": [\"29396402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal relevance of FER-CRMP2 axis not addressed\", \"Endogenous FER-CRMP2 dynamics in tumors limited\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated Cdk5-CRMP2 phosphorylation at Ser522 is both necessary and sufficient for neuropathic pain, providing bidirectional in vivo causality.\",\n      \"evidence\": \"siRNA knockdown, intrathecal phospho-null/mimetic mutants and spared nerve injury model\",\n      \"pmids\": [\"31080913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of CaV2.2 versus NaV1.7 to the Ser522 pain phenotype not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Quantified the Ubc9-CRMP2 binding affinity and validated SUMOylation-motif peptide disruption (t-CSM) as an analgesic strategy targeting NaV1.7 trafficking.\",\n      \"evidence\": \"Microscale thermophoresis, AlphaLISA, cell-penetrating peptide, biotinylation, electrophysiology and SNI model\",\n      \"pmids\": [\"29847471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of t-CSM for CRMP2 among Ubc9 substrates not fully established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified TGF-\\u03b2/Smad-TGIF transcriptional repression of CRMP2 as a neurodevelopmental morphogenesis axis disrupted by patient pathway mutations.\",\n      \"evidence\": \"ChIP, Smad-TGIF Co-IP, in utero electroporation and human iPSC-derived neuron assays\",\n      \"pmids\": [\"29695415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CRMP2 mutation causality in patients not established here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed GSK3/CRMP2 as a required, mTOR-independent effector branch for PTEN-knockout-mediated optic nerve regeneration.\",\n      \"evidence\": \"PTEN conditional KO, GSK3 knock-in mice and AAV-CRMP2-T/A rescue in optic nerve regeneration\",\n      \"pmids\": [\"31453382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream cytoskeletal events enabling regeneration not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a NgR1/PlexinA2/CRMP2 ternary complex induced by Nogo-A that restricts corticospinal sprouting and functional recovery after injury.\",\n      \"evidence\": \"IP-proteomics, cell contraction assay, double-heterozygous mouse genetics and pyramidotomy\",\n      \"pmids\": [\"30804090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CRMP2 contact within the ternary complex not structurally resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified PTP4A3 (PRL-3) as a CRMP2 Thr514 phosphatase in uveal melanoma, linking CRMP2 dephosphorylation/loss to cytoskeletal remodeling and invasion.\",\n      \"evidence\": \"Phospho-immunoblot, catalytically inactive PTP4A3, CRMP2 knockdown and invasion/xenograft assays\",\n      \"pmids\": [\"30816227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism connecting CRMP2 loss to stiffness/invasion incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed CRMP2 mediates Sema3F as well as Sema3A signaling, controlling stereotyped axon pruning, spine remodeling and ASD-related behavior in vivo.\",\n      \"evidence\": \"crmp2-/- mice, axon pruning quantification, Sema3F stimulation and behavioral assays\",\n      \"pmids\": [\"31919978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling components linking CRMP2 to Sema3F-specific pruning not isolated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided definitive in vivo genetic proof that Lys374 SUMOylation controls peripheral NaV1.7 and neuropathic pain in a sex-specific manner.\",\n      \"evidence\": \"CRMP2-K374A knock-in mice, surface biotinylation, electrophysiology and sex-stratified pain behavior\",\n      \"pmids\": [\"32569093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the female-specific dependence not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the endocytic effector complex (Numb/Nedd4-2/Eps15) that internalizes NaV1.7 when CRMP2 is not SUMOylated, completing the bidirectional trafficking switch.\",\n      \"evidence\": \"siRNA knockdown of endocytic proteins, clathrin inhibition and electrophysiology in CRMP2-K374A knock-in DRG neurons\",\n      \"pmids\": [\"33478555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence of recruitment among Numb/Nedd4-2/Eps15 not ordered\", \"Sex-difference mechanism still open\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an unexpected RNA-binding function: CRMP2 acts as a synaptic m6A reader of Malat1 lncRNA to support spine formation and fear-extinction memory.\",\n      \"evidence\": \"m6A RNA-seq, RIP-mass spectrometry, dendritic spine quantification and fear-extinction behavior\",\n      \"pmids\": [\"37669863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CRMP2 m6A recognition undefined\", \"Limited mechanistic follow-up on the CRMP2 side\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CRMP2's distinct activities \\u2014 tubulin assembly, motor coupling, ion-channel trafficking, and RNA reading \\u2014 are spatially and temporally partitioned within a single neuron by its integrated PTM code remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model integrating phosphorylation, SUMOylation, oxidation and tyrosine modification states\", \"Quantitative partitioning of CRMP2 pools among partners in vivo unknown\", \"Whether m6A-reading and cytoskeletal roles share the same protein pool untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 28, 29]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 2, 9, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10, 25, 39]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [41]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 5, 28]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 25, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 23, 37]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 13, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 11, 25]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 6, 39]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 25, 29]}\n    ],\n    \"complexes\": [\n      \"CRMP2/KLC1/tubulin transport complex\",\n      \"Numb/Nedd4-2/Eps15 endocytic complex\",\n      \"NgR1/PlexinA2/CRMP2 ternary complex\"\n    ],\n    \"partners\": [\n      \"TUBB\",\n      \"KLC1\",\n      \"NUMB\",\n      \"CACNA1B\",\n      \"SCN9A\",\n      \"UBE2I\",\n      \"NF1\",\n      \"FER\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}