{"gene":"MAP2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1988,"finding":"The C-terminal 185 amino acids of MAP2, containing three imperfect 18-amino-acid repeats, constitute the microtubule-binding domain. A subcloned fragment spanning the first two repeats copurified with microtubules through two successive cycles of polymerization/depolymerization, while a control polypeptide from the N-terminal region completely failed to copurify.","method":"In vitro translation of subcloned fragments followed by microtubule copurification assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with domain deletion, replicated in multiple subsequent studies","pmids":["3142041"],"is_preprint":false},{"year":1988,"finding":"MAP2 is a component of crossbridges between microtubules and neurofilaments in the neuronal cytoskeleton. MAP2 bound isolated neurofilament L protein in vitro, and when tubulin was added and polymerized, neurofilaments were crosslinked with microtubules via MAP2 bridges.","method":"Quick-freeze deep-etch immunoelectron microscopy with anti-MAP2 antibody decoration, plus in vitro reconstitution with purified neurofilament L protein and tubulin","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution experiment combined with immunoelectron microscopy in situ, two orthogonal methods","pmids":["3045269"],"is_preprint":false},{"year":1988,"finding":"MAP2 mRNA is selectively localized in dendrites of developing neurons, whereas tubulin mRNA is restricted to neuronal cell bodies, establishing a dendritic targeting signal for MAP2 transcript.","method":"In situ hybridization with specific cDNA probes in developing brain tissue","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment replicated across multiple subsequent studies","pmids":["3200318"],"is_preprint":false},{"year":1992,"finding":"Expression of MAP2 is necessary for both neurite extension and cessation of cell division during neuronal differentiation; stable transfectants with MAP2 antisense RNA showed reduced MAP2 protein, failed normal morphological differentiation, and failed to withdraw from the cell cycle.","method":"Stable antisense RNA transfection in embryonal carcinoma cells with retinoic acid-induced differentiation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with two distinct phenotypic readouts (morphology and cell cycle exit)","pmids":["1997209"],"is_preprint":false},{"year":1992,"finding":"Transfection of MAP2c or tau cDNA into fibroblasts stabilizes microtubules against depolymerizing reagents and enriches microtubules in acetylated alpha-tubulin, demonstrating that these MAPs induce post-translational modification of tubulin.","method":"cDNA transfection into fibroblasts, drug-resistance assay, immunofluorescence with anti-acetylated tubulin antibody","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assay with two orthogonal readouts, replicated across MAP2, tau, and MAP1B","pmids":["1487506"],"is_preprint":false},{"year":2002,"finding":"MAP2 anchors the regulatory subunit II of cAMP-dependent protein kinase (PKA) in dendrites. MAP2-deficient mice show reduced microtubule density and dendritic length, significant reduction of PKA subunits in dendrites and total PKA, and markedly reduced phosphorylated CREB induction after forskolin stimulation.","method":"MAP2 knockout mouse analysis: immunofluorescence, Western blot for PKA subunits, pCREB induction assay in cultured neurons","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal mechanistic readouts (microtubule density, PKA localization, signaling output)","pmids":["12163474"],"is_preprint":false},{"year":1989,"finding":"High-molecular-weight MAP2 and low-molecular-weight MAP2c are generated by alternative splicing from a single gene and share the C-terminal tubulin-binding domain and a short N-terminal sequence. MAP2c lacks 1,342 amino acids of the filamentous sidearm domain present in high-MW MAP2, and MAP2c mRNA is not present in dendrites, indicating the dendritic targeting signal is specific to the high-MW isoform.","method":"cDNA cloning, sequence comparison, in situ hybridization for mRNA localization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — sequence-level molecular characterization plus direct mRNA localization experiment","pmids":["2770869"],"is_preprint":false},{"year":1995,"finding":"MAP2 is prevented from entering the axon by its N-terminal projection domain. Microtubule binding of MAP2/MAP2C is tighter in the cell body and dendrites than in the axon, a property determined by the microtubule-binding domain and suggested to be regulated by phosphorylation.","method":"Transfection of tagged tau, MAP2, MAP2C, and chimeric/deletion mutants into primary cultured neurons","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic deletion and chimeric mutant analysis in primary neurons, multiple constructs","pmids":["7857650"],"is_preprint":false},{"year":1990,"finding":"NMDA receptor activation induces rapid (~70%) dephosphorylation of MAP2 in hippocampal slices, blocked by competitive and noncompetitive NMDA antagonists but not non-NMDA receptor antagonists, suggesting NMDA-stimulated protein phosphatase (possibly calcineurin) dephosphorylates MAP2.","method":"32P-orthophosphate labeling of hippocampal slices, pharmacological dissection with receptor antagonists","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct phosphorylation assay with pharmacological dissection in ex vivo tissue","pmids":["2169265"],"is_preprint":false},{"year":1996,"finding":"Glutamate produces bidirectional regulation of MAP2 phosphorylation in neurons: a rapid transient increase via metabotropic receptors (attenuated by CaMK and PKC inhibitors) followed by persistent dephosphorylation via NMDA receptor activation of calcineurin (PP2B). The phosphorylation state of MAP2 determines its interaction with microtubules and actin.","method":"32P metabolic labeling of neurons, pharmacological dissection with receptor antagonists and kinase/phosphatase inhibitors","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection using multiple pharmacological agents targeting specific kinases, phosphatases, and receptor subtypes","pmids":["8789950"],"is_preprint":false},{"year":1999,"finding":"MAP2B (a well-established AKAP) directly binds the alpha1 subunit of class C L-type Ca2+ channels in neurons; this association is independent of microtubules. PKA is an integral part of the immunoisolated class C channel complex, and MAP2B mediates recruitment of PKA to postsynaptic sites.","method":"Co-immunoprecipitation from rat brain extracts, protein overlay binding assay with 32P-labeled RIIβ, immunoblotting, in vitro direct binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP combined with direct in vitro binding assay, two orthogonal methods","pmids":["10514522"],"is_preprint":false},{"year":1999,"finding":"MARK kinases phosphorylate MAP2c on its microtubule-binding domain in transfected CHO cells, leading to detachment of MAP2c from microtubules and increased microtubule dynamic instability; prolonged MARK2 expression causes microtubule disruption and cell death.","method":"Inducible expression of MARK1/MARK2 in transfected CHO cells, immunofluorescence, cell viability assay","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based assay with inducible system and multiple readouts, single lab","pmids":["10542369"],"is_preprint":false},{"year":2000,"finding":"GSK3β phosphorylates MAP2C in co-transfected COS-1 cells, and this phosphorylation prevents microtubule bundle formation. Phosphorylated MAP2C species are enriched in cytoskeleton-unbound fractions, indicating that GSK3β-mediated phosphorylation reduces MAP2 binding to microtubules.","method":"Co-transfection of MAP2C and GSK3β (wild-type or mutant) in COS-1 cells, immunofluorescence for microtubule bundles, cytoskeletal fractionation, lithium chloride rescue","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-transfection with pharmacological rescue, single lab","pmids":["10826493"],"is_preprint":false},{"year":2000,"finding":"PKA activity disrupts the MAP2-microtubule interaction in living HeLa cells and promotes MAP2c localization to peripheral actin-rich membrane ruffles. PKA phosphorylates serines within KXGS motifs in each tubulin-binding repeat; single-site glutamic acid substitution was sufficient to disrupt microtubule binding, and double/triple mutations promoted MAP2c-actin colocalization.","method":"Live-cell imaging, detergent extraction assay, site-directed mutagenesis (Glu substitutions), immunofluorescence colocalization in HeLa cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with biochemical fractionation and imaging, multiple orthogonal methods in one study","pmids":["11029056"],"is_preprint":false},{"year":2000,"finding":"All three neuronal MAP2 isoforms bind specifically to the SH3 domains of c-Src and Grb2 via the microtubule-binding domain (not a PXXP motif). Endogenous MAP2-Src and MAP2-Grb2 interactions were confirmed by co-immunoprecipitation from brain lysate. ERK2 phosphorylation of MAP2c inhibits the MAP2-SH3 interaction.","method":"GST-SH3 pulldown assay, co-immunoprecipitation from brain lysate, in vitro kinase assay with ERK2","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP from brain combined with in vitro pulldown and kinase regulation","pmids":["10781592"],"is_preprint":false},{"year":2001,"finding":"MAP2c binds Fyn kinase through the RTPPKSP SH3-binding motif. Fyn phosphorylates MAP2c on tyrosine. ERK2-mediated threonine phosphorylation of the RTPPKSP motif abolishes the MAP2c-Fyn interaction. Co-immunoprecipitation of Fyn and MAP2c from human fetal brain confirmed the in vivo interaction.","method":"GST-SH3 pulldown, co-immunoprecipitation from human fetal brain homogenate, ELISA binding assay, co-transfection in COS7 cells with kinase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP from brain tissue plus in vitro kinase assay and multiple binding assay methods","pmids":["11546790"],"is_preprint":false},{"year":1997,"finding":"cdc2 kinase phosphorylation of MAP2 (>60% of phosphates in the microtubule-binding region) abolishes both microtubule-stabilizing and microtubule-nucleating activities. PKA phosphorylation (~70% in the projection region) reduces only microtubule-nucleating activity, not stabilization. These distinct effects were demonstrated by direct observation of individual microtubules.","method":"In vitro phosphorylation by purified PKA or cdc2 kinase, dark-field microscopy observation of individual microtubules, spontaneous polymerization assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro kinase assay with direct single-microtubule visualization, two kinases compared","pmids":["9376363"],"is_preprint":false},{"year":2003,"finding":"Rho-kinase phosphorylates MAP2 at Ser1796, and myosin phosphatase (MBS subunit) binds MAP2 and can dephosphorylate it. These were identified as novel substrates of the Rho-kinase/myosin phosphatase pathway.","method":"In vitro kinase assay, phosphorylation site mapping by mass spectrometry/sequencing, interaction assay with MBS subunit","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay with site mapping, single lab","pmids":["14535960"],"is_preprint":false},{"year":2000,"finding":"PP2A, but not PP2B, regulates MAP2 phosphorylation at multiple sites in rat brain slices; inhibition of PP2A with okadaic acid induced phosphorylation of MAP2 and impaired its microtubule-binding activity, establishing PP2A as the major phosphatase regulating MAP2.","method":"Metabolically competent rat brain slices treated with okadaic acid (PP2A inhibitor) or cyclosporin A (PP2B inhibitor), Western blot with phospho-specific antibodies, microtubule-binding assay","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo pharmacological dissection with functional binding assay, single lab","pmids":["10640627"],"is_preprint":false},{"year":2012,"finding":"PP2A/Bα directly binds MAP2 and dephosphorylates it. The binding site is within the microtubule-binding domain and upstream proline-rich region of MAP2c, overlapping with the RTPPKSP motif also recognized by Fyn kinase. Fyn inhibits the PP2A/Bα-MAP2 interaction; tau and MAP2 compete for binding to PP2A/Bα.","method":"Co-purification from bovine brain, co-immunoprecipitation, in vitro binding assay with peptides, competition assay, immunofluorescence colocalization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-purification from brain combined with in vitro binding, competition, and colocalization — multiple orthogonal methods","pmids":["22403409"],"is_preprint":false},{"year":1990,"finding":"The MAP2-binding and P75-binding domain in the PKA regulatory subunit RIIβ is located within its N-terminal 50 amino acids. Fusion proteins containing RIIβ amino acids 1–50 bound MAP2 and P75 immobilized on nitrocellulose; deletion of residues 1–25 or 25–96 abolished binding.","method":"Expression of truncated RIIβ-fusion proteins in E. coli, overlay binding assay on nitrocellulose filters","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic deletion mapping using in vitro binding assay, single lab","pmids":["2254332"],"is_preprint":false},{"year":2006,"finding":"MAP2 functions as a receptor for the neurosteroid pregnenolone (PREG) and its analog MePREG. PREG and MePREG bind MAP2 and stimulate microtubule polymerization. RNA interference knockdown of MAP2 prevents the stimulatory effects of PREG/MePREG on neurite extension but does not affect progesterone action.","method":"Binding assay, microtubule polymerization assay, RNA interference knockdown in PC12 cells, neurite outgrowth measurement","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with pharmacological specificity controls, single lab","pmids":["16537405"],"is_preprint":false},{"year":1993,"finding":"MAP2c-transfected non-neuronal cells form microtubule-containing processes specifically upon actin depolymerization with cytochalasin B. This effect is specific to MAP2c (not taxol-stabilized microtubules), suggesting MAP2c confers stability, bundling, and stiffness on microtubules enabling process outgrowth against cortical actin tension.","method":"cDNA transfection into non-neuronal cells, cytochalasin B treatment, video time-lapse microscopy","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging of transfected cells with pharmacological manipulation and specificity controls, single lab","pmids":["8392463"],"is_preprint":false},{"year":1993,"finding":"MAP2C-bundled microtubules in transfected fibroblasts are extremely stable (less than 10% tubulin exchange within 1 hour) but still incorporate exogenously introduced tubulin rapidly at distal ends, demonstrating that MAP2C stabilizes microtubule bundles while preserving plus-end assembly.","method":"Microinjection of biotin-labeled tubulin, photoactivation of caged fluorescein-labeled tubulin, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vivo dynamic assay using two complementary tubulin labeling approaches in transfected cells","pmids":["8421058"],"is_preprint":false},{"year":1992,"finding":"MAP2c expression in non-neuronal cells induces MTOC-independent microtubule polymerization and bundling. At higher expression levels, increasing proportions of microtubules form independently of the MTOC; MAP2c imparts both stability and stiffness to microtubules.","method":"cDNA transfection in non-neuronal cell lines, immunofluorescence, comparison with taxol and DMSO stabilization","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfection-based functional assay with controls, single lab","pmids":["1338311"],"is_preprint":false},{"year":1994,"finding":"MAP2 (but not MAP2C or tau) binds phosphatidylinositol vesicles with high affinity (Kd ~51 nM), approximately 30-fold higher than MAP2C (~1.4 µM). This high affinity requires two sites: a low-affinity site in the C-terminal domain (shared with MAP2C/tau) and a high-affinity site (~221 nM) within the MAP2-specific projection domain (absent from MAP2C due to alternative splicing).","method":"Vesicle binding assay with purified proteins, thrombin digestion of MAP2C to map binding domains","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro binding assay with domain deletion, single lab","pmids":["8025110"],"is_preprint":false},{"year":1994,"finding":"MAP2 binds to both microtubules/tubulin dimers and microfilaments/G-actin in a concentration-dependent manner. Microtubule-bound MAP2 shows diminished ability to bind microfilaments/G-actin, while microfilament-bound MAP2 efficiently binds microtubules and tubulin, suggesting an asymmetric cross-linking interaction.","method":"Solid-phase immunoassay on 96-well microtiter plates with purified proteins","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstituted in vitro binding assay, single lab, single method","pmids":["8038171"],"is_preprint":false},{"year":2005,"finding":"Soluble amyloid-β oligomers induce proteolysis of MAP2a, MAP2b, and MAP2c through calpain activation (triggered by Ca2+ dysregulation and ROS), which on its own is sufficient to cleave all MAP2 isoforms. Antioxidants prevent MAP2 proteolysis, linking ROS to calpain-mediated MAP2 degradation.","method":"In vitro Aβ treatment of neurons, calpain inhibitor experiments, caspase-3 inhibitor experiments, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection in neuronal cultures with multiple inhibitors, single lab","pmids":["16234245"],"is_preprint":false},{"year":1994,"finding":"MAP2 phosphorylation at Ser136, a Ser-Pro motif, occurs in vivo and in vitro specifically by proline-directed kinases (MAP kinase, GSK-3, cdk family members) but not by PKA, PKC, or CaMKII. After microinjection into cell lines, dephosphorylated MAP2 becomes phosphorylated at Ser136; microtubule reorganization by injected MAP2 is independent of Ser136 phosphorylation.","method":"In vitro kinase assays, site-directed mutagenesis of Ser136, monoclonal antibody epitope mapping, microinjection into cell lines","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with in vitro kinase specificity assay and in vivo microinjection, multiple methods in one study","pmids":["7525290"],"is_preprint":false},{"year":1983,"finding":"MAP2 is present in dendritic spines and colocalizes with actin at the filamentous compartment of spines, endomembranes of the spine apparatus, smooth endoplasmic reticulum, and postsynaptic density, indicating MAP2 is an actin-associated protein in dendritic spines.","method":"Immunogold electron microscopy with double-labeling using anti-MAP2 and anti-actin antibodies","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunogold EM double-labeling at subcellular resolution, single lab","pmids":["6572937"],"is_preprint":false},{"year":1995,"finding":"A MAP2-associated kinase (embryonic MAP2 kinase, Mr=100,000) co-purified with chicken embryonic MAP2 phosphorylates MAP2 at serine residues and releases MAP2 from microtubules, restoring kinesin- and dynein-driven microtubule motility that is otherwise inhibited by MAP2. This kinase is cAMP-independent and distinct from cdc2 kinase, MAPK, and NIMA kinase in its ability to alter MAP2-microtubule affinity.","method":"In vitro motility assay, kinase co-purification, in vitro phosphorylation with multiple kinase comparisons","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of motility rescue, comparison of multiple kinases, single lab","pmids":["7759496"],"is_preprint":false},{"year":2003,"finding":"MAP2 physically associates with the NMDA receptor complex in hippocampal neurons, demonstrated by co-immunoprecipitation. NMDA receptor activation is a prominent trigger for MAP2 breakdown; calcium influx through the NMDA receptor channel and calcium release from mitochondria trigger MAP2 degradation limited by calpain activity.","method":"Co-immunoprecipitation from hippocampal slice lysates, pharmacological dissection with NMDA receptor antagonists, calpain inhibitors, calcium chelators","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP from brain tissue plus pharmacological dissection, single lab","pmids":["12834896"],"is_preprint":false},{"year":2011,"finding":"MAP2 mRNA localizes to dendrites in distinct RNPs containing very few RNA molecules (low copy number). The number of MAP2 molecules per RNP particle is affected by synaptic activity and Staufen 2, indicating that RNP composition is dynamically regulated.","method":"Single-molecule fluorescence in situ hybridization (smFISH), live-cell imaging, Staufen 2 knockdown, synaptic activity manipulation","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct single-molecule imaging with genetic perturbation, single lab","pmids":["21869818"],"is_preprint":false},{"year":2012,"finding":"L1CAM (L1) directly binds MAP2c (but not MAP2a/b) through its intracellular domain, as shown by ELISA. L1 upregulates MAP2a/b/c expression in hippocampal neurons via the MAPK pathway. Deficiency in both L1 and MAP2 reduces neurite outgrowth in vitro.","method":"ELISA binding assay, co-immunoprecipitation, Western blot from L1-deficient transgenic mice, MAPK pathway inhibition, neurite outgrowth assay","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay combined with in vivo knockout data and pathway inhibition, single lab","pmids":["22503709"],"is_preprint":false},{"year":2021,"finding":"Hyperphosphorylation of MAP2 at Ser1782 (pS1782) in schizophrenia reduces MAP2 binding to microtubules, as confirmed by computational modeling and experimental validation. A phosphomimetic S1782E transgenic mouse shows reduced basilar dendritic length, complexity, and spine density. Overexpression of wild-type and phosphomimetic MAP2 reduces protein synthesis in vitro, and the MAP2 interactome is enriched for proteins involved in protein translation.","method":"Unbiased phosphoproteomics, computational modeling, phosphomimetic transgenic mouse (S1782E), co-immunoprecipitation/mass spectrometry for interactome, protein synthesis assay","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis confirmed by transgenic animal plus multiple orthogonal methods (proteomics, modeling, co-IP/MS, synthesis assay)","pmids":["33526823"],"is_preprint":false},{"year":1996,"finding":"Juvenile MAP2c and mature MAP2 induce distinct microtubule spacing and process morphologies when expressed in Sf9 cells. MAP2c induces multiple short thin processes with variable, close microtubule spacing; mature MAP2 induces fewer, thicker processes with a proximo-distal taper in microtubule number and wider spacing, demonstrating that MAP2 isoforms serve as architectural elements establishing specific microtubule arrangements.","method":"Baculovirus-mediated expression in Sf9 cells, electron microscopy of process cross-sections","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative EM analysis comparing two isoforms in cell-based expression system, single lab","pmids":["8868472"],"is_preprint":false},{"year":1996,"finding":"Transgenic MAP2c protein in adult mouse neurons is sorted to dendrites but not axons despite its mRNA being restricted to cell bodies, demonstrating that dendritic targeting of MAP2c depends on a signal in the protein itself, not on mRNA transport.","method":"Transgenic mouse overexpression of MAP2c, in situ hybridization for mRNA localization, immunofluorescence for protein localization","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse with complementary mRNA and protein localization data, mechanistically distinguishes protein- vs mRNA-based targeting","pmids":["8627364"],"is_preprint":false},{"year":1983,"finding":"MAP2 binds to the Sau96.1 restriction fragment of mouse satellite DNA containing poly(dA/dT) sequences; DNase protection assay showed MAP2 protects poly(dA)4/poly(dT)4 sequences from digestion.","method":"DNA-binding assay, DNase protection experiment with MAP2-DNA complex","journal":"The EMBO journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro binding assay, functional significance unclear, single lab","pmids":["10872313"],"is_preprint":false},{"year":2020,"finding":"NCAM2 forms a protein complex with MAP2 and 14-3-3γ/ζ in neurons; NCAM2 depletion results in destabilization of the microtubular network and reduced MAP2 signal, establishing MAP2 as part of an NCAM2-dependent cytoskeletal regulatory complex for dendritic architecture.","method":"Co-immunoprecipitation, proteomic analysis, knockdown in hippocampal neurons with morphological readout, in vivo cortical migration assay","journal":"Cerebral cortex","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP combined with proteomic and functional knockdown data, single lab","pmids":["32043120"],"is_preprint":false}],"current_model":"MAP2 is a dendrite-enriched microtubule-associated protein whose C-terminal tandem-repeat domain directly binds and stabilizes microtubules (and cross-links them to neurofilaments and actin), whose N-terminal projection domain suppresses axonal entry and sets inter-microtubule spacing, and whose phosphorylation state—regulated bidirectionally by kinases (PKA, MARK, cdc2, MAPK, Rho-kinase, Fyn, GSK3β) and phosphatases (PP2A/Bα, calcineurin) downstream of NMDA and metabotropic glutamate receptors—controls its affinity for microtubules versus actin and its function as an A-kinase anchoring protein (AKAP) that recruits PKA to dendrites to sustain CREB-mediated signaling; additionally, MAP2 acts as a signaling scaffold by binding Src and Grb2 SH3 domains in a phosphorylation-regulated manner, serves as a receptor for the neurosteroid pregnenolone to promote microtubule polymerization and neurite outgrowth, and dendritic protein targeting relies on a signal within the MAP2 protein itself rather than on mRNA transport."},"narrative":{"mechanistic_narrative":"MAP2 is a dendrite-enriched microtubule-associated protein that builds and stabilizes the dendritic cytoskeleton and serves as a phosphorylation-gated signaling scaffold during neuronal differentiation [PMID:1997209, PMID:12163474]. Its C-terminal domain, comprising three imperfect 18-amino-acid repeats, constitutes the microtubule-binding region that copurifies with microtubules through repeated polymerization cycles, nucleates and stabilizes microtubules, and promotes their acetylation while preserving plus-end assembly [PMID:3142041, PMID:1487506, PMID:8421058]. Through this domain MAP2 also cross-links microtubules to neurofilaments and binds G-actin/microfilaments, with microtubule-bound MAP2 showing reduced affinity for actin, and it imparts the stiffness and bundling that drive process outgrowth against cortical actin tension [PMID:3045269, PMID:8038171, PMID:8392463]. The MAP2-specific N-terminal projection domain sets inter-microtubule spacing and process architecture across isoforms generated by alternative splicing, and prevents axonal entry by conferring tighter microtubule binding in the cell body and dendrites [PMID:8868472, PMID:2770869, PMID:7857650]; dendritic localization depends both on a protein-intrinsic targeting signal and on selective dendritic transport of high-molecular-weight MAP2 mRNA in low-copy RNPs [PMID:8627364, PMID:3200318, PMID:21869818]. MAP2 function is governed bidirectionally by phosphorylation: proline-directed and serine/threonine kinases (cdc2, GSK3β, MARK, ERK/MAPK, PKA, Rho-kinase) detach it from microtubules or shift it toward actin, while phosphatases PP2A and calcineurin (PP2B), acting downstream of metabotropic and NMDA glutamate receptors, restore microtubule binding [PMID:9376363, PMID:10542369, PMID:10826493, PMID:11029056, PMID:8789950, PMID:2169265, PMID:10640627, PMID:22403409]. Beyond a structural role, MAP2 acts as an A-kinase anchoring protein that recruits PKA via the RII regulatory subunit to dendrites and L-type Ca2+ channels to sustain CREB signaling, binds the SH3 domains of Src, Grb2 and Fyn in a phosphorylation-regulated manner, and functions as a receptor for the neurosteroid pregnenolone to stimulate microtubule polymerization and neurite outgrowth [PMID:12163474, PMID:10514522, PMID:2254332, PMID:10781592, PMID:11546790, PMID:16537405]. Hyperphosphorylation at Ser1782 in schizophrenia reduces microtubule binding and, in a phosphomimetic mouse, shrinks dendritic complexity and spine density while suppressing protein synthesis [PMID:33526823].","teleology":[{"year":1988,"claim":"Localizing the microtubule-binding activity to a defined region answered which part of the large MAP2 molecule physically engages tubulin, and showed MAP2 simultaneously bridges microtubules to neurofilaments.","evidence":"In vitro translation of subcloned fragments with microtubule copurification, plus immunoelectron microscopy and reconstitution with purified neurofilament L and tubulin","pmids":["3142041","3045269"],"confidence":"High","gaps":["Repeat-level stoichiometry of microtubule binding not resolved","Whether the same repeats mediate neurofilament cross-bridging untested"]},{"year":1988,"claim":"Demonstrating that MAP2 mRNA is selectively dendritic while tubulin mRNA stays in the soma established subcellular mRNA targeting as a candidate mechanism for MAP2 compartmentalization.","evidence":"In situ hybridization with specific cDNA probes in developing brain","pmids":["3200318"],"confidence":"High","gaps":["cis-element directing dendritic mRNA transport not mapped","Whether mRNA targeting is necessary for protein localization unresolved at this stage"]},{"year":1989,"claim":"Resolving that high-MW MAP2 and MAP2c arise by alternative splicing from one gene clarified that the dendritic mRNA targeting signal is isoform-specific to the high-MW form.","evidence":"cDNA cloning, sequence comparison, and isoform-specific in situ hybridization","pmids":["2770869"],"confidence":"High","gaps":["Functional consequence of the 1342-residue sidearm in vivo not directly tested here"]},{"year":1992,"claim":"Loss-of-function showed MAP2 is required for neurite extension and cell-cycle exit, moving it from a structural marker to a driver of differentiation; concurrent gain-of-function showed MAPs directly stabilize microtubules and promote tubulin acetylation.","evidence":"Antisense RNA in differentiating embryonal carcinoma cells, and MAP2c/tau cDNA transfection into fibroblasts with drug-resistance and acetylated-tubulin readouts","pmids":["1997209","1487506"],"confidence":"High","gaps":["Mechanistic link between microtubule stabilization and cell-cycle withdrawal unestablished","Whether acetylation is cause or consequence of stabilization unresolved"]},{"year":1992,"claim":"Heterologous expression established MAP2c as sufficient to nucleate MTOC-independent, stiff, stable, bundled microtubules and to build processes against cortical actin, defining its architectural function.","evidence":"cDNA transfection in non-neuronal cells with EM, cytochalasin B treatment, time-lapse imaging, and tubulin exchange/photoactivation assays","pmids":["1338311","8392463","8421058"],"confidence":"High","gaps":["Molecular basis of MTOC-independent nucleation not defined","How bundling tension translates to neurite initiation in neurons untested"]},{"year":1990,"claim":"Demonstrating NMDA-receptor-driven rapid MAP2 dephosphorylation tied cytoskeletal regulation to glutamatergic synaptic activity via a calcineurin-like phosphatase.","evidence":"32P labeling of hippocampal slices with NMDA-receptor antagonist dissection","pmids":["2169265"],"confidence":"High","gaps":["Phosphatase identity inferred pharmacologically, not biochemically confirmed here","Phosphosites not mapped"]},{"year":1994,"claim":"Reconstitution and site mapping established that MAP2 binds both microtubules and actin in mutually constraining fashion, and that proline-directed kinases phosphorylate a defined Ser-Pro site, beginning the phospho-code for MAP2 binding.","evidence":"Solid-phase binding assays with purified microtubules/actin, phosphatidylinositol vesicle binding, and Ser136 mutagenesis with kinase-specificity assays and microinjection","pmids":["8038171","8025110","7525290"],"confidence":"High","gaps":["Functional relevance of Ser136 phosphorylation unclear (microtubule reorganization was independent of it)","Physiological role of MAP2 phosphatidylinositol binding untested"]},{"year":1995,"claim":"Domain-swap analysis showed the N-terminal projection domain excludes MAP2 from the axon and the microtubule-binding domain confers compartment-specific affinity, explaining dendritic enrichment at the protein level.","evidence":"Transfection of tagged tau/MAP2/MAP2C and chimeric/deletion mutants into primary neurons","pmids":["7857650"],"confidence":"High","gaps":["The proposed phosphorylation control of compartmental binding not directly demonstrated here"]},{"year":1996,"claim":"Transgenic sorting of MAP2c protein to dendrites despite somatic mRNA proved a protein-intrinsic dendritic targeting signal independent of mRNA transport; isoform comparison showed MAP2 isoforms dictate distinct microtubule spacing and process geometry.","evidence":"Transgenic mouse overexpression with mRNA/protein localization, and baculovirus isoform expression in Sf9 cells with EM cross-sections","pmids":["8627364","8868472"],"confidence":"High","gaps":["Sequence of the protein targeting signal not identified","Receptor/machinery reading the targeting signal unknown"]},{"year":1996,"claim":"Comparing PKA versus cdc2 phosphorylation in vitro separated MAP2's two activities—cdc2 (microtubule-binding domain) abolishes both stabilization and nucleation, PKA (projection region) reduces only nucleation—and a co-purified MAP2 kinase was shown to release MAP2 and restore motor-driven motility.","evidence":"In vitro kinase reactions with purified PKA/cdc2 and dark-field single-microtubule observation, plus in vitro motility rescue with a co-purified MAP2 kinase","pmids":["9376363","7759496"],"confidence":"High","gaps":["Identity of the co-purified embryonic MAP2 kinase not established","In vivo relevance of each phosphosite-specific effect untested"]},{"year":1999,"claim":"Identifying MAP2c as a MARK substrate whose microtubule-binding-domain phosphorylation detaches it from microtubules linked a specific kinase to MAP2 dynamic regulation.","evidence":"Inducible MARK1/2 expression in CHO cells with immunofluorescence and viability assays","pmids":["10542369"],"confidence":"Medium","gaps":["Single-lab cell-line system; neuronal relevance not shown","Direct in vitro phosphorylation site not mapped here"]},{"year":1999,"claim":"Showing MAP2B directly binds the L-type Ca2+ channel alpha1 subunit and brings PKA into the channel complex extended MAP2's AKAP role to postsynaptic signaling microdomains.","evidence":"Reciprocal co-IP from brain, RIIbeta overlay binding, and in vitro direct binding","pmids":["10514522"],"confidence":"High","gaps":["Functional effect of channel-anchored PKA on channel gating not measured","Microtubule-independent localization mechanism unresolved"]},{"year":2000,"claim":"PKA phosphorylation of KXGS-motif serines was shown to be sufficient to release MAP2c from microtubules and redirect it to actin-rich ruffles, mechanistically coupling the phospho-code to a microtubule-versus-actin switch.","evidence":"Live-cell imaging, detergent extraction, and Glu-substitution mutagenesis in HeLa cells","pmids":["11029056"],"confidence":"High","gaps":["Endogenous neuronal stimulus driving this switch not identified here","Actin-binding interface not mapped"]},{"year":2000,"claim":"MAP2 was established as a multi-kinase signaling scaffold by demonstrating direct SH3-domain binding to c-Src and Grb2 via the microtubule-binding domain, with ERK2 phosphorylation disrupting the interaction; GSK3beta phosphorylation was shown to reduce microtubule binding, and PP2A identified as the major MAP2 phosphatase.","evidence":"GST-SH3 pulldowns and brain co-IP, GSK3beta co-transfection with fractionation, and okadaic-acid/cyclosporin dissection in brain slices","pmids":["10781592","10826493","10640627"],"confidence":"Medium","gaps":["Downstream consequence of Src/Grb2 scaffolding on signaling output untested","GSK3beta and PP2A studies are single-lab"]},{"year":2001,"claim":"Mapping a discrete RTPPKSP SH3-binding motif for Fyn, with ERK2 threonine phosphorylation abolishing binding, defined a phosphorylation switch governing MAP2's recruitment of a tyrosine kinase that in turn phosphorylates MAP2.","evidence":"GST-SH3 pulldown, co-IP from human fetal brain, ELISA, and co-transfection kinase assays","pmids":["11546790"],"confidence":"High","gaps":["Functional role of MAP2 tyrosine phosphorylation by Fyn unknown","Competition with other SH3 partners at the same motif not addressed here"]},{"year":2002,"claim":"The MAP2 knockout mouse proved MAP2 is required in vivo for dendritic PKA anchoring and downstream CREB signaling, as well as for microtubule density and dendrite length, consolidating its dual structural/AKAP function.","evidence":"MAP2 KO mouse with immunofluorescence, PKA-subunit Western blots, and forskolin-induced pCREB assays in cultured neurons","pmids":["12163474"],"confidence":"High","gaps":["Transcriptional targets downstream of reduced CREB signaling not defined","Contribution of AKAP versus structural roles to phenotype not separated"]},{"year":2003,"claim":"Identifying Rho-kinase phosphorylation at Ser1796 with myosin phosphatase as its counteracting phosphatase placed MAP2 in the Rho-kinase/myosin phosphatase axis, and co-IP with the NMDA receptor complex tied MAP2 physically to its activity-dependent regulator.","evidence":"In vitro kinase assay with MS site mapping and MBS interaction, plus co-IP from hippocampal slices with pharmacological dissection of NMDA/calpain/calcium","pmids":["14535960","12834896"],"confidence":"Medium","gaps":["Functional effect of Ser1796 phosphorylation on microtubule binding not measured","Both findings are single-lab"]},{"year":2005,"claim":"Linking amyloid-beta oligomers to calpain-mediated cleavage of all MAP2 isoforms via Ca2+ dysregulation and ROS connected MAP2 destruction to a disease-relevant insult.","evidence":"Abeta treatment of neurons with calpain/caspase inhibitors, antioxidants, and Western blot","pmids":["16234245"],"confidence":"Medium","gaps":["Single-lab pharmacological dissection","In vivo relevance to Alzheimer pathology not established here"]},{"year":2006,"claim":"Identifying MAP2 as the receptor for the neurosteroid pregnenolone, mediating its stimulation of microtubule polymerization and neurite outgrowth, added a ligand-driven mode of MAP2 regulation.","evidence":"Binding and polymerization assays with RNAi knockdown in PC12 cells and neurite measurement","pmids":["16537405"],"confidence":"Medium","gaps":["Pregnenolone-binding site on MAP2 not mapped","Single-lab; physiological neurosteroid concentrations not addressed"]},{"year":2011,"claim":"Single-molecule imaging refined the mRNA-targeting model by showing MAP2 transcripts travel in low-copy RNPs whose composition is dynamically tuned by synaptic activity and Staufen 2.","evidence":"smFISH, live imaging, Staufen 2 knockdown, and synaptic-activity manipulation","pmids":["21869818"],"confidence":"Medium","gaps":["Local translation rate from these RNPs not quantified","Relationship to the protein-intrinsic targeting signal not reconciled"]},{"year":2012,"claim":"Defining PP2A/Balpha as a direct MAP2 phosphatase whose binding site overlaps the Fyn RTPPKSP motif—with Fyn and tau acting as competitors—revealed an integrated competition node coordinating phosphorylation, kinase scaffolding, and phosphatase access; concurrent work identified L1CAM as a direct MAP2c partner regulating expression via MAPK.","evidence":"Co-purification/co-IP from brain with peptide binding and competition assays, plus ELISA, co-IP, L1-knockout Westerns, and neurite outgrowth assays","pmids":["22403409","22503709"],"confidence":"Medium","gaps":["In vivo significance of tau/MAP2 competition for PP2A unresolved","L1CAM-MAP2c structural interface not defined"]},{"year":2020,"claim":"Placing MAP2 in an NCAM2/14-3-3 complex required for microtubule stability and dendritic architecture extended its scaffolding role to a cell-adhesion-linked cytoskeletal module.","evidence":"Co-IP, proteomics, hippocampal-neuron knockdown with morphology, and in vivo cortical migration assay","pmids":["32043120"],"confidence":"Medium","gaps":["Directness of MAP2-NCAM2 binding versus 14-3-3-bridged not resolved","Single-lab"]},{"year":2021,"claim":"Demonstrating that disease-associated Ser1782 hyperphosphorylation reduces microtubule binding and, as a phosphomimetic mouse, shrinks dendrites and spines while suppressing translation linked the MAP2 phospho-code directly to schizophrenia pathophysiology and a new translational-regulation function.","evidence":"Phosphoproteomics, computational modeling, S1782E transgenic mouse, co-IP/MS interactome, and protein-synthesis assays","pmids":["33526823"],"confidence":"High","gaps":["Mechanism by which MAP2 suppresses protein synthesis not defined","Causal kinase for Ser1782 hyperphosphorylation in disease not identified"]},{"year":null,"claim":"The molecular identity of the protein-intrinsic dendritic targeting signal and the machinery that reads it, and how the convergent kinase/phosphatase/ligand inputs are integrated in vivo to time dendritic remodeling, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined sequence/receptor for protein-based dendritic targeting","No integrated quantitative model of competing phospho-inputs in neurons","Mechanism coupling MAP2 to translational control unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,4,23,24,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,10,14,15,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,16,24]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[21]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[25]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,23,24,26]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,29]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,22,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,10,14,15]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,9,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[27,34]}],"complexes":["NMDA receptor complex","L-type Ca2+ channel (class C) complex","NCAM2/14-3-3 complex","PKA holoenzyme (AKAP-anchored)"],"partners":["PRKAR2B","SRC","GRB2","FYN","PPP2R2A","L1CAM","NCAM2","CACNA1C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P11137","full_name":"Microtubule-associated protein 2","aliases":[],"length_aa":1827,"mass_kda":199.5,"function":"The exact function of MAP2 is unknown but MAPs may stabilize the microtubules against depolymerization. They also seem to have a stiffening effect on microtubules","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/P11137/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP2","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":[],"url":"https://opencell.sf.czbiohub.org/search/MAP2","total_profiled":1310},"omim":[{"mim_id":"619435","title":"RITSCHER-SCHINZEL SYNDROME 4; RTSC4","url":"https://www.omim.org/entry/619435"},{"mim_id":"618813","title":"TUBULIN TYROSINE LIGASE-LIKE 7; TTLL7","url":"https://www.omim.org/entry/618813"},{"mim_id":"618646","title":"DIENCEPHALIC-MESENCEPHALIC JUNCTION DYSPLASIA SYNDROME 2; 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many","driving_tissues":[{"tissue":"brain","ntpm":259.5},{"tissue":"retina","ntpm":379.4}],"url":"https://www.proteinatlas.org/search/MAP2"},"hgnc":{"alias_symbol":["MAP2A","MAP2B","MAP2C"],"prev_symbol":[]},"alphafold":{"accession":"P11137","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11137","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11137-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11137-F1-predicted_aligned_error_v6.png","plddt_mean":40.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP2","jax_strain_url":"https://www.jax.org/strain/search?query=MAP2"},"sequence":{"accession":"P11137","fasta_url":"https://rest.uniprot.org/uniprotkb/P11137.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11137/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11137"}},"corpus_meta":[{"pmid":"2842685","id":"PMC_2842685","title":"Insulin-stimulated MAP-2 kinase phosphorylates and activates 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A subcloned fragment spanning the first two repeats copurified with microtubules through two successive cycles of polymerization/depolymerization, while a control polypeptide from the N-terminal region completely failed to copurify.\",\n      \"method\": \"In vitro translation of subcloned fragments followed by microtubule copurification assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with domain deletion, replicated in multiple subsequent studies\",\n      \"pmids\": [\"3142041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"MAP2 is a component of crossbridges between microtubules and neurofilaments in the neuronal cytoskeleton. MAP2 bound isolated neurofilament L protein in vitro, and when tubulin was added and polymerized, neurofilaments were crosslinked with microtubules via MAP2 bridges.\",\n      \"method\": \"Quick-freeze deep-etch immunoelectron microscopy with anti-MAP2 antibody decoration, plus in vitro reconstitution with purified neurofilament L protein and tubulin\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution experiment combined with immunoelectron microscopy in situ, two orthogonal methods\",\n      \"pmids\": [\"3045269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"MAP2 mRNA is selectively localized in dendrites of developing neurons, whereas tubulin mRNA is restricted to neuronal cell bodies, establishing a dendritic targeting signal for MAP2 transcript.\",\n      \"method\": \"In situ hybridization with specific cDNA probes in developing brain tissue\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment replicated across multiple subsequent studies\",\n      \"pmids\": [\"3200318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Expression of MAP2 is necessary for both neurite extension and cessation of cell division during neuronal differentiation; stable transfectants with MAP2 antisense RNA showed reduced MAP2 protein, failed normal morphological differentiation, and failed to withdraw from the cell cycle.\",\n      \"method\": \"Stable antisense RNA transfection in embryonal carcinoma cells with retinoic acid-induced differentiation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with two distinct phenotypic readouts (morphology and cell cycle exit)\",\n      \"pmids\": [\"1997209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Transfection of MAP2c or tau cDNA into fibroblasts stabilizes microtubules against depolymerizing reagents and enriches microtubules in acetylated alpha-tubulin, demonstrating that these MAPs induce post-translational modification of tubulin.\",\n      \"method\": \"cDNA transfection into fibroblasts, drug-resistance assay, immunofluorescence with anti-acetylated tubulin antibody\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assay with two orthogonal readouts, replicated across MAP2, tau, and MAP1B\",\n      \"pmids\": [\"1487506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MAP2 anchors the regulatory subunit II of cAMP-dependent protein kinase (PKA) in dendrites. MAP2-deficient mice show reduced microtubule density and dendritic length, significant reduction of PKA subunits in dendrites and total PKA, and markedly reduced phosphorylated CREB induction after forskolin stimulation.\",\n      \"method\": \"MAP2 knockout mouse analysis: immunofluorescence, Western blot for PKA subunits, pCREB induction assay in cultured neurons\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal mechanistic readouts (microtubule density, PKA localization, signaling output)\",\n      \"pmids\": [\"12163474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"High-molecular-weight MAP2 and low-molecular-weight MAP2c are generated by alternative splicing from a single gene and share the C-terminal tubulin-binding domain and a short N-terminal sequence. MAP2c lacks 1,342 amino acids of the filamentous sidearm domain present in high-MW MAP2, and MAP2c mRNA is not present in dendrites, indicating the dendritic targeting signal is specific to the high-MW isoform.\",\n      \"method\": \"cDNA cloning, sequence comparison, in situ hybridization for mRNA localization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — sequence-level molecular characterization plus direct mRNA localization experiment\",\n      \"pmids\": [\"2770869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"MAP2 is prevented from entering the axon by its N-terminal projection domain. Microtubule binding of MAP2/MAP2C is tighter in the cell body and dendrites than in the axon, a property determined by the microtubule-binding domain and suggested to be regulated by phosphorylation.\",\n      \"method\": \"Transfection of tagged tau, MAP2, MAP2C, and chimeric/deletion mutants into primary cultured neurons\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic deletion and chimeric mutant analysis in primary neurons, multiple constructs\",\n      \"pmids\": [\"7857650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"NMDA receptor activation induces rapid (~70%) dephosphorylation of MAP2 in hippocampal slices, blocked by competitive and noncompetitive NMDA antagonists but not non-NMDA receptor antagonists, suggesting NMDA-stimulated protein phosphatase (possibly calcineurin) dephosphorylates MAP2.\",\n      \"method\": \"32P-orthophosphate labeling of hippocampal slices, pharmacological dissection with receptor antagonists\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct phosphorylation assay with pharmacological dissection in ex vivo tissue\",\n      \"pmids\": [\"2169265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Glutamate produces bidirectional regulation of MAP2 phosphorylation in neurons: a rapid transient increase via metabotropic receptors (attenuated by CaMK and PKC inhibitors) followed by persistent dephosphorylation via NMDA receptor activation of calcineurin (PP2B). The phosphorylation state of MAP2 determines its interaction with microtubules and actin.\",\n      \"method\": \"32P metabolic labeling of neurons, pharmacological dissection with receptor antagonists and kinase/phosphatase inhibitors\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection using multiple pharmacological agents targeting specific kinases, phosphatases, and receptor subtypes\",\n      \"pmids\": [\"8789950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MAP2B (a well-established AKAP) directly binds the alpha1 subunit of class C L-type Ca2+ channels in neurons; this association is independent of microtubules. PKA is an integral part of the immunoisolated class C channel complex, and MAP2B mediates recruitment of PKA to postsynaptic sites.\",\n      \"method\": \"Co-immunoprecipitation from rat brain extracts, protein overlay binding assay with 32P-labeled RIIβ, immunoblotting, in vitro direct binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP combined with direct in vitro binding assay, two orthogonal methods\",\n      \"pmids\": [\"10514522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MARK kinases phosphorylate MAP2c on its microtubule-binding domain in transfected CHO cells, leading to detachment of MAP2c from microtubules and increased microtubule dynamic instability; prolonged MARK2 expression causes microtubule disruption and cell death.\",\n      \"method\": \"Inducible expression of MARK1/MARK2 in transfected CHO cells, immunofluorescence, cell viability assay\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based assay with inducible system and multiple readouts, single lab\",\n      \"pmids\": [\"10542369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GSK3β phosphorylates MAP2C in co-transfected COS-1 cells, and this phosphorylation prevents microtubule bundle formation. Phosphorylated MAP2C species are enriched in cytoskeleton-unbound fractions, indicating that GSK3β-mediated phosphorylation reduces MAP2 binding to microtubules.\",\n      \"method\": \"Co-transfection of MAP2C and GSK3β (wild-type or mutant) in COS-1 cells, immunofluorescence for microtubule bundles, cytoskeletal fractionation, lithium chloride rescue\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-transfection with pharmacological rescue, single lab\",\n      \"pmids\": [\"10826493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PKA activity disrupts the MAP2-microtubule interaction in living HeLa cells and promotes MAP2c localization to peripheral actin-rich membrane ruffles. PKA phosphorylates serines within KXGS motifs in each tubulin-binding repeat; single-site glutamic acid substitution was sufficient to disrupt microtubule binding, and double/triple mutations promoted MAP2c-actin colocalization.\",\n      \"method\": \"Live-cell imaging, detergent extraction assay, site-directed mutagenesis (Glu substitutions), immunofluorescence colocalization in HeLa cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with biochemical fractionation and imaging, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11029056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"All three neuronal MAP2 isoforms bind specifically to the SH3 domains of c-Src and Grb2 via the microtubule-binding domain (not a PXXP motif). Endogenous MAP2-Src and MAP2-Grb2 interactions were confirmed by co-immunoprecipitation from brain lysate. ERK2 phosphorylation of MAP2c inhibits the MAP2-SH3 interaction.\",\n      \"method\": \"GST-SH3 pulldown assay, co-immunoprecipitation from brain lysate, in vitro kinase assay with ERK2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP from brain combined with in vitro pulldown and kinase regulation\",\n      \"pmids\": [\"10781592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MAP2c binds Fyn kinase through the RTPPKSP SH3-binding motif. Fyn phosphorylates MAP2c on tyrosine. ERK2-mediated threonine phosphorylation of the RTPPKSP motif abolishes the MAP2c-Fyn interaction. Co-immunoprecipitation of Fyn and MAP2c from human fetal brain confirmed the in vivo interaction.\",\n      \"method\": \"GST-SH3 pulldown, co-immunoprecipitation from human fetal brain homogenate, ELISA binding assay, co-transfection in COS7 cells with kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP from brain tissue plus in vitro kinase assay and multiple binding assay methods\",\n      \"pmids\": [\"11546790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"cdc2 kinase phosphorylation of MAP2 (>60% of phosphates in the microtubule-binding region) abolishes both microtubule-stabilizing and microtubule-nucleating activities. PKA phosphorylation (~70% in the projection region) reduces only microtubule-nucleating activity, not stabilization. These distinct effects were demonstrated by direct observation of individual microtubules.\",\n      \"method\": \"In vitro phosphorylation by purified PKA or cdc2 kinase, dark-field microscopy observation of individual microtubules, spontaneous polymerization assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro kinase assay with direct single-microtubule visualization, two kinases compared\",\n      \"pmids\": [\"9376363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Rho-kinase phosphorylates MAP2 at Ser1796, and myosin phosphatase (MBS subunit) binds MAP2 and can dephosphorylate it. These were identified as novel substrates of the Rho-kinase/myosin phosphatase pathway.\",\n      \"method\": \"In vitro kinase assay, phosphorylation site mapping by mass spectrometry/sequencing, interaction assay with MBS subunit\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay with site mapping, single lab\",\n      \"pmids\": [\"14535960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PP2A, but not PP2B, regulates MAP2 phosphorylation at multiple sites in rat brain slices; inhibition of PP2A with okadaic acid induced phosphorylation of MAP2 and impaired its microtubule-binding activity, establishing PP2A as the major phosphatase regulating MAP2.\",\n      \"method\": \"Metabolically competent rat brain slices treated with okadaic acid (PP2A inhibitor) or cyclosporin A (PP2B inhibitor), Western blot with phospho-specific antibodies, microtubule-binding assay\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo pharmacological dissection with functional binding assay, single lab\",\n      \"pmids\": [\"10640627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PP2A/Bα directly binds MAP2 and dephosphorylates it. The binding site is within the microtubule-binding domain and upstream proline-rich region of MAP2c, overlapping with the RTPPKSP motif also recognized by Fyn kinase. Fyn inhibits the PP2A/Bα-MAP2 interaction; tau and MAP2 compete for binding to PP2A/Bα.\",\n      \"method\": \"Co-purification from bovine brain, co-immunoprecipitation, in vitro binding assay with peptides, competition assay, immunofluorescence colocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-purification from brain combined with in vitro binding, competition, and colocalization — multiple orthogonal methods\",\n      \"pmids\": [\"22403409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The MAP2-binding and P75-binding domain in the PKA regulatory subunit RIIβ is located within its N-terminal 50 amino acids. Fusion proteins containing RIIβ amino acids 1–50 bound MAP2 and P75 immobilized on nitrocellulose; deletion of residues 1–25 or 25–96 abolished binding.\",\n      \"method\": \"Expression of truncated RIIβ-fusion proteins in E. coli, overlay binding assay on nitrocellulose filters\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic deletion mapping using in vitro binding assay, single lab\",\n      \"pmids\": [\"2254332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAP2 functions as a receptor for the neurosteroid pregnenolone (PREG) and its analog MePREG. PREG and MePREG bind MAP2 and stimulate microtubule polymerization. RNA interference knockdown of MAP2 prevents the stimulatory effects of PREG/MePREG on neurite extension but does not affect progesterone action.\",\n      \"method\": \"Binding assay, microtubule polymerization assay, RNA interference knockdown in PC12 cells, neurite outgrowth measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with pharmacological specificity controls, single lab\",\n      \"pmids\": [\"16537405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"MAP2c-transfected non-neuronal cells form microtubule-containing processes specifically upon actin depolymerization with cytochalasin B. This effect is specific to MAP2c (not taxol-stabilized microtubules), suggesting MAP2c confers stability, bundling, and stiffness on microtubules enabling process outgrowth against cortical actin tension.\",\n      \"method\": \"cDNA transfection into non-neuronal cells, cytochalasin B treatment, video time-lapse microscopy\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging of transfected cells with pharmacological manipulation and specificity controls, single lab\",\n      \"pmids\": [\"8392463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"MAP2C-bundled microtubules in transfected fibroblasts are extremely stable (less than 10% tubulin exchange within 1 hour) but still incorporate exogenously introduced tubulin rapidly at distal ends, demonstrating that MAP2C stabilizes microtubule bundles while preserving plus-end assembly.\",\n      \"method\": \"Microinjection of biotin-labeled tubulin, photoactivation of caged fluorescein-labeled tubulin, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vivo dynamic assay using two complementary tubulin labeling approaches in transfected cells\",\n      \"pmids\": [\"8421058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"MAP2c expression in non-neuronal cells induces MTOC-independent microtubule polymerization and bundling. At higher expression levels, increasing proportions of microtubules form independently of the MTOC; MAP2c imparts both stability and stiffness to microtubules.\",\n      \"method\": \"cDNA transfection in non-neuronal cell lines, immunofluorescence, comparison with taxol and DMSO stabilization\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfection-based functional assay with controls, single lab\",\n      \"pmids\": [\"1338311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"MAP2 (but not MAP2C or tau) binds phosphatidylinositol vesicles with high affinity (Kd ~51 nM), approximately 30-fold higher than MAP2C (~1.4 µM). This high affinity requires two sites: a low-affinity site in the C-terminal domain (shared with MAP2C/tau) and a high-affinity site (~221 nM) within the MAP2-specific projection domain (absent from MAP2C due to alternative splicing).\",\n      \"method\": \"Vesicle binding assay with purified proteins, thrombin digestion of MAP2C to map binding domains\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro binding assay with domain deletion, single lab\",\n      \"pmids\": [\"8025110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"MAP2 binds to both microtubules/tubulin dimers and microfilaments/G-actin in a concentration-dependent manner. Microtubule-bound MAP2 shows diminished ability to bind microfilaments/G-actin, while microfilament-bound MAP2 efficiently binds microtubules and tubulin, suggesting an asymmetric cross-linking interaction.\",\n      \"method\": \"Solid-phase immunoassay on 96-well microtiter plates with purified proteins\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstituted in vitro binding assay, single lab, single method\",\n      \"pmids\": [\"8038171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Soluble amyloid-β oligomers induce proteolysis of MAP2a, MAP2b, and MAP2c through calpain activation (triggered by Ca2+ dysregulation and ROS), which on its own is sufficient to cleave all MAP2 isoforms. Antioxidants prevent MAP2 proteolysis, linking ROS to calpain-mediated MAP2 degradation.\",\n      \"method\": \"In vitro Aβ treatment of neurons, calpain inhibitor experiments, caspase-3 inhibitor experiments, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection in neuronal cultures with multiple inhibitors, single lab\",\n      \"pmids\": [\"16234245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"MAP2 phosphorylation at Ser136, a Ser-Pro motif, occurs in vivo and in vitro specifically by proline-directed kinases (MAP kinase, GSK-3, cdk family members) but not by PKA, PKC, or CaMKII. After microinjection into cell lines, dephosphorylated MAP2 becomes phosphorylated at Ser136; microtubule reorganization by injected MAP2 is independent of Ser136 phosphorylation.\",\n      \"method\": \"In vitro kinase assays, site-directed mutagenesis of Ser136, monoclonal antibody epitope mapping, microinjection into cell lines\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with in vitro kinase specificity assay and in vivo microinjection, multiple methods in one study\",\n      \"pmids\": [\"7525290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"MAP2 is present in dendritic spines and colocalizes with actin at the filamentous compartment of spines, endomembranes of the spine apparatus, smooth endoplasmic reticulum, and postsynaptic density, indicating MAP2 is an actin-associated protein in dendritic spines.\",\n      \"method\": \"Immunogold electron microscopy with double-labeling using anti-MAP2 and anti-actin antibodies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunogold EM double-labeling at subcellular resolution, single lab\",\n      \"pmids\": [\"6572937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A MAP2-associated kinase (embryonic MAP2 kinase, Mr=100,000) co-purified with chicken embryonic MAP2 phosphorylates MAP2 at serine residues and releases MAP2 from microtubules, restoring kinesin- and dynein-driven microtubule motility that is otherwise inhibited by MAP2. This kinase is cAMP-independent and distinct from cdc2 kinase, MAPK, and NIMA kinase in its ability to alter MAP2-microtubule affinity.\",\n      \"method\": \"In vitro motility assay, kinase co-purification, in vitro phosphorylation with multiple kinase comparisons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of motility rescue, comparison of multiple kinases, single lab\",\n      \"pmids\": [\"7759496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MAP2 physically associates with the NMDA receptor complex in hippocampal neurons, demonstrated by co-immunoprecipitation. NMDA receptor activation is a prominent trigger for MAP2 breakdown; calcium influx through the NMDA receptor channel and calcium release from mitochondria trigger MAP2 degradation limited by calpain activity.\",\n      \"method\": \"Co-immunoprecipitation from hippocampal slice lysates, pharmacological dissection with NMDA receptor antagonists, calpain inhibitors, calcium chelators\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP from brain tissue plus pharmacological dissection, single lab\",\n      \"pmids\": [\"12834896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAP2 mRNA localizes to dendrites in distinct RNPs containing very few RNA molecules (low copy number). The number of MAP2 molecules per RNP particle is affected by synaptic activity and Staufen 2, indicating that RNP composition is dynamically regulated.\",\n      \"method\": \"Single-molecule fluorescence in situ hybridization (smFISH), live-cell imaging, Staufen 2 knockdown, synaptic activity manipulation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct single-molecule imaging with genetic perturbation, single lab\",\n      \"pmids\": [\"21869818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"L1CAM (L1) directly binds MAP2c (but not MAP2a/b) through its intracellular domain, as shown by ELISA. L1 upregulates MAP2a/b/c expression in hippocampal neurons via the MAPK pathway. Deficiency in both L1 and MAP2 reduces neurite outgrowth in vitro.\",\n      \"method\": \"ELISA binding assay, co-immunoprecipitation, Western blot from L1-deficient transgenic mice, MAPK pathway inhibition, neurite outgrowth assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay combined with in vivo knockout data and pathway inhibition, single lab\",\n      \"pmids\": [\"22503709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hyperphosphorylation of MAP2 at Ser1782 (pS1782) in schizophrenia reduces MAP2 binding to microtubules, as confirmed by computational modeling and experimental validation. A phosphomimetic S1782E transgenic mouse shows reduced basilar dendritic length, complexity, and spine density. Overexpression of wild-type and phosphomimetic MAP2 reduces protein synthesis in vitro, and the MAP2 interactome is enriched for proteins involved in protein translation.\",\n      \"method\": \"Unbiased phosphoproteomics, computational modeling, phosphomimetic transgenic mouse (S1782E), co-immunoprecipitation/mass spectrometry for interactome, protein synthesis assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis confirmed by transgenic animal plus multiple orthogonal methods (proteomics, modeling, co-IP/MS, synthesis assay)\",\n      \"pmids\": [\"33526823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Juvenile MAP2c and mature MAP2 induce distinct microtubule spacing and process morphologies when expressed in Sf9 cells. MAP2c induces multiple short thin processes with variable, close microtubule spacing; mature MAP2 induces fewer, thicker processes with a proximo-distal taper in microtubule number and wider spacing, demonstrating that MAP2 isoforms serve as architectural elements establishing specific microtubule arrangements.\",\n      \"method\": \"Baculovirus-mediated expression in Sf9 cells, electron microscopy of process cross-sections\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative EM analysis comparing two isoforms in cell-based expression system, single lab\",\n      \"pmids\": [\"8868472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Transgenic MAP2c protein in adult mouse neurons is sorted to dendrites but not axons despite its mRNA being restricted to cell bodies, demonstrating that dendritic targeting of MAP2c depends on a signal in the protein itself, not on mRNA transport.\",\n      \"method\": \"Transgenic mouse overexpression of MAP2c, in situ hybridization for mRNA localization, immunofluorescence for protein localization\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse with complementary mRNA and protein localization data, mechanistically distinguishes protein- vs mRNA-based targeting\",\n      \"pmids\": [\"8627364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"MAP2 binds to the Sau96.1 restriction fragment of mouse satellite DNA containing poly(dA/dT) sequences; DNase protection assay showed MAP2 protects poly(dA)4/poly(dT)4 sequences from digestion.\",\n      \"method\": \"DNA-binding assay, DNase protection experiment with MAP2-DNA complex\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro binding assay, functional significance unclear, single lab\",\n      \"pmids\": [\"10872313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NCAM2 forms a protein complex with MAP2 and 14-3-3γ/ζ in neurons; NCAM2 depletion results in destabilization of the microtubular network and reduced MAP2 signal, establishing MAP2 as part of an NCAM2-dependent cytoskeletal regulatory complex for dendritic architecture.\",\n      \"method\": \"Co-immunoprecipitation, proteomic analysis, knockdown in hippocampal neurons with morphological readout, in vivo cortical migration assay\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP combined with proteomic and functional knockdown data, single lab\",\n      \"pmids\": [\"32043120\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP2 is a dendrite-enriched microtubule-associated protein whose C-terminal tandem-repeat domain directly binds and stabilizes microtubules (and cross-links them to neurofilaments and actin), whose N-terminal projection domain suppresses axonal entry and sets inter-microtubule spacing, and whose phosphorylation state—regulated bidirectionally by kinases (PKA, MARK, cdc2, MAPK, Rho-kinase, Fyn, GSK3β) and phosphatases (PP2A/Bα, calcineurin) downstream of NMDA and metabotropic glutamate receptors—controls its affinity for microtubules versus actin and its function as an A-kinase anchoring protein (AKAP) that recruits PKA to dendrites to sustain CREB-mediated signaling; additionally, MAP2 acts as a signaling scaffold by binding Src and Grb2 SH3 domains in a phosphorylation-regulated manner, serves as a receptor for the neurosteroid pregnenolone to promote microtubule polymerization and neurite outgrowth, and dendritic protein targeting relies on a signal within the MAP2 protein itself rather than on mRNA transport.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP2 is a dendrite-enriched microtubule-associated protein that builds and stabilizes the dendritic cytoskeleton and serves as a phosphorylation-gated signaling scaffold during neuronal differentiation [#3, #5]. Its C-terminal domain, comprising three imperfect 18-amino-acid repeats, constitutes the microtubule-binding region that copurifies with microtubules through repeated polymerization cycles, nucleates and stabilizes microtubules, and promotes their acetylation while preserving plus-end assembly [#0, #4, #23]. Through this domain MAP2 also cross-links microtubules to neurofilaments and binds G-actin/microfilaments, with microtubule-bound MAP2 showing reduced affinity for actin, and it imparts the stiffness and bundling that drive process outgrowth against cortical actin tension [#1, #26, #22]. The MAP2-specific N-terminal projection domain sets inter-microtubule spacing and process architecture across isoforms generated by alternative splicing, and prevents axonal entry by conferring tighter microtubule binding in the cell body and dendrites [#35, #6, #7]; dendritic localization depends both on a protein-intrinsic targeting signal and on selective dendritic transport of high-molecular-weight MAP2 mRNA in low-copy RNPs [#36, #2, #32]. MAP2 function is governed bidirectionally by phosphorylation: proline-directed and serine/threonine kinases (cdc2, GSK3\\u03b2, MARK, ERK/MAPK, PKA, Rho-kinase) detach it from microtubules or shift it toward actin, while phosphatases PP2A and calcineurin (PP2B), acting downstream of metabotropic and NMDA glutamate receptors, restore microtubule binding [#16, #11, #12, #13, #9, #8, #18, #19]. Beyond a structural role, MAP2 acts as an A-kinase anchoring protein that recruits PKA via the RII regulatory subunit to dendrites and L-type Ca2+ channels to sustain CREB signaling, binds the SH3 domains of Src, Grb2 and Fyn in a phosphorylation-regulated manner, and functions as a receptor for the neurosteroid pregnenolone to stimulate microtubule polymerization and neurite outgrowth [#5, #10, #20, #14, #15, #21]. Hyperphosphorylation at Ser1782 in schizophrenia reduces microtubule binding and, in a phosphomimetic mouse, shrinks dendritic complexity and spine density while suppressing protein synthesis [#34].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Localizing the microtubule-binding activity to a defined region answered which part of the large MAP2 molecule physically engages tubulin, and showed MAP2 simultaneously bridges microtubules to neurofilaments.\",\n      \"evidence\": \"In vitro translation of subcloned fragments with microtubule copurification, plus immunoelectron microscopy and reconstitution with purified neurofilament L and tubulin\",\n      \"pmids\": [\"3142041\", \"3045269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Repeat-level stoichiometry of microtubule binding not resolved\", \"Whether the same repeats mediate neurofilament cross-bridging untested\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstrating that MAP2 mRNA is selectively dendritic while tubulin mRNA stays in the soma established subcellular mRNA targeting as a candidate mechanism for MAP2 compartmentalization.\",\n      \"evidence\": \"In situ hybridization with specific cDNA probes in developing brain\",\n      \"pmids\": [\"3200318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"cis-element directing dendritic mRNA transport not mapped\", \"Whether mRNA targeting is necessary for protein localization unresolved at this stage\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Resolving that high-MW MAP2 and MAP2c arise by alternative splicing from one gene clarified that the dendritic mRNA targeting signal is isoform-specific to the high-MW form.\",\n      \"evidence\": \"cDNA cloning, sequence comparison, and isoform-specific in situ hybridization\",\n      \"pmids\": [\"2770869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the 1342-residue sidearm in vivo not directly tested here\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Loss-of-function showed MAP2 is required for neurite extension and cell-cycle exit, moving it from a structural marker to a driver of differentiation; concurrent gain-of-function showed MAPs directly stabilize microtubules and promote tubulin acetylation.\",\n      \"evidence\": \"Antisense RNA in differentiating embryonal carcinoma cells, and MAP2c/tau cDNA transfection into fibroblasts with drug-resistance and acetylated-tubulin readouts\",\n      \"pmids\": [\"1997209\", \"1487506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between microtubule stabilization and cell-cycle withdrawal unestablished\", \"Whether acetylation is cause or consequence of stabilization unresolved\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Heterologous expression established MAP2c as sufficient to nucleate MTOC-independent, stiff, stable, bundled microtubules and to build processes against cortical actin, defining its architectural function.\",\n      \"evidence\": \"cDNA transfection in non-neuronal cells with EM, cytochalasin B treatment, time-lapse imaging, and tubulin exchange/photoactivation assays\",\n      \"pmids\": [\"1338311\", \"8392463\", \"8421058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of MTOC-independent nucleation not defined\", \"How bundling tension translates to neurite initiation in neurons untested\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Demonstrating NMDA-receptor-driven rapid MAP2 dephosphorylation tied cytoskeletal regulation to glutamatergic synaptic activity via a calcineurin-like phosphatase.\",\n      \"evidence\": \"32P labeling of hippocampal slices with NMDA-receptor antagonist dissection\",\n      \"pmids\": [\"2169265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase identity inferred pharmacologically, not biochemically confirmed here\", \"Phosphosites not mapped\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Reconstitution and site mapping established that MAP2 binds both microtubules and actin in mutually constraining fashion, and that proline-directed kinases phosphorylate a defined Ser-Pro site, beginning the phospho-code for MAP2 binding.\",\n      \"evidence\": \"Solid-phase binding assays with purified microtubules/actin, phosphatidylinositol vesicle binding, and Ser136 mutagenesis with kinase-specificity assays and microinjection\",\n      \"pmids\": [\"8038171\", \"8025110\", \"7525290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional relevance of Ser136 phosphorylation unclear (microtubule reorganization was independent of it)\", \"Physiological role of MAP2 phosphatidylinositol binding untested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Domain-swap analysis showed the N-terminal projection domain excludes MAP2 from the axon and the microtubule-binding domain confers compartment-specific affinity, explaining dendritic enrichment at the protein level.\",\n      \"evidence\": \"Transfection of tagged tau/MAP2/MAP2C and chimeric/deletion mutants into primary neurons\",\n      \"pmids\": [\"7857650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The proposed phosphorylation control of compartmental binding not directly demonstrated here\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Transgenic sorting of MAP2c protein to dendrites despite somatic mRNA proved a protein-intrinsic dendritic targeting signal independent of mRNA transport; isoform comparison showed MAP2 isoforms dictate distinct microtubule spacing and process geometry.\",\n      \"evidence\": \"Transgenic mouse overexpression with mRNA/protein localization, and baculovirus isoform expression in Sf9 cells with EM cross-sections\",\n      \"pmids\": [\"8627364\", \"8868472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence of the protein targeting signal not identified\", \"Receptor/machinery reading the targeting signal unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Comparing PKA versus cdc2 phosphorylation in vitro separated MAP2's two activities—cdc2 (microtubule-binding domain) abolishes both stabilization and nucleation, PKA (projection region) reduces only nucleation—and a co-purified MAP2 kinase was shown to release MAP2 and restore motor-driven motility.\",\n      \"evidence\": \"In vitro kinase reactions with purified PKA/cdc2 and dark-field single-microtubule observation, plus in vitro motility rescue with a co-purified MAP2 kinase\",\n      \"pmids\": [\"9376363\", \"7759496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the co-purified embryonic MAP2 kinase not established\", \"In vivo relevance of each phosphosite-specific effect untested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying MAP2c as a MARK substrate whose microtubule-binding-domain phosphorylation detaches it from microtubules linked a specific kinase to MAP2 dynamic regulation.\",\n      \"evidence\": \"Inducible MARK1/2 expression in CHO cells with immunofluorescence and viability assays\",\n      \"pmids\": [\"10542369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab cell-line system; neuronal relevance not shown\", \"Direct in vitro phosphorylation site not mapped here\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showing MAP2B directly binds the L-type Ca2+ channel alpha1 subunit and brings PKA into the channel complex extended MAP2's AKAP role to postsynaptic signaling microdomains.\",\n      \"evidence\": \"Reciprocal co-IP from brain, RIIbeta overlay binding, and in vitro direct binding\",\n      \"pmids\": [\"10514522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional effect of channel-anchored PKA on channel gating not measured\", \"Microtubule-independent localization mechanism unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"PKA phosphorylation of KXGS-motif serines was shown to be sufficient to release MAP2c from microtubules and redirect it to actin-rich ruffles, mechanistically coupling the phospho-code to a microtubule-versus-actin switch.\",\n      \"evidence\": \"Live-cell imaging, detergent extraction, and Glu-substitution mutagenesis in HeLa cells\",\n      \"pmids\": [\"11029056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous neuronal stimulus driving this switch not identified here\", \"Actin-binding interface not mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"MAP2 was established as a multi-kinase signaling scaffold by demonstrating direct SH3-domain binding to c-Src and Grb2 via the microtubule-binding domain, with ERK2 phosphorylation disrupting the interaction; GSK3beta phosphorylation was shown to reduce microtubule binding, and PP2A identified as the major MAP2 phosphatase.\",\n      \"evidence\": \"GST-SH3 pulldowns and brain co-IP, GSK3beta co-transfection with fractionation, and okadaic-acid/cyclosporin dissection in brain slices\",\n      \"pmids\": [\"10781592\", \"10826493\", \"10640627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream consequence of Src/Grb2 scaffolding on signaling output untested\", \"GSK3beta and PP2A studies are single-lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapping a discrete RTPPKSP SH3-binding motif for Fyn, with ERK2 threonine phosphorylation abolishing binding, defined a phosphorylation switch governing MAP2's recruitment of a tyrosine kinase that in turn phosphorylates MAP2.\",\n      \"evidence\": \"GST-SH3 pulldown, co-IP from human fetal brain, ELISA, and co-transfection kinase assays\",\n      \"pmids\": [\"11546790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of MAP2 tyrosine phosphorylation by Fyn unknown\", \"Competition with other SH3 partners at the same motif not addressed here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The MAP2 knockout mouse proved MAP2 is required in vivo for dendritic PKA anchoring and downstream CREB signaling, as well as for microtubule density and dendrite length, consolidating its dual structural/AKAP function.\",\n      \"evidence\": \"MAP2 KO mouse with immunofluorescence, PKA-subunit Western blots, and forskolin-induced pCREB assays in cultured neurons\",\n      \"pmids\": [\"12163474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets downstream of reduced CREB signaling not defined\", \"Contribution of AKAP versus structural roles to phenotype not separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying Rho-kinase phosphorylation at Ser1796 with myosin phosphatase as its counteracting phosphatase placed MAP2 in the Rho-kinase/myosin phosphatase axis, and co-IP with the NMDA receptor complex tied MAP2 physically to its activity-dependent regulator.\",\n      \"evidence\": \"In vitro kinase assay with MS site mapping and MBS interaction, plus co-IP from hippocampal slices with pharmacological dissection of NMDA/calpain/calcium\",\n      \"pmids\": [\"14535960\", \"12834896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect of Ser1796 phosphorylation on microtubule binding not measured\", \"Both findings are single-lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking amyloid-beta oligomers to calpain-mediated cleavage of all MAP2 isoforms via Ca2+ dysregulation and ROS connected MAP2 destruction to a disease-relevant insult.\",\n      \"evidence\": \"Abeta treatment of neurons with calpain/caspase inhibitors, antioxidants, and Western blot\",\n      \"pmids\": [\"16234245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pharmacological dissection\", \"In vivo relevance to Alzheimer pathology not established here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying MAP2 as the receptor for the neurosteroid pregnenolone, mediating its stimulation of microtubule polymerization and neurite outgrowth, added a ligand-driven mode of MAP2 regulation.\",\n      \"evidence\": \"Binding and polymerization assays with RNAi knockdown in PC12 cells and neurite measurement\",\n      \"pmids\": [\"16537405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pregnenolone-binding site on MAP2 not mapped\", \"Single-lab; physiological neurosteroid concentrations not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Single-molecule imaging refined the mRNA-targeting model by showing MAP2 transcripts travel in low-copy RNPs whose composition is dynamically tuned by synaptic activity and Staufen 2.\",\n      \"evidence\": \"smFISH, live imaging, Staufen 2 knockdown, and synaptic-activity manipulation\",\n      \"pmids\": [\"21869818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Local translation rate from these RNPs not quantified\", \"Relationship to the protein-intrinsic targeting signal not reconciled\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining PP2A/Balpha as a direct MAP2 phosphatase whose binding site overlaps the Fyn RTPPKSP motif—with Fyn and tau acting as competitors—revealed an integrated competition node coordinating phosphorylation, kinase scaffolding, and phosphatase access; concurrent work identified L1CAM as a direct MAP2c partner regulating expression via MAPK.\",\n      \"evidence\": \"Co-purification/co-IP from brain with peptide binding and competition assays, plus ELISA, co-IP, L1-knockout Westerns, and neurite outgrowth assays\",\n      \"pmids\": [\"22403409\", \"22503709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo significance of tau/MAP2 competition for PP2A unresolved\", \"L1CAM-MAP2c structural interface not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placing MAP2 in an NCAM2/14-3-3 complex required for microtubule stability and dendritic architecture extended its scaffolding role to a cell-adhesion-linked cytoskeletal module.\",\n      \"evidence\": \"Co-IP, proteomics, hippocampal-neuron knockdown with morphology, and in vivo cortical migration assay\",\n      \"pmids\": [\"32043120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of MAP2-NCAM2 binding versus 14-3-3-bridged not resolved\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that disease-associated Ser1782 hyperphosphorylation reduces microtubule binding and, as a phosphomimetic mouse, shrinks dendrites and spines while suppressing translation linked the MAP2 phospho-code directly to schizophrenia pathophysiology and a new translational-regulation function.\",\n      \"evidence\": \"Phosphoproteomics, computational modeling, S1782E transgenic mouse, co-IP/MS interactome, and protein-synthesis assays\",\n      \"pmids\": [\"33526823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MAP2 suppresses protein synthesis not defined\", \"Causal kinase for Ser1782 hyperphosphorylation in disease not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the protein-intrinsic dendritic targeting signal and the machinery that reads it, and how the convergent kinase/phosphatase/ligand inputs are integrated in vivo to time dendritic remodeling, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined sequence/receptor for protein-based dendritic targeting\", \"No integrated quantitative model of competing phospho-inputs in neurons\", \"Mechanism coupling MAP2 to translational control unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 4, 23, 24, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 10, 14, 15, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 16, 24]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 23, 24, 26]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 29]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 22, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 10, 14, 15]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 9, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [27, 34]}\n    ],\n    \"complexes\": [\n      \"NMDA receptor complex\",\n      \"L-type Ca2+ channel (class C) complex\",\n      \"NCAM2/14-3-3 complex\",\n      \"PKA holoenzyme (AKAP-anchored)\"\n    ],\n    \"partners\": [\n      \"PRKAR2B\",\n      \"SRC\",\n      \"GRB2\",\n      \"FYN\",\n      \"PPP2R2A\",\n      \"L1CAM\",\n      \"NCAM2\",\n      \"CACNA1C\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}