{"gene":"CD2AP","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2001,"finding":"CD2AP localizes to the slit diaphragm in podocytes and interacts with nephrin via a novel C-terminal domain of CD2AP that binds the C-terminal portion of the nephrin cytoplasmic domain, as demonstrated by immunoelectron microscopy and co-immunoprecipitation from podocyte cell lines.","method":"Immunoelectron microscopy, co-immunoprecipitation, domain mapping","journal":"The American Journal of Pathology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping, localization confirmed by immunoelectron microscopy, replicated across multiple labs","pmids":["11733379"],"is_preprint":false},{"year":2001,"finding":"Podocin associates with CD2AP via its C-terminal domain and with nephrin, forming a ternary complex in lipid rafts at the slit diaphragm; direct interaction between podocin and CD2AP was confirmed in vitro by GST pull-down and co-immunoprecipitation from glomerular extracts.","method":"GST pull-down, co-immunoprecipitation, immunoelectron microscopy","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro GST pull-down plus reciprocal Co-IP from native tissue, replicated independently","pmids":["11733557"],"is_preprint":false},{"year":2006,"finding":"CD2AP associates with Fyn and synaptopodin in podocytes; bigenic heterozygosity of Cd2ap with either Synpo or Fyn (but not Neph1) leads to spontaneous proteinuria and FSGS-like glomerular damage, establishing a genetic and physical interaction network.","method":"Co-immunoprecipitation, bigenic mouse models, epistasis analysis","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP combined with rigorous in vivo genetic epistasis in multiple bigenic mouse models","pmids":["16628251"],"is_preprint":false},{"year":2004,"finding":"CD2AP forms a ternary complex with c-Cbl and activated Flt-1 (VEGFR-1) upon VEGF stimulation, and wild-type CD2AP (but not a dominant-negative form) enhances VEGF-stimulated internalization and ubiquitination of Flt-1, promoting receptor endocytosis and degradation.","method":"Co-immunoprecipitation, dominant-negative overexpression, internalization assay, ubiquitination assay","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, dominant-negative, functional internalization, ubiquitination assays) in a single study","pmids":["15001553"],"is_preprint":false},{"year":2007,"finding":"Dendrin directly binds to both nephrin and CD2AP at the slit diaphragm; upon glomerular injury or high-dose TGF-β1 stimulation, dendrin relocates from the slit diaphragm to the nucleus where it enhances apoptosis.","method":"Co-immunoprecipitation, immunofluorescence, nuclear import assay, apoptosis assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated by Co-IP, functional consequence (nuclear translocation and apoptosis) validated by multiple methods","pmids":["17537921"],"is_preprint":false},{"year":2009,"finding":"CD2AP C-terminal region directly interacts with the cytoplasmic tail of TGF-β receptor type I (TβRI) in a kinase-dependent manner, and CD2AP is required for the interaction between TβRI and the p85 subunit of PI3K, thereby activating the antiapoptotic PI3K/AKT pathway independently of Smad2/3 signaling.","method":"Co-immunoprecipitation, CD2AP-deficient cell lines, genetic mouse models","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — direct interaction mapped by Co-IP, confirmed by in vivo genetic models with defined phenotypic readouts","pmids":["19679673"],"is_preprint":false},{"year":2011,"finding":"CD2AP regulates TGF-β1-dependent translocation of dendrin from the slit diaphragm to the nucleus, where dendrin acts as a transcription factor inducing cytosolic cathepsin L (CatL) expression; CatL then proteolyzed dynamin and synaptopodin, reorganizing the podocyte microfilament system. CD2AP itself is proteolyzed by CatL in a feedback loop promoting sustained CatL expression and podocyte apoptosis.","method":"Loss-of-function mouse models, nuclear fractionation, in vitro proteolysis assays, cell biological assays","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — defined molecular pathway with multiple orthogonal methods including in vitro proteolysis, nuclear fractionation, and genetic mouse models","pmids":["21911934"],"is_preprint":false},{"year":2012,"finding":"CD2AP forms a complex with SHIP1, and upon BDCA2 cross-linking in plasmacytoid dendritic cells, this CD2AP/SHIP1 complex associates with the E3 ubiquitin ligase Cbl at the plasma membrane and inhibits its E3 ubiquitin ligase activity, thereby preventing degradation of Syk and FcεRIγ and sustaining ITAM signaling.","method":"Immunoprecipitation/mass spectrometry, knockdown (siRNA), ubiquitination assay, immunofluorescence","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — MS-confirmed interaction, functional ubiquitination assay, siRNA knockdown with defined signaling readout","pmids":["22706086"],"is_preprint":false},{"year":2012,"finding":"Septin 7 forms a complex with CD2AP and nephrin in podocytes; depletion of septin 7 increases VAMP2-nephrin interaction and glucose uptake, indicating that the septin 7/CD2AP/nephrin complex regulates GLUT4 storage vesicle trafficking.","method":"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, 2-deoxy-D-glucose uptake assay","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, fractionation, and functional glucose uptake assay with multiple orthogonal approaches","pmids":["22809625"],"is_preprint":false},{"year":2013,"finding":"CD2AP (FSGS3) functions as a barbed-end actin-capping protein at the adherens junction; knockdown of CD2AP compromises actin stability and accumulation at the adherens junction, reducing adhesive strength and disrupting barrier function.","method":"In vitro reconstitution biochemistry, cross-linking approach, siRNA knockdown, mechanical stress assay","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of capping activity combined with functional cellular assays","pmids":["24322428"],"is_preprint":false},{"year":2005,"finding":"In podocytes, CD2AP colocalizes with cortactin and F-actin on motile vesicular spots; FRAP shows high turnover of CD2AP (half-time <10 s) at these spots, which depend on actin polymerization and are associated with a late endosomal-sorting compartment (Rab4-positive), implicating CD2AP in endosomal sorting/trafficking via actin assembly regulation.","method":"Confocal time-lapse microscopy, FRAP, microinjection of fluorescent G-actin, endosomal marker co-localization","journal":"American Journal of Physiology – Renal Physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple live-imaging methods with functional pharmacological validation (jasplakinolide) and FRAP","pmids":["15956777"],"is_preprint":false},{"year":2007,"finding":"CD2AP deficiency in podocytes leads to diminished signal initiation and termination via receptor tyrosine kinases (RTKs); CIN85 expression is increased in CD2AP-/- podocytes, and repression of CIN85 restores RTK signaling (PI3K/AKT and ERK), establishing the CD2AP/CIN85 balance as a determinant of RTK signaling in podocytes.","method":"CD2AP-/- mouse and cell models, growth factor stimulation, siRNA knockdown of CIN85, signaling pathway assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout models combined with siRNA rescue experiments and defined signaling readouts","pmids":["17213204"],"is_preprint":false},{"year":2014,"finding":"CD2AP enhances Cbl-3/c-mediated ubiquitination and degradation of Ret51 (but not Ret9) isoform specifically; the SH3 domains of CD2AP are sufficient for this activity, while the coiled-coil C-terminal domain is dispensable; Ret51 ubiquitination requires functional ring finger and TKB domains in Cbl-3/c.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, domain deletion/mutagenesis, site-directed mutagenesis of ubiquitination sites","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — domain mutagenesis combined with functional ubiquitination assays and siRNA knockdown","pmids":["24425877"],"is_preprint":false},{"year":2015,"finding":"CD2AP forms a complex with GGA2 (a clathrin adaptor that sorts Glut4 to storage vesicles), connects clathrin to actin in the perinuclear region, and is required for clathrin recycling back to trans-Golgi membranes; CD2AP-/- podocytes fail to increase glucose uptake in response to insulin and show perinuclear clustering of Glut4.","method":"Co-immunoprecipitation, live-cell imaging, subcellular fractionation, 2-deoxy-D-glucose uptake assay, CD2AP-/- podocytes","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking CD2AP to Glut4 trafficking with defined functional consequence","pmids":["26546360"],"is_preprint":false},{"year":2016,"finding":"CD2AP forms a complex with tankyrases; in the absence of CD2AP, tankyrase-mediated PARylation and Wnt/β-catenin signaling (LEF1, fibronectin) are increased in podocytes, identifying CD2AP as a regulator of the Wnt/β-catenin pathway through control of tankyrase PARylation activity.","method":"Co-immunoprecipitation, CD2AP-/- podocytes, tankyrase inhibitor, zebrafish model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and genetic knockout with signaling readouts, but single lab study","pmids":["27441654"],"is_preprint":false},{"year":2017,"finding":"CD2AP in endothelial cells binds directly to the receptor ICAM-1 and is required for ICAM-1-mediated PI3K activation, F-actin and cortactin recruitment, and Rac1 activation; loss of CD2AP increases ICAM-1 clustering, neutrophil adhesion, and promotes transcellular over paracellular diapedesis.","method":"Co-immunoprecipitation, siRNA knockdown, force application on ICAM-1, Rac1 activation assay, neutrophil adhesion/transmigration assay","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — direct binding shown by Co-IP, multiple signaling and functional readouts, mechanosensing validated with force application","pmids":["28484055"],"is_preprint":false},{"year":2016,"finding":"CD2AP forms a complex with TrkA and the PI3K regulatory subunit p85 in neurons; CD2AP levels positively regulate TrkA:p85 association and NGF signaling through AKT (but not ERK), and regulate long-range signaling through TrkA+/RAB5+ signaling endosomes, controlling axon arbor growth and collateral sprouting.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, neurite outgrowth assay, signaling assays","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — novel complex identified by Co-IP, confirmed by functional in vitro and in vivo assays with multiple orthogonal methods","pmids":["27076424"],"is_preprint":false},{"year":2019,"finding":"In Drosophila, loss of cindr (CD2AP ortholog) impairs synapse maturation, synaptic vesicle recycling and release; Cindr associates with and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and PMCA; loss of cindr elevates PMCA and reduces cytosolic calcium. Cd2ap null mice show conserved synaptic proteostasis defects, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains.","method":"Genetic loss-of-function (Drosophila mutants, Cd2ap null mice), co-immunoprecipitation, electrophysiology, proteomics, calcium measurements","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across three model systems (Drosophila, mouse, human tissue) with defined mechanistic readouts","pmids":["31412248"],"is_preprint":false},{"year":2019,"finding":"VEGF-A stimulation induces tyrosine phosphorylation of CD2AP in podocytes; phosphorylation at Y10 in the SH3-1 domain is indispensable for CD2AP function in vivo (shown by cross-species rescue in zebrafish and Drosophila). Absence of Y10 phosphorylation enhances nephrin binding affinity to CD2AP but paradoxically impairs glomerular filtration barrier function.","method":"Isoelectric focusing, site-directed mutagenesis, phospho-specific antibodies, cross-species rescue (zebrafish, Drosophila), western blot","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 1-2 — site-directed mutagenesis with in vivo rescue across two model organisms","pmids":["31235616"],"is_preprint":false},{"year":2011,"finding":"NMR structural characterization of all three SH3 domains of CD2AP reveals that the N-terminal SH3 domain (SH3-A) is the most stable SH3 domain characterized, due to a more extensive intramolecular interaction network; the high stability is proposed to be crucial for maintaining proper conformation for target interaction.","method":"NMR spectroscopy, differential scanning calorimetry (DSC), FoldX structure-based analysis","journal":"Journal of Biomolecular NMR","confidence":"Medium","confidence_rationale":"Tier 1 — NMR structure, but functional validation of stability significance is computational/indirect","pmids":["21519904"],"is_preprint":false},{"year":2007,"finding":"NMR high-resolution structure of the CD2AP SH3-C domain was determined, revealing all canonical SH3 features including the polyproline-binding site.","method":"NMR spectroscopy, triple-resonance experiments, NOESY","journal":"Journal of Biomolecular NMR","confidence":"Medium","confidence_rationale":"Tier 1 — high-resolution NMR structure, but limited direct functional validation beyond binding site identification","pmids":["17922258"],"is_preprint":false},{"year":2013,"finding":"NMR, ITC, and SAXS characterization shows that CD2AP SH3-A forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b, revealing multimeric and differential binding modes that generate signaling diversity.","method":"NMR spectroscopy, isothermal titration calorimetry (ITC), small-angle X-ray scattering (SAXS)","journal":"The FEBS Journal","confidence":"High","confidence_rationale":"Tier 1 — three orthogonal biophysical methods characterizing binding modes at atomic resolution","pmids":["23663663"],"is_preprint":false},{"year":2018,"finding":"PAWS1 interacts dynamically with CD2AP at lamellae; CRISPR/Cas9 knockout of CD2AP in U2OS cells causes defects in F-actin organization, lamellipodial organization, and impairs cell migration, phenocopying PAWS1-knockout cells.","method":"CRISPR/Cas9 knockout, co-immunoprecipitation, confocal microscopy, live-cell imaging, migration assay","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR knockout with defined actin and migration phenotype, Co-IP interaction, single lab","pmids":["29175910"],"is_preprint":false},{"year":2008,"finding":"Cindr (Drosophila CD2AP ortholog) links E-cadherin and Roughest (IgCAM adhesion receptor) to actin-capping proteins (capping protein alpha and beta); reducing cindr activity disrupts normal localization of E-cadherin and Roughest and causes defects in local cell movement and tissue patterning.","method":"Genetic loss-of-function (Drosophila), co-immunoprecipitation, immunofluorescence, co-localization","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis combined with physical interactions and localization studies in Drosophila, ortholog context consistent with mammalian CD2AP","pmids":["18362180"],"is_preprint":false},{"year":2010,"finding":"CD2AP is recruited to EPEC actin pedestals in a manner dependent on Tir Y474 phosphorylation, and CD2AP functions as a novel component of EPEC pedestal formation; CD2AP co-localizes with the endocytic machinery (clathrin) in pedestals.","method":"Immunofluorescence, genetic knockout/knockdown, pedestal formation assay","journal":"Infection and Immunity","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with defined genetic requirements, but mechanistic depth limited to localization and loss-of-function","pmids":["20515931"],"is_preprint":false},{"year":2006,"finding":"CFBP (CIN85/CD2AP family binding protein) is phosphorylated at tyrosine 204 upon EGF stimulation; its proline-rich motif is recognized by one of the three SH3 domains of CD2AP, with binding affinity regulated by tyrosine phosphorylation; CFBP accelerates EGF receptor down-regulation by facilitating Cbl recruitment to the CD2AP/CIN85 complex.","method":"Proteomic phosphorylation screen, co-immunoprecipitation, EGF receptor internalization assay, overexpression","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and functional receptor degradation assay, single lab","pmids":["16895919"],"is_preprint":false},{"year":2015,"finding":"CD2AP loss maintains blood-brain barrier integrity; CD2AP-deficient mice (with kidney-specific CD2AP transgene) show reduced blood-brain barrier integrity measured by sodium fluorescein extravasation, independent of nephrotic syndrome.","method":"CD2AP-/- mouse model with kidney-specific rescue transgene, sodium fluorescein extravasation assay, seizure latency measurement","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with defined physiological readout, dissociation from systemic illness confirmed by control experiment","pmids":["26358779"],"is_preprint":false},{"year":2018,"finding":"In chronic LCMV infection, CD2AP in CD4 T cells suppresses follicular helper (Tfh) differentiation; CD2AP-deficient CD4 T cells show extended TCR signaling duration and enhanced cytokine production specifically under TH1 conditions, promoting Tfh differentiation and germinal center responses. CIN85 shows non-overlapping/antagonistic roles.","method":"T cell-specific conditional knockout, LCMV infection model, TCR signaling assays, Tfh differentiation assays","journal":"PLOS Pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — conditional knockout with defined signaling and differentiation phenotypes, single lab","pmids":["29734372"],"is_preprint":false},{"year":2005,"finding":"CD2AP co-localizes with F-actin in the leading edges of migrating gastric epithelial cells and co-immunoprecipitates with E-cadherin upon HGF stimulation; intracellular injection of anti-CD2AP antibody significantly retards cell migration speed.","method":"Co-immunoprecipitation, immunofluorescence, intracellular antibody injection, migration assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional migration assay by antibody injection combined with Co-IP, single lab","pmids":["15910750"],"is_preprint":false},{"year":2008,"finding":"EGF recruits c-fos and JunD (AP-1 components) to an AP-1-like element in the CD2AP gene promoter, increasing CD2AP expression and suppressing angiotensin II-induced apoptosis in renal tubular epithelial cells; CD2AP knockdown attenuates the antiapoptotic effect of EGF.","method":"Promoter deletion/mutation analysis, EMSA, chromatin immunoprecipitation, siRNA knockdown, apoptosis assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and EMSA with functional apoptosis readout, single lab","pmids":["19095050"],"is_preprint":false},{"year":2024,"finding":"CD2AP deficiency in neurons activates p38 MAPK signaling, leading to increased tau phosphorylation, synaptic injury, neuronal apoptosis, and cognitive impairment in APP/PS1 mice; pharmacological inhibition of p38 MAPK ameliorates these phenotypes.","method":"Neuron-specific Cd2ap conditional knockout in APP/PS1 mice, immunoblotting, immunofluorescence, electrophysiology, behavioral tests, p38 inhibitor treatment","journal":"Translational Neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout in disease model with pharmacological rescue, multiple orthogonal readouts","pmids":["39696695"],"is_preprint":false},{"year":2024,"finding":"CD2AP interacts with TRIM5 and its overexpression increases TRIM5 levels and NF-κB activity in glioblastoma cells; CD2AP promotes GBM cell proliferation, migration, invasion, and resistance to apoptosis through the TRIM5-NF-κB axis.","method":"Co-immunoprecipitation, overexpression/knockdown, NF-κB activity assay, in vitro proliferation/invasion/apoptosis assays, in vivo tumorigenesis","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional rescue experiments, single lab, cancer context","pmids":["39353894"],"is_preprint":false},{"year":2003,"finding":"CD2AP (CMS) binds the same highly conserved segment of the CD2 cytoplasmic tail as CIN85/CD2BP3 via its SH3 domains; unlike CIN85/CD2BP3, CD2AP co-localizes with F-actin and binds p130Cas; CD2AP and CIN85 activities are antagonistic in T cell adhesion and polarization.","method":"Interaction trap cloning, co-localization studies, protein interaction assays, T cell functional assays","journal":"International Immunology","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid and co-localization, functional antagonism demonstrated but mechanism not fully delineated","pmids":["12618476"],"is_preprint":false},{"year":2019,"finding":"CD2AP interacts with CHIKV nsP3 HVD via its SH3-A and SH3-C domains simultaneously (bivalent interaction), as determined by NMR; this increases binding affinity through cooperativity and leaves SH3-B available for other partners; BIN1, CD2AP, and SH3KBP1 play redundant roles in initiation of CHIKV replication.","method":"NMR spectroscopy, chemical shift perturbation, mutagenesis, viral replication assays","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1 — NMR structural characterization of binding mechanism with mutational validation and functional viral replication assays","pmids":["31493651"],"is_preprint":false}],"current_model":"CD2AP is a multi-SH3 domain scaffolding/adaptor protein that organizes multiprotein complexes at membrane-cytoskeleton interfaces: in podocytes it links nephrin, podocin, and the actin cytoskeleton at the slit diaphragm, gates TGF-β1 signaling by controlling dendrin nuclear translocation and cathepsin L expression, and supports PI3K/AKT survival signaling through direct interaction with TβRI; it also functions as a barbed-end actin-capping protein stabilizing adherens junctions, regulates receptor tyrosine kinase endocytosis and ubiquitination (via c-Cbl complexes), controls GLUT4 vesicle trafficking and glucose uptake, modulates synaptic proteostasis and calcium handling in neurons, maintains blood-brain barrier integrity, and tunes TCR and ICAM-1 signaling, with its tyrosine phosphorylation at Y10 by VEGF-A providing a fine-tuned regulatory switch for slit diaphragm stability."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that CD2AP is a core slit diaphragm scaffolding protein resolved the question of how nephrin signaling is linked to the podocyte cytoskeleton, revealing that CD2AP binds the nephrin cytoplasmic tail and forms a ternary complex with podocin in lipid rafts.","evidence":"Immunoelectron microscopy, co-IP, and GST pull-down from podocyte cell lines and glomerular extracts","pmids":["11733379","11733557"],"confidence":"High","gaps":["Stoichiometry of the nephrin–CD2AP–podocin complex unresolved","Dynamic regulation of complex assembly not addressed"]},{"year":2003,"claim":"Defining the antagonistic relationship between CD2AP and CIN85 at the CD2 cytoplasmic tail established that these paralogous adaptors have opposing roles in T cell adhesion and polarization, raising the broader principle that their balance tunes signaling output.","evidence":"Interaction trap cloning, co-localization, and T cell functional assays","pmids":["12618476"],"confidence":"Medium","gaps":["Mechanism of antagonism between CD2AP and CIN85 not molecularly defined","No structural basis for differential target recognition"]},{"year":2004,"claim":"Demonstrating that CD2AP bridges c-Cbl to activated VEGFR-1 and promotes its ubiquitination and internalization established CD2AP as a general adaptor for Cbl-dependent receptor tyrosine kinase endocytosis.","evidence":"Co-IP, dominant-negative overexpression, internalization and ubiquitination assays","pmids":["15001553"],"confidence":"High","gaps":["Whether CD2AP recruits Cbl to all RTKs or only specific subsets unclear","Structural basis for CD2AP–Cbl–RTK ternary complex unknown"]},{"year":2005,"claim":"Live imaging of CD2AP on cortactin/F-actin–positive endosomal structures with rapid FRAP turnover linked CD2AP to actin-dependent endosomal sorting, moving its role beyond static scaffolding.","evidence":"Confocal time-lapse microscopy, FRAP, Rab4 co-localization in podocytes","pmids":["15956777"],"confidence":"High","gaps":["Cargo specificity of CD2AP-dependent endosomal sorting not identified","How CD2AP turnover is regulated at endosomes unknown"]},{"year":2006,"claim":"Bigenic haploinsufficiency between Cd2ap and Fyn or synaptopodin causing spontaneous proteinuria established a genetic interaction network at the slit diaphragm and demonstrated that partial loss of CD2AP sensitizes to glomerular disease.","evidence":"Bigenic heterozygous mouse models, co-IP, epistasis analysis","pmids":["16628251"],"confidence":"High","gaps":["Molecular mechanism by which reduced CD2AP plus Fyn or synaptopodin triggers FSGS not delineated","Human genetic confirmation of digenic inheritance lacking"]},{"year":2007,"claim":"Identifying dendrin as a dual-function molecule that binds CD2AP/nephrin at the slit diaphragm but translocates to the nucleus upon injury to drive apoptosis revealed a signaling relay gated by CD2AP.","evidence":"Co-IP, immunofluorescence, nuclear import and apoptosis assays","pmids":["17537921"],"confidence":"High","gaps":["Signal that triggers dendrin release from the CD2AP complex not fully defined","Transcriptional targets of nuclear dendrin beyond CatL unclear"]},{"year":2007,"claim":"Showing that CIN85 upregulation in CD2AP-null podocytes impairs RTK signaling, and that CIN85 knockdown rescues PI3K/AKT and ERK output, quantified the CD2AP/CIN85 balance as a determinant of podocyte survival signaling.","evidence":"CD2AP−/− podocytes, siRNA rescue of CIN85, growth factor stimulation and signaling assays","pmids":["17213204"],"confidence":"High","gaps":["Mechanism by which CIN85 is upregulated upon CD2AP loss not identified","Whether this balance operates in non-podocyte contexts untested"]},{"year":2008,"claim":"Drosophila Cindr linking IgCAM adhesion receptors and E-cadherin to actin-capping proteins demonstrated an evolutionarily conserved role for CD2AP in coupling adhesion receptors to barbed-end actin dynamics.","evidence":"Genetic loss-of-function in Drosophila, co-IP, immunofluorescence","pmids":["18362180"],"confidence":"High","gaps":["Whether mammalian CD2AP recruits the same capping protein heterodimer at adherens junctions untested at this point"]},{"year":2009,"claim":"Direct binding of CD2AP to TβRI and its requirement for TβRI–p85 interaction activating PI3K/AKT (independently of Smad2/3) uncovered a non-canonical TGF-β survival pathway in podocytes that depends on CD2AP scaffolding.","evidence":"Co-IP, CD2AP-deficient cell lines and genetic mouse models","pmids":["19679673"],"confidence":"High","gaps":["Whether CD2AP discriminates between TβRI and TβRII binding unknown","Structural basis for CD2AP–TβRI interaction not determined"]},{"year":2011,"claim":"Elucidating a feed-forward loop in which CD2AP loss permits dendrin nuclear translocation, cathepsin L induction, and cathepsin L-mediated proteolysis of CD2AP itself, dynamin, and synaptopodin provided a complete molecular cascade from slit diaphragm disassembly to podocyte death.","evidence":"Knockout mice, nuclear fractionation, in vitro proteolysis, cell biological assays","pmids":["21911934"],"confidence":"High","gaps":["Whether the CatL feedback loop is active in human FSGS not directly shown","Kinetics and regulation of CatL-mediated CD2AP cleavage in vivo uncharacterized"]},{"year":2011,"claim":"NMR structural characterization of all three CD2AP SH3 domains revealed that SH3-A is exceptionally thermostable, providing a structural basis for its role as the primary target-binding domain.","evidence":"NMR spectroscopy and differential scanning calorimetry","pmids":["21519904"],"confidence":"Medium","gaps":["Functional significance of SH3-A thermostability not experimentally validated in cells","No co-crystal structures with full-length physiological targets"]},{"year":2012,"claim":"Discovery that CD2AP/SHIP1 inhibits Cbl E3 ligase activity to sustain ITAM signaling in plasmacytoid dendritic cells expanded CD2AP's role from a Cbl co-activator (in RTK degradation) to a context-dependent Cbl inhibitor.","evidence":"IP/mass spectrometry, siRNA knockdown, ubiquitination assays in pDCs","pmids":["22706086"],"confidence":"High","gaps":["Molecular switch determining whether CD2AP promotes or inhibits Cbl activity not identified"]},{"year":2012,"claim":"Identification of a septin 7–CD2AP–nephrin complex controlling GLUT4 storage vesicle trafficking and glucose uptake connected the slit diaphragm scaffold to metabolic regulation.","evidence":"Co-IP, siRNA knockdown, subcellular fractionation, glucose uptake assay","pmids":["22809625"],"confidence":"High","gaps":["Whether insulin directly modulates the septin 7–CD2AP interaction unknown","In vivo metabolic consequence of podocyte GLUT4 missorting not characterized"]},{"year":2013,"claim":"In vitro reconstitution demonstrating that CD2AP directly caps actin filament barbed ends and is required for adherens junction actin stability and adhesive strength established a direct biochemical activity beyond scaffolding.","evidence":"In vitro actin reconstitution, cross-linking, siRNA knockdown, mechanical stress assays","pmids":["24322428"],"confidence":"High","gaps":["Whether capping activity requires dimerization or co-factors in vivo unknown","Regulation of capping versus scaffolding modes not addressed"]},{"year":2013,"claim":"Biophysical demonstration that CD2AP SH3-A forms distinct dimeric binding modes (type I and type II) with CD2 versus Cbl-b revealed how a single SH3 domain generates signaling diversity through multimeric complex formation.","evidence":"NMR, ITC, and SAXS","pmids":["23663663"],"confidence":"High","gaps":["Whether these multimeric modes occur in intact cellular complexes not shown","Allosteric coupling between SH3 domains during multivalent binding unexplored"]},{"year":2014,"claim":"Demonstrating that CD2AP SH3 domains selectively enhance Cbl-3/c-mediated ubiquitination of Ret51 (but not Ret9) defined isoform-selective RTK degradation as a CD2AP function.","evidence":"siRNA, Co-IP, ubiquitination assays, domain deletion/mutagenesis","pmids":["24425877"],"confidence":"High","gaps":["Structural basis for Ret51 versus Ret9 discrimination by CD2AP not defined"]},{"year":2015,"claim":"Linking CD2AP to GGA2, clathrin recycling, and insulin-stimulated GLUT4 trafficking (with CD2AP−/− podocytes failing to increase glucose uptake) provided the trafficking mechanism underlying the earlier septin 7 observation.","evidence":"Co-IP, live-cell imaging, subcellular fractionation, glucose uptake in CD2AP−/− podocytes","pmids":["26546360"],"confidence":"High","gaps":["Whether CD2AP–GGA2 interaction is relevant in adipocytes or muscle cells unknown"]},{"year":2015,"claim":"Showing that CD2AP-deficient mice (with kidney rescue) have reduced blood-brain barrier integrity independent of nephrotic syndrome established a CNS-intrinsic role for CD2AP.","evidence":"CD2AP−/− mice with kidney-specific rescue transgene, sodium fluorescein extravasation","pmids":["26358779"],"confidence":"Medium","gaps":["Cell type mediating BBB defect (endothelial, pericyte, astrocyte) not identified","Molecular mechanism at the BBB not defined"]},{"year":2016,"claim":"Discovery that CD2AP complexes with TrkA and p85 and regulates NGF/AKT signaling through Rab5+ signaling endosomes to control axonal arborization extended CD2AP's RTK-adaptor function to neurotrophin signaling.","evidence":"Co-IP, siRNA, overexpression, neurite outgrowth and signaling assays","pmids":["27076424"],"confidence":"High","gaps":["Whether CD2AP regulates other Trk family receptors untested","In vivo neuronal phenotype in CD2AP knockout brain not examined at this stage"]},{"year":2017,"claim":"Demonstrating that CD2AP directly binds ICAM-1 and is required for ICAM-1-triggered PI3K/Rac1 activation and cortactin recruitment in endothelial cells, with CD2AP loss shifting leukocyte transmigration from paracellular to transcellular, defined CD2AP as a mechanosensitive regulator of endothelial barrier function.","evidence":"Co-IP, siRNA, force application on ICAM-1, Rac1 and migration assays","pmids":["28484055"],"confidence":"High","gaps":["Whether ICAM-1–CD2AP interaction occurs in other cell types unknown","Structural interface between CD2AP and ICAM-1 not mapped"]},{"year":2018,"claim":"Conditional knockout in CD4 T cells showing that CD2AP limits TCR signal duration and suppresses Tfh differentiation during chronic viral infection identified CD2AP as an immune checkpoint modulator distinct from CIN85.","evidence":"T cell-specific conditional knockout, LCMV infection, TCR signaling and Tfh assays","pmids":["29734372"],"confidence":"Medium","gaps":["Molecular target through which CD2AP dampens TCR signaling not identified","Relevance to human chronic infections or autoimmunity not tested"]},{"year":2019,"claim":"Cross-species rescue experiments showing that VEGF-A–induced Y10 phosphorylation of CD2AP's SH3-1 domain is essential for glomerular barrier function, despite Y10A mutation enhancing nephrin binding, revealed a counterintuitive regulatory switch where phosphorylation tunes affinity to enable dynamic slit diaphragm remodeling.","evidence":"Site-directed mutagenesis, phospho-specific antibodies, zebrafish and Drosophila rescue","pmids":["31235616"],"confidence":"High","gaps":["Kinase(s) responsible for Y10 phosphorylation in vivo not confirmed beyond VEGF-A context","Effect of Y10 phosphorylation on non-nephrin partners unknown"]},{"year":2019,"claim":"Demonstrating conserved synaptic phenotypes across Drosophila cindr mutants, Cd2ap null mice, and human brain tissue—including impaired vesicle recycling, altered ubiquitin-proteasome-mediated turnover of Synapsin and PMCA, and reduced cytosolic calcium—established CD2AP as a synaptic proteostasis regulator with relevance to neurodegeneration.","evidence":"Genetic mutants in fly and mouse, co-IP, electrophysiology, proteomics, calcium imaging, human postmortem correlation","pmids":["31412248"],"confidence":"High","gaps":["Whether synaptic defects are cell-autonomous in mammalian neurons not fully resolved","Direct proteasome target of CD2AP regulation not identified"]},{"year":2019,"claim":"NMR characterization showing bivalent binding of CD2AP SH3-A and SH3-C to chikungunya nsP3 HVD, with SH3-B left free, defined a cooperative multidomain binding mode exploited by an alphavirus for replication.","evidence":"NMR chemical shift perturbation, mutagenesis, viral replication assays","pmids":["31493651"],"confidence":"High","gaps":["Whether other RNA viruses exploit the same bivalent SH3 mechanism untested","Role of SH3-B during viral infection not identified"]},{"year":2024,"claim":"Neuron-specific Cd2ap deletion in APP/PS1 mice causing p38 MAPK-dependent tau hyperphosphorylation, synaptic loss, and cognitive decline—rescued by p38 inhibition—provided the first direct in vivo evidence that CD2AP loss drives Alzheimer's-relevant pathology through a defined kinase cascade.","evidence":"Conditional neuronal knockout in APP/PS1 mice, immunoblotting, electrophysiology, behavioral tests, p38 inhibitor rescue","pmids":["39696695"],"confidence":"High","gaps":["Whether p38 activation is the primary or sole pathway downstream of neuronal CD2AP loss not established","Mechanism connecting CD2AP to p38 MAPK activation not molecularly defined"]},{"year":null,"claim":"How CD2AP's barbed-end capping activity, SH3-mediated scaffolding, and phosphoregulation are coordinated in a single molecule to switch between its diverse cellular roles—podocyte slit diaphragm maintenance, RTK endocytosis, synaptic proteostasis, and immune signaling—remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length CD2AP structure available","Allosteric communication between the three SH3 domains and the C-terminal coiled-coil region unexplored","Cell-type-specific regulatory mechanisms controlling CD2AP mode-switching not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5,7,8,13,15,16]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[9,10,22,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,12,14,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,7,9,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,13]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[9,10,22,23]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,11,15,16,30]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,10,13,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,7,12,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,15,27]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[9,15,23]}],"complexes":["nephrin–podocin–CD2AP slit diaphragm complex","CD2AP–c-Cbl RTK endocytic complex","septin 7–CD2AP–nephrin complex"],"partners":["NPHS1","NPHS2","CBL","FYN","SYNPO","TGFBR1","NTRK1","ICAM1"],"other_free_text":[]},"mechanistic_narrative":"CD2AP is a multi-SH3-domain scaffolding protein that organizes signaling complexes at membrane-cytoskeleton interfaces, functioning in podocyte slit diaphragm integrity, receptor tyrosine kinase endocytosis, vesicle trafficking, cell adhesion, and synaptic proteostasis. At the slit diaphragm, CD2AP bridges nephrin, podocin, and the actin cytoskeleton, gates TGF-β1–induced dendrin nuclear translocation and cathepsin L expression to control podocyte survival, and activates PI3K/AKT antiapoptotic signaling through direct interaction with TβRI [PMID:11733379, PMID:11733557, PMID:21911934, PMID:19679673]. CD2AP also caps barbed ends of actin filaments to stabilize adherens junctions, enhances c-Cbl–mediated ubiquitination and endocytic degradation of receptor tyrosine kinases including VEGFR-1 and Ret51, regulates GLUT4 vesicle trafficking and insulin-stimulated glucose uptake, and modulates TCR signal duration in T cells [PMID:24322428, PMID:15001553, PMID:24425877, PMID:26546360, PMID:29734372]. In neurons, CD2AP controls synaptic vesicle recycling, synaptic protein turnover via the ubiquitin-proteasome system, and calcium homeostasis, and its neuronal loss activates p38 MAPK leading to tau hyperphosphorylation and cognitive impairment [PMID:31412248, PMID:39696695]."},"prefetch_data":{"uniprot":{"accession":"Q9Y5K6","full_name":"CD2-associated protein","aliases":["Adapter protein CMS","Cas ligand with multiple SH3 domains"],"length_aa":639,"mass_kda":71.5,"function":"Seems to act as an adapter protein between membrane proteins and the actin cytoskeleton (PubMed:10339567). In collaboration with CBLC, modulates the rate of RET turnover and may act as regulatory checkpoint that limits the potency of GDNF on neuronal survival. Controls CBLC function, converting it from an inhibitor to a promoter of RET degradation (By similarity). May play a role in receptor clustering and cytoskeletal polarity in the junction between T-cell and antigen-presenting cell (By similarity). May anchor the podocyte slit diaphragm to the actin cytoskeleton in renal glomerolus. Also required for cytokinesis (PubMed:15800069). Plays a role in epithelial cell junctions formation (PubMed:22891260)","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection, ruffle; Cell junction","url":"https://www.uniprot.org/uniprotkb/Q9Y5K6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD2AP","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":10.0},{"gene":"ARFGAP1","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"EIF5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CD2AP","total_profiled":1310},"omim":[{"mim_id":"621453","title":"MULTIVESICULAR BODY SUBUNIT 12A; MVB12A","url":"https://www.omim.org/entry/621453"},{"mim_id":"619583","title":"EH DOMAIN-BINDING PROTEIN 1-LIKE 1; EHBP1L1","url":"https://www.omim.org/entry/619583"},{"mim_id":"617368","title":"SH3 DOMAIN-BINDING PROTEIN 1; SH3BP1","url":"https://www.omim.org/entry/617368"},{"mim_id":"616032","title":"FOCAL SEGMENTAL GLOMERULOSCLEROSIS 8; FSGS8","url":"https://www.omim.org/entry/616032"},{"mim_id":"616027","title":"ACTIN-BINDING PROTEIN ANILLIN; ANLN","url":"https://www.omim.org/entry/616027"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CD2AP"},"hgnc":{"alias_symbol":["CMS"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5K6","domains":[{"cath_id":"2.30.30.40","chopping":"3-58","consensus_level":"high","plddt":91.758,"start":3,"end":58},{"cath_id":"2.30.30.40","chopping":"113-166","consensus_level":"high","plddt":92.7487,"start":113,"end":166},{"cath_id":"2.30.30.40","chopping":"274-329","consensus_level":"high","plddt":91.8484,"start":274,"end":329}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5K6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5K6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5K6-F1-predicted_aligned_error_v6.png","plddt_mean":62.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD2AP","jax_strain_url":"https://www.jax.org/strain/search?query=CD2AP"},"sequence":{"accession":"Q9Y5K6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5K6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5K6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5K6"}},"corpus_meta":[{"pmid":"21460840","id":"PMC_21460840","title":"Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21460840","citation_count":1626,"is_preprint":false},{"pmid":"16037678","id":"PMC_16037678","title":"Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS.","date":"2005","source":"Neuropsychobiology","url":"https://pubmed.ncbi.nlm.nih.gov/16037678","citation_count":1281,"is_preprint":false},{"pmid":"11733557","id":"PMC_11733557","title":"Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin.","date":"2001","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11733557","citation_count":474,"is_preprint":false},{"pmid":"11733379","id":"PMC_11733379","title":"CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain.","date":"2001","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11733379","citation_count":226,"is_preprint":false},{"pmid":"26905724","id":"PMC_26905724","title":"Cytoplasmic male sterility (CMS) in hybrid breeding in field crops.","date":"2016","source":"Plant cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26905724","citation_count":148,"is_preprint":false},{"pmid":"10997929","id":"PMC_10997929","title":"CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere.","date":"2000","source":"American journal of physiology. 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Basic to translational science","url":"https://pubmed.ncbi.nlm.nih.gov/38984045","citation_count":13,"is_preprint":false},{"pmid":"15910750","id":"PMC_15910750","title":"CD2AP contributes to cell migration and adhesion in cultured gastric epithelium.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15910750","citation_count":12,"is_preprint":false},{"pmid":"24425877","id":"PMC_24425877","title":"CD2-associated protein (CD2AP) enhances casitas B lineage lymphoma-3/c (Cbl-3/c)-mediated Ret isoform-specific ubiquitination and degradation via its amino-terminal Src homology 3 domains.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24425877","citation_count":12,"is_preprint":false},{"pmid":"23027549","id":"PMC_23027549","title":"Interactions between Drosophila IgCAM adhesion receptors and cindr, the Cd2ap/Cin85 ortholog.","date":"2012","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/23027549","citation_count":12,"is_preprint":false},{"pmid":"30326665","id":"PMC_30326665","title":"iTRAQ-Based Proteomic Analysis of Ogura-CMS Cabbage and Its Maintainer Line.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30326665","citation_count":12,"is_preprint":false},{"pmid":"21519904","id":"PMC_21519904","title":"Solution structure, dynamics and thermodynamics of the three SH3 domains of CD2AP.","date":"2011","source":"Journal of biomolecular NMR","url":"https://pubmed.ncbi.nlm.nih.gov/21519904","citation_count":12,"is_preprint":false},{"pmid":"31131477","id":"PMC_31131477","title":"Excessive apoptosis of podocytes caused by dysregulation of microRNA-182-5p and CD2AP confers to an increased risk of diabetic nephropathy.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31131477","citation_count":12,"is_preprint":false},{"pmid":"32764959","id":"PMC_32764959","title":"miR-188-5p Promotes Tumor Growth by Targeting CD2AP Through PI3K/AKT/mTOR Signaling in Children with Acute Promyelocytic Leukemia.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32764959","citation_count":12,"is_preprint":false},{"pmid":"17922258","id":"PMC_17922258","title":"The high resolution NMR structure of the third SH3 domain of CD2AP.","date":"2007","source":"Journal of biomolecular NMR","url":"https://pubmed.ncbi.nlm.nih.gov/17922258","citation_count":12,"is_preprint":false},{"pmid":"10447596","id":"PMC_10447596","title":"Nuclear genes from Tx CMS maintainer lines are unable to maintain atp6 RNA editing in any anther cell-type in the sorghum bicolor A3 cytoplasm.","date":"1999","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10447596","citation_count":12,"is_preprint":false},{"pmid":"34638057","id":"PMC_34638057","title":"Blebbistatin protects iPSC-CMs from hypercontraction and facilitates automated patch-clamp based electrophysiological study.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34638057","citation_count":11,"is_preprint":false},{"pmid":"30385414","id":"PMC_30385414","title":"Cytological and iTRAQ-based quantitative proteomic analyses of hau CMS in Brassica napus L.","date":"2018","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/30385414","citation_count":11,"is_preprint":false},{"pmid":"39696695","id":"PMC_39696695","title":"CD2AP deficiency aggravates Alzheimer's disease phenotypes and pathology through p38 MAPK activation.","date":"2024","source":"Translational neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/39696695","citation_count":10,"is_preprint":false},{"pmid":"39589648","id":"PMC_39589648","title":"From Subtypes to Solutions: Integrating CMS Classification with Precision Therapeutics in Colorectal Cancer.","date":"2024","source":"Current treatment options in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39589648","citation_count":10,"is_preprint":false},{"pmid":"9701728","id":"PMC_9701728","title":"Microsensor-aided measurements of cellular signalling and metabolism on tumor cells. 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direct interaction between podocin and CD2AP was confirmed in vitro by GST pull-down and co-immunoprecipitation from glomerular extracts.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, immunoelectron microscopy\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro GST pull-down plus reciprocal Co-IP from native tissue, replicated independently\",\n      \"pmids\": [\"11733557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD2AP associates with Fyn and synaptopodin in podocytes; bigenic heterozygosity of Cd2ap with either Synpo or Fyn (but not Neph1) leads to spontaneous proteinuria and FSGS-like glomerular damage, establishing a genetic and physical interaction network.\",\n      \"method\": \"Co-immunoprecipitation, bigenic mouse models, epistasis analysis\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP combined with rigorous in vivo genetic epistasis in multiple bigenic mouse models\",\n      \"pmids\": [\"16628251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD2AP forms a ternary complex with c-Cbl and activated Flt-1 (VEGFR-1) upon VEGF stimulation, and wild-type CD2AP (but not a dominant-negative form) enhances VEGF-stimulated internalization and ubiquitination of Flt-1, promoting receptor endocytosis and degradation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, internalization assay, ubiquitination assay\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, dominant-negative, functional internalization, ubiquitination assays) in a single study\",\n      \"pmids\": [\"15001553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dendrin directly binds to both nephrin and CD2AP at the slit diaphragm; upon glomerular injury or high-dose TGF-β1 stimulation, dendrin relocates from the slit diaphragm to the nucleus where it enhances apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, nuclear import assay, apoptosis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated by Co-IP, functional consequence (nuclear translocation and apoptosis) validated by multiple methods\",\n      \"pmids\": [\"17537921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD2AP C-terminal region directly interacts with the cytoplasmic tail of TGF-β receptor type I (TβRI) in a kinase-dependent manner, and CD2AP is required for the interaction between TβRI and the p85 subunit of PI3K, thereby activating the antiapoptotic PI3K/AKT pathway independently of Smad2/3 signaling.\",\n      \"method\": \"Co-immunoprecipitation, CD2AP-deficient cell lines, genetic mouse models\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped by Co-IP, confirmed by in vivo genetic models with defined phenotypic readouts\",\n      \"pmids\": [\"19679673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD2AP regulates TGF-β1-dependent translocation of dendrin from the slit diaphragm to the nucleus, where dendrin acts as a transcription factor inducing cytosolic cathepsin L (CatL) expression; CatL then proteolyzed dynamin and synaptopodin, reorganizing the podocyte microfilament system. CD2AP itself is proteolyzed by CatL in a feedback loop promoting sustained CatL expression and podocyte apoptosis.\",\n      \"method\": \"Loss-of-function mouse models, nuclear fractionation, in vitro proteolysis assays, cell biological assays\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined molecular pathway with multiple orthogonal methods including in vitro proteolysis, nuclear fractionation, and genetic mouse models\",\n      \"pmids\": [\"21911934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD2AP forms a complex with SHIP1, and upon BDCA2 cross-linking in plasmacytoid dendritic cells, this CD2AP/SHIP1 complex associates with the E3 ubiquitin ligase Cbl at the plasma membrane and inhibits its E3 ubiquitin ligase activity, thereby preventing degradation of Syk and FcεRIγ and sustaining ITAM signaling.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, knockdown (siRNA), ubiquitination assay, immunofluorescence\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-confirmed interaction, functional ubiquitination assay, siRNA knockdown with defined signaling readout\",\n      \"pmids\": [\"22706086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Septin 7 forms a complex with CD2AP and nephrin in podocytes; depletion of septin 7 increases VAMP2-nephrin interaction and glucose uptake, indicating that the septin 7/CD2AP/nephrin complex regulates GLUT4 storage vesicle trafficking.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, 2-deoxy-D-glucose uptake assay\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, fractionation, and functional glucose uptake assay with multiple orthogonal approaches\",\n      \"pmids\": [\"22809625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD2AP (FSGS3) functions as a barbed-end actin-capping protein at the adherens junction; knockdown of CD2AP compromises actin stability and accumulation at the adherens junction, reducing adhesive strength and disrupting barrier function.\",\n      \"method\": \"In vitro reconstitution biochemistry, cross-linking approach, siRNA knockdown, mechanical stress assay\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of capping activity combined with functional cellular assays\",\n      \"pmids\": [\"24322428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In podocytes, CD2AP colocalizes with cortactin and F-actin on motile vesicular spots; FRAP shows high turnover of CD2AP (half-time <10 s) at these spots, which depend on actin polymerization and are associated with a late endosomal-sorting compartment (Rab4-positive), implicating CD2AP in endosomal sorting/trafficking via actin assembly regulation.\",\n      \"method\": \"Confocal time-lapse microscopy, FRAP, microinjection of fluorescent G-actin, endosomal marker co-localization\",\n      \"journal\": \"American Journal of Physiology – Renal Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple live-imaging methods with functional pharmacological validation (jasplakinolide) and FRAP\",\n      \"pmids\": [\"15956777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD2AP deficiency in podocytes leads to diminished signal initiation and termination via receptor tyrosine kinases (RTKs); CIN85 expression is increased in CD2AP-/- podocytes, and repression of CIN85 restores RTK signaling (PI3K/AKT and ERK), establishing the CD2AP/CIN85 balance as a determinant of RTK signaling in podocytes.\",\n      \"method\": \"CD2AP-/- mouse and cell models, growth factor stimulation, siRNA knockdown of CIN85, signaling pathway assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout models combined with siRNA rescue experiments and defined signaling readouts\",\n      \"pmids\": [\"17213204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD2AP enhances Cbl-3/c-mediated ubiquitination and degradation of Ret51 (but not Ret9) isoform specifically; the SH3 domains of CD2AP are sufficient for this activity, while the coiled-coil C-terminal domain is dispensable; Ret51 ubiquitination requires functional ring finger and TKB domains in Cbl-3/c.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, domain deletion/mutagenesis, site-directed mutagenesis of ubiquitination sites\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mutagenesis combined with functional ubiquitination assays and siRNA knockdown\",\n      \"pmids\": [\"24425877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD2AP forms a complex with GGA2 (a clathrin adaptor that sorts Glut4 to storage vesicles), connects clathrin to actin in the perinuclear region, and is required for clathrin recycling back to trans-Golgi membranes; CD2AP-/- podocytes fail to increase glucose uptake in response to insulin and show perinuclear clustering of Glut4.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, subcellular fractionation, 2-deoxy-D-glucose uptake assay, CD2AP-/- podocytes\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking CD2AP to Glut4 trafficking with defined functional consequence\",\n      \"pmids\": [\"26546360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD2AP forms a complex with tankyrases; in the absence of CD2AP, tankyrase-mediated PARylation and Wnt/β-catenin signaling (LEF1, fibronectin) are increased in podocytes, identifying CD2AP as a regulator of the Wnt/β-catenin pathway through control of tankyrase PARylation activity.\",\n      \"method\": \"Co-immunoprecipitation, CD2AP-/- podocytes, tankyrase inhibitor, zebrafish model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and genetic knockout with signaling readouts, but single lab study\",\n      \"pmids\": [\"27441654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD2AP in endothelial cells binds directly to the receptor ICAM-1 and is required for ICAM-1-mediated PI3K activation, F-actin and cortactin recruitment, and Rac1 activation; loss of CD2AP increases ICAM-1 clustering, neutrophil adhesion, and promotes transcellular over paracellular diapedesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, force application on ICAM-1, Rac1 activation assay, neutrophil adhesion/transmigration assay\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding shown by Co-IP, multiple signaling and functional readouts, mechanosensing validated with force application\",\n      \"pmids\": [\"28484055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD2AP forms a complex with TrkA and the PI3K regulatory subunit p85 in neurons; CD2AP levels positively regulate TrkA:p85 association and NGF signaling through AKT (but not ERK), and regulate long-range signaling through TrkA+/RAB5+ signaling endosomes, controlling axon arbor growth and collateral sprouting.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, neurite outgrowth assay, signaling assays\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel complex identified by Co-IP, confirmed by functional in vitro and in vivo assays with multiple orthogonal methods\",\n      \"pmids\": [\"27076424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila, loss of cindr (CD2AP ortholog) impairs synapse maturation, synaptic vesicle recycling and release; Cindr associates with and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and PMCA; loss of cindr elevates PMCA and reduces cytosolic calcium. Cd2ap null mice show conserved synaptic proteostasis defects, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains.\",\n      \"method\": \"Genetic loss-of-function (Drosophila mutants, Cd2ap null mice), co-immunoprecipitation, electrophysiology, proteomics, calcium measurements\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across three model systems (Drosophila, mouse, human tissue) with defined mechanistic readouts\",\n      \"pmids\": [\"31412248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VEGF-A stimulation induces tyrosine phosphorylation of CD2AP in podocytes; phosphorylation at Y10 in the SH3-1 domain is indispensable for CD2AP function in vivo (shown by cross-species rescue in zebrafish and Drosophila). Absence of Y10 phosphorylation enhances nephrin binding affinity to CD2AP but paradoxically impairs glomerular filtration barrier function.\",\n      \"method\": \"Isoelectric focusing, site-directed mutagenesis, phospho-specific antibodies, cross-species rescue (zebrafish, Drosophila), western blot\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-directed mutagenesis with in vivo rescue across two model organisms\",\n      \"pmids\": [\"31235616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMR structural characterization of all three SH3 domains of CD2AP reveals that the N-terminal SH3 domain (SH3-A) is the most stable SH3 domain characterized, due to a more extensive intramolecular interaction network; the high stability is proposed to be crucial for maintaining proper conformation for target interaction.\",\n      \"method\": \"NMR spectroscopy, differential scanning calorimetry (DSC), FoldX structure-based analysis\",\n      \"journal\": \"Journal of Biomolecular NMR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure, but functional validation of stability significance is computational/indirect\",\n      \"pmids\": [\"21519904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NMR high-resolution structure of the CD2AP SH3-C domain was determined, revealing all canonical SH3 features including the polyproline-binding site.\",\n      \"method\": \"NMR spectroscopy, triple-resonance experiments, NOESY\",\n      \"journal\": \"Journal of Biomolecular NMR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution NMR structure, but limited direct functional validation beyond binding site identification\",\n      \"pmids\": [\"17922258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NMR, ITC, and SAXS characterization shows that CD2AP SH3-A forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b, revealing multimeric and differential binding modes that generate signaling diversity.\",\n      \"method\": \"NMR spectroscopy, isothermal titration calorimetry (ITC), small-angle X-ray scattering (SAXS)\",\n      \"journal\": \"The FEBS Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — three orthogonal biophysical methods characterizing binding modes at atomic resolution\",\n      \"pmids\": [\"23663663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAWS1 interacts dynamically with CD2AP at lamellae; CRISPR/Cas9 knockout of CD2AP in U2OS cells causes defects in F-actin organization, lamellipodial organization, and impairs cell migration, phenocopying PAWS1-knockout cells.\",\n      \"method\": \"CRISPR/Cas9 knockout, co-immunoprecipitation, confocal microscopy, live-cell imaging, migration assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR knockout with defined actin and migration phenotype, Co-IP interaction, single lab\",\n      \"pmids\": [\"29175910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cindr (Drosophila CD2AP ortholog) links E-cadherin and Roughest (IgCAM adhesion receptor) to actin-capping proteins (capping protein alpha and beta); reducing cindr activity disrupts normal localization of E-cadherin and Roughest and causes defects in local cell movement and tissue patterning.\",\n      \"method\": \"Genetic loss-of-function (Drosophila), co-immunoprecipitation, immunofluorescence, co-localization\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis combined with physical interactions and localization studies in Drosophila, ortholog context consistent with mammalian CD2AP\",\n      \"pmids\": [\"18362180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD2AP is recruited to EPEC actin pedestals in a manner dependent on Tir Y474 phosphorylation, and CD2AP functions as a novel component of EPEC pedestal formation; CD2AP co-localizes with the endocytic machinery (clathrin) in pedestals.\",\n      \"method\": \"Immunofluorescence, genetic knockout/knockdown, pedestal formation assay\",\n      \"journal\": \"Infection and Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with defined genetic requirements, but mechanistic depth limited to localization and loss-of-function\",\n      \"pmids\": [\"20515931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CFBP (CIN85/CD2AP family binding protein) is phosphorylated at tyrosine 204 upon EGF stimulation; its proline-rich motif is recognized by one of the three SH3 domains of CD2AP, with binding affinity regulated by tyrosine phosphorylation; CFBP accelerates EGF receptor down-regulation by facilitating Cbl recruitment to the CD2AP/CIN85 complex.\",\n      \"method\": \"Proteomic phosphorylation screen, co-immunoprecipitation, EGF receptor internalization assay, overexpression\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and functional receptor degradation assay, single lab\",\n      \"pmids\": [\"16895919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD2AP loss maintains blood-brain barrier integrity; CD2AP-deficient mice (with kidney-specific CD2AP transgene) show reduced blood-brain barrier integrity measured by sodium fluorescein extravasation, independent of nephrotic syndrome.\",\n      \"method\": \"CD2AP-/- mouse model with kidney-specific rescue transgene, sodium fluorescein extravasation assay, seizure latency measurement\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined physiological readout, dissociation from systemic illness confirmed by control experiment\",\n      \"pmids\": [\"26358779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In chronic LCMV infection, CD2AP in CD4 T cells suppresses follicular helper (Tfh) differentiation; CD2AP-deficient CD4 T cells show extended TCR signaling duration and enhanced cytokine production specifically under TH1 conditions, promoting Tfh differentiation and germinal center responses. CIN85 shows non-overlapping/antagonistic roles.\",\n      \"method\": \"T cell-specific conditional knockout, LCMV infection model, TCR signaling assays, Tfh differentiation assays\",\n      \"journal\": \"PLOS Pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with defined signaling and differentiation phenotypes, single lab\",\n      \"pmids\": [\"29734372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD2AP co-localizes with F-actin in the leading edges of migrating gastric epithelial cells and co-immunoprecipitates with E-cadherin upon HGF stimulation; intracellular injection of anti-CD2AP antibody significantly retards cell migration speed.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, intracellular antibody injection, migration assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional migration assay by antibody injection combined with Co-IP, single lab\",\n      \"pmids\": [\"15910750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGF recruits c-fos and JunD (AP-1 components) to an AP-1-like element in the CD2AP gene promoter, increasing CD2AP expression and suppressing angiotensin II-induced apoptosis in renal tubular epithelial cells; CD2AP knockdown attenuates the antiapoptotic effect of EGF.\",\n      \"method\": \"Promoter deletion/mutation analysis, EMSA, chromatin immunoprecipitation, siRNA knockdown, apoptosis assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and EMSA with functional apoptosis readout, single lab\",\n      \"pmids\": [\"19095050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD2AP deficiency in neurons activates p38 MAPK signaling, leading to increased tau phosphorylation, synaptic injury, neuronal apoptosis, and cognitive impairment in APP/PS1 mice; pharmacological inhibition of p38 MAPK ameliorates these phenotypes.\",\n      \"method\": \"Neuron-specific Cd2ap conditional knockout in APP/PS1 mice, immunoblotting, immunofluorescence, electrophysiology, behavioral tests, p38 inhibitor treatment\",\n      \"journal\": \"Translational Neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout in disease model with pharmacological rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"39696695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD2AP interacts with TRIM5 and its overexpression increases TRIM5 levels and NF-κB activity in glioblastoma cells; CD2AP promotes GBM cell proliferation, migration, invasion, and resistance to apoptosis through the TRIM5-NF-κB axis.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, NF-κB activity assay, in vitro proliferation/invasion/apoptosis assays, in vivo tumorigenesis\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional rescue experiments, single lab, cancer context\",\n      \"pmids\": [\"39353894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD2AP (CMS) binds the same highly conserved segment of the CD2 cytoplasmic tail as CIN85/CD2BP3 via its SH3 domains; unlike CIN85/CD2BP3, CD2AP co-localizes with F-actin and binds p130Cas; CD2AP and CIN85 activities are antagonistic in T cell adhesion and polarization.\",\n      \"method\": \"Interaction trap cloning, co-localization studies, protein interaction assays, T cell functional assays\",\n      \"journal\": \"International Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and co-localization, functional antagonism demonstrated but mechanism not fully delineated\",\n      \"pmids\": [\"12618476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD2AP interacts with CHIKV nsP3 HVD via its SH3-A and SH3-C domains simultaneously (bivalent interaction), as determined by NMR; this increases binding affinity through cooperativity and leaves SH3-B available for other partners; BIN1, CD2AP, and SH3KBP1 play redundant roles in initiation of CHIKV replication.\",\n      \"method\": \"NMR spectroscopy, chemical shift perturbation, mutagenesis, viral replication assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural characterization of binding mechanism with mutational validation and functional viral replication assays\",\n      \"pmids\": [\"31493651\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD2AP is a multi-SH3 domain scaffolding/adaptor protein that organizes multiprotein complexes at membrane-cytoskeleton interfaces: in podocytes it links nephrin, podocin, and the actin cytoskeleton at the slit diaphragm, gates TGF-β1 signaling by controlling dendrin nuclear translocation and cathepsin L expression, and supports PI3K/AKT survival signaling through direct interaction with TβRI; it also functions as a barbed-end actin-capping protein stabilizing adherens junctions, regulates receptor tyrosine kinase endocytosis and ubiquitination (via c-Cbl complexes), controls GLUT4 vesicle trafficking and glucose uptake, modulates synaptic proteostasis and calcium handling in neurons, maintains blood-brain barrier integrity, and tunes TCR and ICAM-1 signaling, with its tyrosine phosphorylation at Y10 by VEGF-A providing a fine-tuned regulatory switch for slit diaphragm stability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD2AP is a multi-SH3-domain scaffolding protein that organizes signaling complexes at membrane-cytoskeleton interfaces, functioning in podocyte slit diaphragm integrity, receptor tyrosine kinase endocytosis, vesicle trafficking, cell adhesion, and synaptic proteostasis. At the slit diaphragm, CD2AP bridges nephrin, podocin, and the actin cytoskeleton, gates TGF-β1–induced dendrin nuclear translocation and cathepsin L expression to control podocyte survival, and activates PI3K/AKT antiapoptotic signaling through direct interaction with TβRI [PMID:11733379, PMID:11733557, PMID:21911934, PMID:19679673]. CD2AP also caps barbed ends of actin filaments to stabilize adherens junctions, enhances c-Cbl–mediated ubiquitination and endocytic degradation of receptor tyrosine kinases including VEGFR-1 and Ret51, regulates GLUT4 vesicle trafficking and insulin-stimulated glucose uptake, and modulates TCR signal duration in T cells [PMID:24322428, PMID:15001553, PMID:24425877, PMID:26546360, PMID:29734372]. In neurons, CD2AP controls synaptic vesicle recycling, synaptic protein turnover via the ubiquitin-proteasome system, and calcium homeostasis, and its neuronal loss activates p38 MAPK leading to tau hyperphosphorylation and cognitive impairment [PMID:31412248, PMID:39696695].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that CD2AP is a core slit diaphragm scaffolding protein resolved the question of how nephrin signaling is linked to the podocyte cytoskeleton, revealing that CD2AP binds the nephrin cytoplasmic tail and forms a ternary complex with podocin in lipid rafts.\",\n      \"evidence\": \"Immunoelectron microscopy, co-IP, and GST pull-down from podocyte cell lines and glomerular extracts\",\n      \"pmids\": [\"11733379\", \"11733557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the nephrin–CD2AP–podocin complex unresolved\", \"Dynamic regulation of complex assembly not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining the antagonistic relationship between CD2AP and CIN85 at the CD2 cytoplasmic tail established that these paralogous adaptors have opposing roles in T cell adhesion and polarization, raising the broader principle that their balance tunes signaling output.\",\n      \"evidence\": \"Interaction trap cloning, co-localization, and T cell functional assays\",\n      \"pmids\": [\"12618476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of antagonism between CD2AP and CIN85 not molecularly defined\", \"No structural basis for differential target recognition\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that CD2AP bridges c-Cbl to activated VEGFR-1 and promotes its ubiquitination and internalization established CD2AP as a general adaptor for Cbl-dependent receptor tyrosine kinase endocytosis.\",\n      \"evidence\": \"Co-IP, dominant-negative overexpression, internalization and ubiquitination assays\",\n      \"pmids\": [\"15001553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD2AP recruits Cbl to all RTKs or only specific subsets unclear\", \"Structural basis for CD2AP–Cbl–RTK ternary complex unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Live imaging of CD2AP on cortactin/F-actin–positive endosomal structures with rapid FRAP turnover linked CD2AP to actin-dependent endosomal sorting, moving its role beyond static scaffolding.\",\n      \"evidence\": \"Confocal time-lapse microscopy, FRAP, Rab4 co-localization in podocytes\",\n      \"pmids\": [\"15956777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo specificity of CD2AP-dependent endosomal sorting not identified\", \"How CD2AP turnover is regulated at endosomes unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Bigenic haploinsufficiency between Cd2ap and Fyn or synaptopodin causing spontaneous proteinuria established a genetic interaction network at the slit diaphragm and demonstrated that partial loss of CD2AP sensitizes to glomerular disease.\",\n      \"evidence\": \"Bigenic heterozygous mouse models, co-IP, epistasis analysis\",\n      \"pmids\": [\"16628251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which reduced CD2AP plus Fyn or synaptopodin triggers FSGS not delineated\", \"Human genetic confirmation of digenic inheritance lacking\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying dendrin as a dual-function molecule that binds CD2AP/nephrin at the slit diaphragm but translocates to the nucleus upon injury to drive apoptosis revealed a signaling relay gated by CD2AP.\",\n      \"evidence\": \"Co-IP, immunofluorescence, nuclear import and apoptosis assays\",\n      \"pmids\": [\"17537921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that triggers dendrin release from the CD2AP complex not fully defined\", \"Transcriptional targets of nuclear dendrin beyond CatL unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing that CIN85 upregulation in CD2AP-null podocytes impairs RTK signaling, and that CIN85 knockdown rescues PI3K/AKT and ERK output, quantified the CD2AP/CIN85 balance as a determinant of podocyte survival signaling.\",\n      \"evidence\": \"CD2AP−/− podocytes, siRNA rescue of CIN85, growth factor stimulation and signaling assays\",\n      \"pmids\": [\"17213204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CIN85 is upregulated upon CD2AP loss not identified\", \"Whether this balance operates in non-podocyte contexts untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Drosophila Cindr linking IgCAM adhesion receptors and E-cadherin to actin-capping proteins demonstrated an evolutionarily conserved role for CD2AP in coupling adhesion receptors to barbed-end actin dynamics.\",\n      \"evidence\": \"Genetic loss-of-function in Drosophila, co-IP, immunofluorescence\",\n      \"pmids\": [\"18362180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian CD2AP recruits the same capping protein heterodimer at adherens junctions untested at this point\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Direct binding of CD2AP to TβRI and its requirement for TβRI–p85 interaction activating PI3K/AKT (independently of Smad2/3) uncovered a non-canonical TGF-β survival pathway in podocytes that depends on CD2AP scaffolding.\",\n      \"evidence\": \"Co-IP, CD2AP-deficient cell lines and genetic mouse models\",\n      \"pmids\": [\"19679673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD2AP discriminates between TβRI and TβRII binding unknown\", \"Structural basis for CD2AP–TβRI interaction not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Elucidating a feed-forward loop in which CD2AP loss permits dendrin nuclear translocation, cathepsin L induction, and cathepsin L-mediated proteolysis of CD2AP itself, dynamin, and synaptopodin provided a complete molecular cascade from slit diaphragm disassembly to podocyte death.\",\n      \"evidence\": \"Knockout mice, nuclear fractionation, in vitro proteolysis, cell biological assays\",\n      \"pmids\": [\"21911934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the CatL feedback loop is active in human FSGS not directly shown\", \"Kinetics and regulation of CatL-mediated CD2AP cleavage in vivo uncharacterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"NMR structural characterization of all three CD2AP SH3 domains revealed that SH3-A is exceptionally thermostable, providing a structural basis for its role as the primary target-binding domain.\",\n      \"evidence\": \"NMR spectroscopy and differential scanning calorimetry\",\n      \"pmids\": [\"21519904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of SH3-A thermostability not experimentally validated in cells\", \"No co-crystal structures with full-length physiological targets\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that CD2AP/SHIP1 inhibits Cbl E3 ligase activity to sustain ITAM signaling in plasmacytoid dendritic cells expanded CD2AP's role from a Cbl co-activator (in RTK degradation) to a context-dependent Cbl inhibitor.\",\n      \"evidence\": \"IP/mass spectrometry, siRNA knockdown, ubiquitination assays in pDCs\",\n      \"pmids\": [\"22706086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular switch determining whether CD2AP promotes or inhibits Cbl activity not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of a septin 7–CD2AP–nephrin complex controlling GLUT4 storage vesicle trafficking and glucose uptake connected the slit diaphragm scaffold to metabolic regulation.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, subcellular fractionation, glucose uptake assay\",\n      \"pmids\": [\"22809625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether insulin directly modulates the septin 7–CD2AP interaction unknown\", \"In vivo metabolic consequence of podocyte GLUT4 missorting not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"In vitro reconstitution demonstrating that CD2AP directly caps actin filament barbed ends and is required for adherens junction actin stability and adhesive strength established a direct biochemical activity beyond scaffolding.\",\n      \"evidence\": \"In vitro actin reconstitution, cross-linking, siRNA knockdown, mechanical stress assays\",\n      \"pmids\": [\"24322428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether capping activity requires dimerization or co-factors in vivo unknown\", \"Regulation of capping versus scaffolding modes not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Biophysical demonstration that CD2AP SH3-A forms distinct dimeric binding modes (type I and type II) with CD2 versus Cbl-b revealed how a single SH3 domain generates signaling diversity through multimeric complex formation.\",\n      \"evidence\": \"NMR, ITC, and SAXS\",\n      \"pmids\": [\"23663663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these multimeric modes occur in intact cellular complexes not shown\", \"Allosteric coupling between SH3 domains during multivalent binding unexplored\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that CD2AP SH3 domains selectively enhance Cbl-3/c-mediated ubiquitination of Ret51 (but not Ret9) defined isoform-selective RTK degradation as a CD2AP function.\",\n      \"evidence\": \"siRNA, Co-IP, ubiquitination assays, domain deletion/mutagenesis\",\n      \"pmids\": [\"24425877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for Ret51 versus Ret9 discrimination by CD2AP not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking CD2AP to GGA2, clathrin recycling, and insulin-stimulated GLUT4 trafficking (with CD2AP−/− podocytes failing to increase glucose uptake) provided the trafficking mechanism underlying the earlier septin 7 observation.\",\n      \"evidence\": \"Co-IP, live-cell imaging, subcellular fractionation, glucose uptake in CD2AP−/− podocytes\",\n      \"pmids\": [\"26546360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD2AP–GGA2 interaction is relevant in adipocytes or muscle cells unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that CD2AP-deficient mice (with kidney rescue) have reduced blood-brain barrier integrity independent of nephrotic syndrome established a CNS-intrinsic role for CD2AP.\",\n      \"evidence\": \"CD2AP−/− mice with kidney-specific rescue transgene, sodium fluorescein extravasation\",\n      \"pmids\": [\"26358779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell type mediating BBB defect (endothelial, pericyte, astrocyte) not identified\", \"Molecular mechanism at the BBB not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that CD2AP complexes with TrkA and p85 and regulates NGF/AKT signaling through Rab5+ signaling endosomes to control axonal arborization extended CD2AP's RTK-adaptor function to neurotrophin signaling.\",\n      \"evidence\": \"Co-IP, siRNA, overexpression, neurite outgrowth and signaling assays\",\n      \"pmids\": [\"27076424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD2AP regulates other Trk family receptors untested\", \"In vivo neuronal phenotype in CD2AP knockout brain not examined at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that CD2AP directly binds ICAM-1 and is required for ICAM-1-triggered PI3K/Rac1 activation and cortactin recruitment in endothelial cells, with CD2AP loss shifting leukocyte transmigration from paracellular to transcellular, defined CD2AP as a mechanosensitive regulator of endothelial barrier function.\",\n      \"evidence\": \"Co-IP, siRNA, force application on ICAM-1, Rac1 and migration assays\",\n      \"pmids\": [\"28484055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ICAM-1–CD2AP interaction occurs in other cell types unknown\", \"Structural interface between CD2AP and ICAM-1 not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional knockout in CD4 T cells showing that CD2AP limits TCR signal duration and suppresses Tfh differentiation during chronic viral infection identified CD2AP as an immune checkpoint modulator distinct from CIN85.\",\n      \"evidence\": \"T cell-specific conditional knockout, LCMV infection, TCR signaling and Tfh assays\",\n      \"pmids\": [\"29734372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target through which CD2AP dampens TCR signaling not identified\", \"Relevance to human chronic infections or autoimmunity not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cross-species rescue experiments showing that VEGF-A–induced Y10 phosphorylation of CD2AP's SH3-1 domain is essential for glomerular barrier function, despite Y10A mutation enhancing nephrin binding, revealed a counterintuitive regulatory switch where phosphorylation tunes affinity to enable dynamic slit diaphragm remodeling.\",\n      \"evidence\": \"Site-directed mutagenesis, phospho-specific antibodies, zebrafish and Drosophila rescue\",\n      \"pmids\": [\"31235616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for Y10 phosphorylation in vivo not confirmed beyond VEGF-A context\", \"Effect of Y10 phosphorylation on non-nephrin partners unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating conserved synaptic phenotypes across Drosophila cindr mutants, Cd2ap null mice, and human brain tissue—including impaired vesicle recycling, altered ubiquitin-proteasome-mediated turnover of Synapsin and PMCA, and reduced cytosolic calcium—established CD2AP as a synaptic proteostasis regulator with relevance to neurodegeneration.\",\n      \"evidence\": \"Genetic mutants in fly and mouse, co-IP, electrophysiology, proteomics, calcium imaging, human postmortem correlation\",\n      \"pmids\": [\"31412248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether synaptic defects are cell-autonomous in mammalian neurons not fully resolved\", \"Direct proteasome target of CD2AP regulation not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"NMR characterization showing bivalent binding of CD2AP SH3-A and SH3-C to chikungunya nsP3 HVD, with SH3-B left free, defined a cooperative multidomain binding mode exploited by an alphavirus for replication.\",\n      \"evidence\": \"NMR chemical shift perturbation, mutagenesis, viral replication assays\",\n      \"pmids\": [\"31493651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other RNA viruses exploit the same bivalent SH3 mechanism untested\", \"Role of SH3-B during viral infection not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Neuron-specific Cd2ap deletion in APP/PS1 mice causing p38 MAPK-dependent tau hyperphosphorylation, synaptic loss, and cognitive decline—rescued by p38 inhibition—provided the first direct in vivo evidence that CD2AP loss drives Alzheimer's-relevant pathology through a defined kinase cascade.\",\n      \"evidence\": \"Conditional neuronal knockout in APP/PS1 mice, immunoblotting, electrophysiology, behavioral tests, p38 inhibitor rescue\",\n      \"pmids\": [\"39696695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p38 activation is the primary or sole pathway downstream of neuronal CD2AP loss not established\", \"Mechanism connecting CD2AP to p38 MAPK activation not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD2AP's barbed-end capping activity, SH3-mediated scaffolding, and phosphoregulation are coordinated in a single molecule to switch between its diverse cellular roles—podocyte slit diaphragm maintenance, RTK endocytosis, synaptic proteostasis, and immune signaling—remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length CD2AP structure available\", \"Allosteric communication between the three SH3 domains and the C-terminal coiled-coil region unexplored\", \"Cell-type-specific regulatory mechanisms controlling CD2AP mode-switching not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5, 7, 8, 13, 15, 16]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [9, 10, 22, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 12, 14, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 7, 9, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9, 10, 22, 23]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 11, 15, 16, 30]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 10, 13, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 7, 12, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 15, 27]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [9, 15, 23]}\n    ],\n    \"complexes\": [\n      \"nephrin–podocin–CD2AP slit diaphragm complex\",\n      \"CD2AP–c-Cbl RTK endocytic complex\",\n      \"septin 7–CD2AP–nephrin complex\"\n    ],\n    \"partners\": [\n      \"NPHS1\",\n      \"NPHS2\",\n      \"CBL\",\n      \"FYN\",\n      \"SYNPO\",\n      \"TGFBR1\",\n      \"NTRK1\",\n      \"ICAM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}