{"gene":"CD2AP","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1999,"finding":"CMS/CD2AP interacts with the focal adhesion protein p130(Cas) via its proline-rich sequences binding to the SH3 domains of p130(Cas); its SH3 domains also bind Src-family kinases, p85 subunit of PI3K, and Grb2. The C-terminal coiled-coil domain mediates homodimerization. CD2AP colocalizes with F-actin and p130(Cas) at membrane ruffles and leading edges, and ectopic expression alters actin cytoskeleton organization.","method":"Co-immunoprecipitation, domain mapping, immunofluorescence, ectopic expression in COS-7 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays, domain mapping, and functional overexpression phenotype in a single study","pmids":["10339567"],"is_preprint":false},{"year":2000,"finding":"CD2AP binds the proto-oncogenic protein c-Cbl through its second SH3 domain interacting with the carboxyl terminus of c-Cbl; this interaction is dependent on tyrosine phosphorylation of CMS/CD2AP and is induced upon stimulation of cell-surface receptors (e.g., EGF). Both proteins colocalize at lamellipodia and leading edges of cells.","method":"SH3 domain binding assays, co-immunoprecipitation, immunofluorescence, EGF stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped binding, phosphorylation-dependence demonstrated, colocalization confirmed, single lab","pmids":["11067845"],"is_preprint":false},{"year":2001,"finding":"CD2AP localizes to the slit diaphragm of podocytes (demonstrated by immunoelectron microscopy), co-immunoprecipitates with nephrin from a podocyte cell line, and interacts with the cytoplasmic C-terminal domain of nephrin via a novel C-terminal domain of CD2AP.","method":"Immunoelectron microscopy, co-immunoprecipitation, domain mapping studies","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — immunoelectron microscopy for localization, reciprocal co-IP, domain mapping; confirmed by multiple independent studies","pmids":["11733379"],"is_preprint":false},{"year":2001,"finding":"In cultured podocytes, CD2AP colocalizes with F-actin at lamellipodia leading edges and in small spots associated with the Arp2/3 complex and cortactin (sites of dynamic actin assembly), whereas p130Cas localizes to focal adhesions. CD2AP thus associates with dynamic rather than stable actin structures in podocyte foot processes.","method":"Immunofluorescence, immunoelectron microscopy, co-localization with Arp2/3 and cortactin markers","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with multiple markers, single lab","pmids":["11553524"],"is_preprint":false},{"year":2003,"finding":"Both nephrin and CD2AP interact with the p85 regulatory subunit of PI3K in vivo, recruit PI3K to the plasma membrane, and together with podocin stimulate PI3K-dependent AKT signaling in podocytes. AKT mediates phosphorylation of Bad, protecting podocytes from detachment-induced cell death.","method":"Co-immunoprecipitation in vivo, PI3K recruitment assay, AKT signaling readouts, phosphoserine 2D gel analysis, podocyte cell culture","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo co-IP, functional PI3K/AKT signaling assay, multiple downstream readouts, replicated concept across labs","pmids":["12832477"],"is_preprint":false},{"year":2003,"finding":"CD2AP interacts constitutively with endophilin; EGF stimulation induces transient association of Cbl and EGFR with the CD2AP-endophilin complex. CD2AP binds cortactin via its second proline-rich region, and cortactin binds CD2AP through its SH3 domain. This links EGFR endocytosis to actin polymerization via the Arp2/3 complex. CD2AP and cortactin co-localize in EGF-induced membrane ruffles.","method":"Proteomics-based co-purification, co-immunoprecipitation at endogenous levels, domain mapping, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP, domain mapping, EGF-stimulated complex formation, single lab","pmids":["12672817"],"is_preprint":false},{"year":2003,"finding":"CD2AP/CMS interacts with GTP-bound Rab4 (Rab4-Q67L) via yeast two-hybrid and in vitro binding. Co-expression of Rab4-Q67L with CD2AP induces enlargement of EEA1-positive early endosomes. CD2AP also interacts with c-Cbl, and early endosome enlargement requires CD2AP to interact with both Rab4 and c-Cbl. A truncated CD2AP that binds Rab4 but not c-Cbl inhibits PDGF receptor degradation, placing CD2AP in the early-to-late endosome trafficking/degradative pathway.","method":"Yeast two-hybrid, in vitro binding, co-expression, truncation mutant analysis, fluorescence microscopy, PDGF receptor degradation assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding, yeast two-hybrid, domain requirement established by truncation mutants with functional readout (receptor degradation)","pmids":["12559036"],"is_preprint":false},{"year":2003,"finding":"CD2AP functions downstream of CD2 and the PSTPIP1 adaptor to promote formation of the immunological synapse; PSTPIP1 coiled-coil domain binds both CD2 and CD2AP, and the PSTPIP1 proline-rich region interacts with WASp. Expression of coiled-coil domain-deleted PSTPIP1 disrupts co-localization at the synapse and CD2-induced actin polymerization in WASp-deficient T cells is impaired.","method":"Co-immunoprecipitation, dominant-negative PSTPIP1 expression, T cell:APC conjugate formation assay, immunofluorescence","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by dominant-negative, co-IP, functional synapse formation assay, single lab","pmids":["12530983"],"is_preprint":false},{"year":2004,"finding":"VEGF stimulation induces formation of a ternary complex of Flt-1 (VEGFR-1), c-Cbl, and CD2AP in endocytic vesicles. Wild-type CD2AP enhances VEGF-stimulated internalization and ubiquitination of Flt-1, whereas dominant-negative CD2AP or mutated c-Cbl fails to do so, demonstrating that the c-Cbl/CD2AP complex is required for Flt-1 endocytosis and degradation.","method":"Co-immunoprecipitation, transient expression, immunofluorescence colocalization, endocytosis assay, ubiquitination assay, dominant-negative CD2AP","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative and functional endocytosis/ubiquitination assays, single lab","pmids":["15001553"],"is_preprint":false},{"year":2005,"finding":"Podocyte-specific expression of CD2AP in CD2AP-null mice rescues lethality and prevents proteinuria, demonstrating that the essential function of CD2AP for survival is specifically in podocytes and not in immune or other renal cells. CD2AP-deficient mice show age-related testicular abnormalities.","method":"Transgenic rescue with podocyte-specific promoter, histological and functional analysis of CD2AP-null mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue experiment with tissue-specific transgene, definitive functional localization to podocytes","pmids":["15951437"],"is_preprint":false},{"year":2005,"finding":"In living podocytes, CD2AP localizes to dynamic, motile actin-rich spots (≤0.5 μm) that are frequently associated with vesicles. These spots are enriched for cortactin and F-actin, belong to a Rab4-positive late endosomal compartment, and their motility depends on actin polymerization. CD2AP has a high turnover rate (FRAP half-time <10 s) in these spots.","method":"Confocal time-lapse microscopy (GFP-CD2AP), FRAP, G-actin microinjection, jasplakinolide treatment, marker co-localization","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with FRAP and pharmacological perturbation, single lab, multiple orthogonal methods","pmids":["15956777"],"is_preprint":false},{"year":2006,"finding":"VEGF-A signaling in podocytes induces upregulation of podocin and increases the interaction between podocin and CD2AP, linking VEGFR2 signaling to modulation of the slit diaphragm complex composition.","method":"Co-immunoprecipitation, VEGFR2 neutralizing antibody, recombinant VEGF165 treatment, Western blot","journal":"American journal of physiology. Renal physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP assay, one lab, limited mechanistic follow-up","pmids":["16597608"],"is_preprint":false},{"year":2006,"finding":"CD2AP forms a complex with TGF-beta receptor type I (TβRI) in Sertoli cells; when TβRI preferentially associates with CD2AP (rather than TAB1), only Sertoli-germ cell adhesion is disrupted without compromising the blood-testis barrier. This differential adaptor association routes TGF-β3 signaling selectively through p38 MAPK or ERK.","method":"Co-immunoprecipitation, in vivo TGF-β3 administration, p38/ERK signaling readouts, overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating complex, in vivo functional readout, pathway epistasis, single lab","pmids":["16617054"],"is_preprint":false},{"year":2007,"finding":"Dendrin is a constituent of the slit diaphragm complex that directly binds both nephrin and CD2AP. In experimental glomerulonephritis and under high-dose TGF-β1 stimulation, dendrin translocates from the slit diaphragm to the podocyte nucleus, where it promotes apoptosis. CD2AP can repress this proapoptotic TGF-β signaling.","method":"Co-immunoprecipitation, immunofluorescence, nuclear translocation assay, TGF-β1 stimulation, apoptosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by co-IP, functional nuclear translocation assay, single lab","pmids":["17537921"],"is_preprint":false},{"year":2007,"finding":"CD2AP deficiency in podocytes leads to diminished signaling initiation and termination of receptor tyrosine kinase (RTK) pathways (IGF-1, VEGF, FGF), with decreased PI3K/AKT and ERK signaling. CIN85, upregulated in CD2AP-deficient podocytes, contributes to RTK signaling termination; repression of CIN85 restores the RTK signaling response, indicating that CD2AP/CIN85 balance regulates podocyte RTK signaling.","method":"CD2AP-/- mouse podocytes, growth factor stimulation, Western blot for p-AKT/p-ERK, CIN85 knockdown rescue experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with defined signaling phenotype, rescue by paralog knockdown, single lab","pmids":["17213204"],"is_preprint":false},{"year":2008,"finding":"CD2AP associates with Ret receptor tyrosine kinase under basal (unstimulated) conditions in sympathetic neurons and dissociates upon GDNF-induced Ret activation. CD2AP also forms a complex with Cbl-3/c upon GDNF stimulation. CD2AP overexpression enhances Ret degradation and inhibits GDNF-dependent survival; CD2AP knockdown blocks Ret degradation and promotes survival, identifying CD2AP as a regulator of Ret downregulation.","method":"Co-immunoprecipitation from neurons, CD2AP overexpression and siRNA knockdown, Ret degradation assay, neuronal survival assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, gain- and loss-of-function with functional readouts (receptor degradation, survival), two orthogonal perturbations","pmids":["18753381"],"is_preprint":false},{"year":2008,"finding":"The Drosophila CD2AP/CIN85 ortholog Cindr links E-cadherin at cell junctions to multiple actin cytoskeleton components including capping protein alpha and capping protein beta. Reducing cindr activity causes defects in cell movement and tissue patterning. Cindr physically and functionally connects junction proteins and actin regulators.","method":"Drosophila genetics (cindr reduction), co-immunoprecipitation, genetic epistasis, fluorescence microscopy in developing retina","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila ortholog, physical interaction and genetic epistasis, defined cellular phenotype, single lab","pmids":["18362180"],"is_preprint":false},{"year":2009,"finding":"CD2AP interacts directly with the cytoplasmic tail of TGF-beta receptor type I (TβRI) in a kinase-dependent manner, and this interaction is required for TβRI to recruit the p85 subunit of PI3K, thereby activating the antiapoptotic PI3K/AKT pathway independently of Smad2/3 signaling. CD2AP-deficient podocytes are hypersensitive to TGF-β-induced apoptosis, while Smad3 deficiency is protective.","method":"Direct binding assay (C-terminal CD2AP with TβRI cytoplasmic tail), co-immunoprecipitation, CD2AP-/- and Smad-/- podocytes, apoptosis assay, TGF-β1 transgenic mouse model","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct interaction mapped by domain experiments, KO cells, in vivo mouse model, multiple orthogonal methods","pmids":["19679673"],"is_preprint":false},{"year":2010,"finding":"CD2AP specifically interacts with the C-terminal hypervariable domain of Rac1 (but not other Rho family members), requiring both the proline-rich domain and the poly-basic region of Rac1 and at least two of the three N-terminal SH3 domains of CD2AP. Constitutively active Rac1 recruits CD2AP to cell-cell contacts in epithelial cells, where CD2AP controls epithelial barrier function and links Rac1 to CAPZ and cortactin.","method":"Peptide-based pulldown with mass spectrometry, co-immunoprecipitation, siRNA knockdown, constitutively active Rac1 expression, barrier function assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide pulldown + MS identification, domain mapping, functional barrier assay, single lab","pmids":["20404345"],"is_preprint":false},{"year":2011,"finding":"CD2AP regulates the TGF-β1-dependent translocation of dendrin from the slit diaphragm to the podocyte nucleus. Nuclear dendrin acts as a transcription factor promoting expression of cytosolic cathepsin L (CatL), which proteolytically cleaves dynamin and synaptopodin, reorganizing the podocyte actin cytoskeleton. CD2AP itself is a CatL substrate, creating a feedforward loop. Loss of CD2AP increases apoptotic susceptibility to TGF-β1.","method":"CD2AP KO mouse and human podocytes, nuclear fractionation, transcription factor reporter assay, cathepsin L activity assay, proteolysis assays, mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic cascade established in KO cells and mice with biochemical reconstitution elements, multiple orthogonal methods, in vivo validation","pmids":["21911934"],"is_preprint":false},{"year":2011,"finding":"CD2AP regulates SUMOylation of its paralog CIN85 in podocytes: full-length CIN85 is SUMOylated by SUMO-1, -2, and -3 in wild-type podocytes and this SUMOylation is enhanced in the presence of CD2AP. SUMOylation at Lys598 prevents CIN85 from binding nephrin; K598R mutation abolishes SUMOylation and increases CIN85-nephrin binding.","method":"Co-immunoprecipitation, SUMOylation assay, site-directed mutagenesis (K598R), Western blot in CD2AP-/- vs WT podocytes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis defines SUMO site, functional consequence on nephrin binding shown, single lab but multiple orthogonal methods","pmids":["22203040"],"is_preprint":false},{"year":2011,"finding":"CD2AP NMR solution structures of all three SH3 domains were determined. The N-terminal SH3 domain of CD2AP (and CIN85) is the most stable SH3 domain characterized, driven by an extensive intramolecular interaction network; this high stability is proposed to be critical for maintaining the conformation needed for target recruitment.","method":"NMR spectroscopy, differential scanning calorimetry (DSC), FoldX structure-based thermodynamic analysis","journal":"Journal of biomolecular NMR","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure with thermodynamic validation, but functional consequence inferred rather than directly tested","pmids":["21519904"],"is_preprint":false},{"year":2012,"finding":"CD2AP links cortactin and actin capping protein (CP) at the cell periphery; loss of CD2AP reduces colocalization of CP and cortactin and impairs formation of short branched actin filaments characteristic of lamellipodia, resulting in defective cell migration. Super-resolution microscopy confirmed that CD2AP is required for efficient colocalization of CP and cortactin.","method":"siRNA knockdown, super-resolution fluorescence microscopy, cell migration assay, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined phenotype, super-resolution microscopy, co-IP, single lab","pmids":["23090967"],"is_preprint":false},{"year":2012,"finding":"Septin 7 forms a complex with CD2AP and nephrin (co-immunoprecipitation) and also with VAMP2. The filamentous localization of septin 7 depends on CD2AP and intact actin. Knockdown of septin 7 facilitates glucose uptake and increases the interaction of VAMP2 with nephrin and syntaxin 4, suggesting septin 7 (in a CD2AP-containing complex) hinders GLUT4 storage vesicle trafficking.","method":"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, 2-deoxy-D-glucose uptake assay, immunofluorescence","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP complex, KD functional assay, subcellular fractionation, single lab","pmids":["22809625"],"is_preprint":false},{"year":2012,"finding":"CD2AP positively regulates BDCA2/FcεR1γ receptor signaling in plasmacytoid dendritic cells by forming a complex with SHIP1 that inhibits the E3 ubiquitin ligase Cbl. CD2AP/SHIP1 knockdown reduces ITAM signaling, enhances ubiquitination and degradation of Syk and FcεR1γ, and blocks inhibition of TLR9-mediated type I IFN production. Upon BDCA2 cross-linking, the CD2AP/SHIP1/Cbl complex recruits to the plasma membrane.","method":"Co-immunoprecipitation, mass spectrometry, siRNA knockdown, ubiquitination assay, IFN production assay, immunofluorescence","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP + MS identification of SHIP1, KD with multiple functional readouts (signaling, ubiquitination, IFN), plasma membrane recruitment shown","pmids":["22706086"],"is_preprint":false},{"year":2013,"finding":"CD2AP (FSGS3) is a barbed-end actin capping protein that stabilizes actin at the adherens junction. Identified by in vitro reconstitution biochemistry with cross-linking approach; CD2AP colocalizes with E-cadherin and α-actinin-4 at the apical junction of MDCK cells. CD2AP knockdown reduces actin accumulation and stability at the adherens junction and compromises adhesive strength and barrier function under mechanical stress.","method":"In vitro reconstitution, actin barbed-end capping assay, siRNA knockdown, mechanical stress apparatus, barrier function assay, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution biochemistry establishing capping activity, functional KD phenotype with mechanical readout","pmids":["24322428"],"is_preprint":false},{"year":2013,"finding":"CD2AP SH3-A forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b, as characterized by NMR, isothermal titration calorimetry (ITC), and small-angle X-ray scattering. This multimeric binding mode enables high diversity in signaling complex assembly.","method":"NMR, isothermal titration calorimetry, small-angle X-ray scattering","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple structural/biophysical methods (NMR, ITC, SAXS) establishing binding modes in a single rigorous study","pmids":["23663663"],"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 to drive Cbl-3/c-dependent Ret51 ubiquitination; the coiled-coil domain of CD2AP is dispensable. Two major ubiquitination sites in Ret51 are Lys1060 and Lys1107. Activated Ret induces CD2AP degradation as a negative feedback.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, domain deletion mutants, site-directed mutagenesis of Ret lysines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain-requirement mapping, site-directed mutagenesis of substrate ubiquitination sites, functional ubiquitination/degradation assay","pmids":["24425877"],"is_preprint":false},{"year":2015,"finding":"CD2AP SH3 domains 1 and 2 show similar binding preferences; SH3-3 binds more weakly and recognizes an extended sequence in ALIX. Preferred binding motif is Px(P/A)xPR. Crystal structures of SH3-1 and SH3-2 in complex with RIN3 epitopes determined at 1.65 Å and 1.11 Å resolution. RIN3 recruits CD2AP to RAB5a-positive early endosomes via two SH3-binding sites.","method":"Crystal structure determination, peptide array screen, isothermal titration calorimetry, permutation arrays, co-immunoprecipitation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures combined with ITC and functional localization, multiple orthogonal methods in one study","pmids":["26296892"],"is_preprint":false},{"year":2015,"finding":"CD2AP is required for blood-brain barrier integrity in mice: CD2AP-deficient mice show increased sodium fluorescein extravasation (reduced BBB integrity) independent of nephrotic syndrome severity, and CD2AP is expressed in brain-adjacent endothelial cells. CD2AP-/- mice also show shorter latency to pentylenetetrazol-induced seizures.","method":"Sodium fluorescein extravasation assay, EEG, behavioral testing, CD2AP-/- mice with kidney-specific CD2AP rescue transgene","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct BBB integrity assay with genetic controls dissociating systemic illness, single lab","pmids":["26358779"],"is_preprint":false},{"year":2015,"finding":"CD2AP deficiency in podocytes disrupts GLUT4 (SLC2A4) trafficking: CD2AP-/- podocytes fail to increase glucose uptake in response to insulin, and HA-Glut4-GFP clusters perinuclearly rather than trafficking dynamically. CD2AP co-fractionates with GLUT4, IRAP, and sortilin on GLUT4 storage vesicles (GSVs), forms a complex with GGA2 (a clathrin adaptor sorting Glut4 to GSVs), and connects clathrin to actin in the perinuclear region.","method":"CD2AP-/- podocytes, live-cell imaging (HA-Glut4-GFP), 2-deoxy-D-glucose uptake assay, subcellular fractionation, co-immunoprecipitation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with direct functional assay, live imaging, fractionation, co-IP complex identification, multiple orthogonal methods","pmids":["26546360"],"is_preprint":false},{"year":2016,"finding":"CD2AP adaptor protein forms a novel complex with the NGF receptor TrkA and the PI3K regulatory subunit p85 in sensory neurons; CD2AP levels positively regulate the degree of TrkA:p85 association. CD2AP regulates NGF signaling through AKT (but not ERK) and regulates long-range NGF signaling through TrkA+/RAB5+ signaling endosomes. CD2AP functions as a positive regulator of axon growth and neurite complexity.","method":"Co-immunoprecipitation, siRNA knockdown and overexpression, neurite morphology assay, AKT/ERK signaling assays, endosome imaging","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel co-IP complex, gain/loss-of-function with defined signaling and morphological readouts, single lab","pmids":["27076424"],"is_preprint":false},{"year":2016,"finding":"CD2AP mediates internalization of the exosome cargo protein GPRC5B following cell surface delivery, contributing to Golgi accumulation of GPRC5B in parallel with biosynthetic trafficking.","method":"Inducible GPRC5B expression system, GPRC5B trafficking assay, siRNA knockdown of CD2AP","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment, limited mechanistic follow-up for CD2AP specifically","pmids":["27765817"],"is_preprint":false},{"year":2017,"finding":"In endothelial cells, CD2AP interacts with ICAM-1 and limits ICAM-1 clustering dynamics. Loss of CD2AP increases ICAM-1 complex formation, increases neutrophil adhesion, decreases crawling, and shifts neutrophil transmigration preference from paracellular to transcellular. Mechanistically, CD2AP is required for ICAM-1-mediated PI3K activation, cortactin/F-actin recruitment, and Rac1 recruitment and activation downstream of ICAM-1. Mechanical force on ICAM-1 impairs CD2AP binding to ICAM-1.","method":"Co-immunoprecipitation, CD2AP siRNA knockdown, neutrophil adhesion/transmigration assay, PI3K activation assay, Rac1 activation assay, mechanical force application","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding identified, KD with multiple mechanistic readouts (PI3K, cortactin, Rac1, transmigration), force-response assay","pmids":["28484057"],"is_preprint":false},{"year":2018,"finding":"Alphavirus (CHIKV) nsP3 HVD binds CD2AP via its SH3 domains; the interaction site was mapped to the second SH3-ligand-like element in nsP3 HVD. Mutation of the CD2AP-binding motif in nsP3 attenuates viral replication and abolishes co-localization of CD2AP with nsP3 and replication complexes. CD2AP binds nsP3 HVDs from many New and Old World alphaviruses.","method":"Quantitative proteomics, site-directed mutagenesis of nsP3, viral replication assay, immunofluorescence colocalization","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding site mapped by mutagenesis, functional viral replication readout, single lab","pmids":["29702546"],"is_preprint":false},{"year":2018,"finding":"CD2AP inactivation in CD4 T cells promotes follicular helper T cell (Tfh) differentiation during chronic LCMV infection, associated with extended TCR signaling duration and enhanced cytokine production specifically under TH1 conditions. CD2AP-deficient CD4 T cells show enhanced germinal center responses.","method":"CD4 T cell-specific CD2AP knockout, LCMV infection model, flow cytometry, TCR signaling duration assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular differentiation and signaling phenotype, in vivo infection model, single lab","pmids":["29734372"],"is_preprint":false},{"year":2018,"finding":"PAWS1 (FAM83G) interacts dynamically with CD2AP at lamellae. PAWS1 knockout causes F-actin disorganization, lamellipodial defects, and impaired cell migration. CD2AP knockout in U2OS cells produces similar actin and migration defects, consistent with the two proteins acting in the same cytoskeletal pathway.","method":"CRISPR/Cas9 knockout of PAWS1 and CD2AP, confocal microscopy, live-cell actin imaging, co-immunoprecipitation (interaction with CD2AP)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO, live imaging, defined actin and migration phenotype, interaction with CD2AP shown, single lab","pmids":["29175910"],"is_preprint":false},{"year":2019,"finding":"CD2AP overexpression accelerates transfer of APP from Rab5-positive early endosomes to Rab7-positive late endosomes, stimulating lysosomal APP degradation. CD2AP knockdown has the opposite effect. This trafficking role is conserved in primary cortical neurons from mice.","method":"CD2AP overexpression and siRNA knockdown in COS-7, HEK293 cells, and primary cortical neurons; Rab5/Rab7 co-localization; APP degradation assay; nutrient starvation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with subcellular localization readout and degradation assay, replicated in neurons, single lab","pmids":["31138646"],"is_preprint":false},{"year":2019,"finding":"VEGF-A stimulation induces tyrosine phosphorylation of CD2AP in podocytes. Phosphorylation of Y10 in the SH3-1 domain is indispensable for CD2AP function in vivo: the Y10 phosphorylation increases nephrin binding affinity to CD2AP, but this enhanced affinity paradoxically impairs glomerular filtration barrier function rather than stabilizing it, as demonstrated by cross-species rescue in cd2ap-knockdown zebrafish and Drosophila cindr mutants.","method":"Isoelectric focusing, site-directed mutagenesis, phospho-CD2AP antibodies, zebrafish cd2ap KD rescue, Drosophila cindr mutant rescue","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis defines phosphorylation site, cross-species in vivo rescue, functional filtration barrier readout, multiple orthogonal methods","pmids":["31235616"],"is_preprint":false},{"year":2019,"finding":"NMR structural analysis of CHIKV nsP3 HVD shows two SH3-binding sites; CD2AP interacts with HVD using its SH3-A and SH3-C domains, leaving SH3-B available for other partners. The cooperative bivalent interaction increases binding affinity. BIN1, CD2AP, and SH3KBP1 play redundant roles in initiation of CHIKV replication.","method":"NMR spectroscopy, chemical shift perturbation, point mutations in HVD binding sites, viral replication assay","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization of binding mode, domain identification, mutagenesis with functional replication readout, single lab","pmids":["31493651"],"is_preprint":false},{"year":2019,"finding":"The Drosophila CD2AP ortholog Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and synaptic vesicle recycling/release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and PMCA. Loss of cindr elevates PMCA levels and reduces cytosolic calcium. CD2AP null mice show conserved synaptic proteostasis defects.","method":"Drosophila cindr mutant analysis, synaptic physiology assays, co-immunoprecipitation (Cindr–14-3-3ζ), ubiquitin-proteasome assay, CD2AP null mouse analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Drosophila ortholog genetics, electrophysiology, biochemical interaction, and mammalian KO validation across two model systems","pmids":["31412248"],"is_preprint":false},{"year":2020,"finding":"CD2AP is a critical determinant of epithelial lateral membrane proportions: depletion of CD2AP or PI3K inhibition causes loss of F-actin and expansion of apical-basal domains at the expense of lateral membrane height in MDCK cells. The SH3 domains of CD2AP bind PI3K and are necessary for PI3K activity along lateral membranes. Tethering CD2AP SH3 domains or p110γ to the membrane rescues CD2AP-KD phenotypes. CD2AP and PI3K form a positive feedback loop linking actin assembly to PI3K activation at lateral membranes.","method":"siRNA knockdown, PI3K inhibition, domain rescue experiments (membrane-tethered SH3/p110γ), F-actin imaging in MDCK cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain-specific rescue experiments, pharmacological and genetic perturbation, defined morphological phenotype with mechanistic interpretation","pmids":["31723006"],"is_preprint":false},{"year":2020,"finding":"CD2AP inhibits gastric cancer cell metastasis by promoting cellular adhesion and cytoskeletal assembly; interaction with the F-actin capping protein CAPZA1 was demonstrated by immunofluorescence and is proposed as a mechanistic basis for CD2AP effects on cytoskeleton.","method":"CD2AP overexpression and knockdown in GC cells, migration/invasion assay, immunofluorescence showing CAPZA1 interaction, IHC of patient samples","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cell assay and co-localization but interaction with CAPZA1 not confirmed by co-IP, limited mechanistic follow-up","pmids":["31989722"],"is_preprint":false},{"year":2009,"finding":"CD2AP is indispensable for NK cell cytotoxicity: CD2AP knockdown reduces NK92 cell cytotoxicity, impairs conjugate formation with target cells, and prevents FasL-bearing granule polarization toward the contact site. CD2AP associates with FasL by co-immunoprecipitation and colocalizes with FasL-bearing granules near the cell contact site during killing.","method":"siRNA knockdown in NK92 cells, cytotoxicity assay, conjugate formation assay, degranulation assay, co-immunoprecipitation (CD2AP–FasL), immunofluorescence","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple functional readouts, co-IP identifying FasL interaction, single lab","pmids":["19945749"],"is_preprint":false},{"year":2016,"finding":"Tankyrases interact with CD2AP and regulate Wnt/β-catenin signaling in podocytes. In the absence of CD2AP, tankyrase-mediated PARylation is increased and β-catenin activity is elevated. CD2AP-deficient podocytes show upregulation of LEF1 and fibronectin, downstream targets of Wnt/β-catenin. In zebrafish, tankyrase inhibition in CD2AP-depleted larvae aggravates kidney injury.","method":"Co-immunoprecipitation (tankyrase–CD2AP), CD2AP-/- podocytes, tankyrase inhibitor XAV939, zebrafish cd2ap knockdown model, β-catenin activity assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, KO cells, in vivo zebrafish model, multiple signaling readouts, single lab","pmids":["27441654"],"is_preprint":false},{"year":2024,"finding":"Neuronal knockout of Cd2ap in APP/PS1 mice activates p38 MAPK signaling, leading to increased tau phosphorylation, synaptic injury, neuronal apoptosis, and cognitive impairment. Treatment with a p38 MAPK inhibitor ameliorates these phenotypes, placing CD2AP upstream of p38 MAPK in a pathway regulating tau pathology.","method":"Neuron-specific Cd2ap knockout in APP/PS1 mice, immunoblotting, immunofluorescence, electrophysiology, behavioral tests, p38 MAPK inhibitor treatment, stable CD2AP-KD SH-SY5Y cells","journal":"Translational neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with rescue by pharmacological inhibitor, multiple readouts (tau phosphorylation, synaptic physiology, behavior), two model systems","pmids":["39696695"],"is_preprint":false},{"year":2024,"finding":"CD2AP promotes glioblastoma progression by interacting with TRIM5, an NF-κB modulator. CD2AP overexpression increases TRIM5 levels and NF-κB activity; CD2AP knockdown has opposite effects. Downregulation of TRIM5 reverses elevated NF-κB activity in CD2AP-overexpressing cells, and NF-κB inhibition attenuates malignant features induced by CD2AP overexpression.","method":"Co-immunoprecipitation (CD2AP–TRIM5), CD2AP overexpression and knockdown in GBM cells, NF-κB reporter assay, TRIM5 knockdown epistasis, in vivo tumorigenesis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, gain/loss-of-function, genetic epistasis (TRIM5 KD rescue), in vivo tumor model, single lab","pmids":["39353894"],"is_preprint":false}],"current_model":"CD2AP is a multifunctional scaffolding adaptor protein containing three SH3 domains, a proline-rich region, and a coiled-coil domain that assembles multiprotein complexes at the plasma membrane and endosomes: in podocytes, it localizes to the slit diaphragm where it directly binds nephrin (via its C-terminal domain) and TGF-β receptor type I (via its C-terminus), recruits PI3K/AKT pro-survival signaling, gates cathepsin L-dependent cytoskeletal remodeling, and controls SUMOylation of its paralog CIN85; it acts as a barbed-end actin capping protein that stabilizes adherens junction actin and, via its SH3 domains, links cortactin and capping protein CP at lamellipodia; it regulates receptor tyrosine kinase downregulation (EGFR, Ret, Flt-1) by forming complexes with c-Cbl/Cbl-3 and endophilin; it regulates endosomal sorting through interaction with Rab4; in the nervous system it coordinates NGF/TrkA–p85–PI3K–AKT signaling endosomes and, through 14-3-3ζ, regulates synaptic proteostasis; and tyrosine phosphorylation (at Y10 of SH3-1 by VEGF-A/RTK signaling) fine-tunes its interaction affinity with nephrin to control slit diaphragm stability."},"narrative":{"mechanistic_narrative":"CD2AP is a multivalent scaffolding adaptor built from three N-terminal SH3 domains, a proline-rich region, and a C-terminal coiled-coil that homodimerizes, assembling signaling and cytoskeletal complexes at the plasma membrane, cell junctions, and endosomes [PMID:10339567, PMID:21519904, PMID:23663663]. Its SH3 domains recognize a Px(P/A)xPR motif and engage diverse partners — Src-family kinases, the PI3K p85 subunit, Grb2, c-Cbl, and cortactin — and can form type I and type II dimeric complexes that diversify the architecture of the assemblies it nucleates [PMID:10339567, PMID:23663663, PMID:26296892]. A dominant function is the coupling of actin dynamics to membrane organization: CD2AP is a barbed-end actin-capping protein that stabilizes junctional actin and bridges cortactin to capping protein at lamellipodia, sustaining branched-filament assembly required for cell migration and epithelial barrier and lateral-membrane integrity, in part through a CD2AP–PI3K positive feedback loop [PMID:23090967, PMID:24322428, PMID:31723006]. CD2AP also drives receptor tyrosine kinase downregulation by partnering with c-Cbl/Cbl-3 and endophilin and with Rab4 to route activated receptors — EGFR, Flt-1, Ret51, and PDGFR — through the endosomal degradative pathway [PMID:12672817, PMID:12559036, PMID:15001553, PMID:24425877]. In podocytes it localizes to the slit diaphragm, binds the cytoplasmic tail of nephrin through a C-terminal domain, and recruits PI3K/AKT pro-survival signaling alongside nephrin and podocin [PMID:11733379, PMID:12832477]; its tissue-specific requirement in podocytes is essential for survival and prevention of proteinuria [PMID:15951437]. CD2AP gates TGF-β signaling by binding TβRI to activate antiapoptotic PI3K/AKT independently of Smad and by restraining dendrin-driven, cathepsin L-dependent cytoskeletal proteolysis, with CD2AP itself a cathepsin L substrate in a feedforward loop [PMID:19679673, PMID:21911934]. Beyond the kidney, CD2AP functions in immune-cell adhesion and synapse formation, endothelial barrier and neutrophil transmigration, neuronal NGF/TrkA–p85–PI3K signaling endosomes, and synaptic proteostasis via 14-3-3ζ, and neuronal loss of CD2AP drives p38 MAPK-dependent tau pathology in an Alzheimer's model [PMID:12530983, PMID:27076424, PMID:28484057, PMID:31412248, PMID:39696695].","teleology":[{"year":1999,"claim":"Defined CD2AP as an SH3-and-coiled-coil adaptor that physically links signaling kinases to the actin cytoskeleton, establishing its core architecture and biochemical logic.","evidence":"Co-IP, domain mapping, and immunofluorescence of ectopically expressed CMS/CD2AP in COS-7 cells","pmids":["10339567"],"confidence":"Medium","gaps":["Functional consequence of each interaction not tested in physiological cells","No endogenous-level validation"]},{"year":2000,"claim":"Showed CD2AP binds c-Cbl in a tyrosine-phosphorylation- and receptor-stimulation-dependent manner, linking the adaptor to receptor signaling at the leading edge.","evidence":"SH3 domain binding assays, co-IP, and EGF stimulation with immunofluorescence","pmids":["11067845"],"confidence":"Medium","gaps":["Functional role in receptor downregulation not yet established","Single lab"]},{"year":2001,"claim":"Placed CD2AP at the podocyte slit diaphragm as a direct nephrin partner, defining its central role in glomerular filtration barrier architecture.","evidence":"Immunoelectron microscopy, reciprocal co-IP, and domain mapping in a podocyte cell line","pmids":["11733379"],"confidence":"High","gaps":["Downstream signaling from the nephrin–CD2AP complex not yet defined"]},{"year":2003,"claim":"Linked the nephrin–CD2AP complex to PI3K/AKT pro-survival signaling, explaining how slit-diaphragm assembly protects podocytes from detachment-induced death.","evidence":"In vivo co-IP, PI3K recruitment and AKT/Bad phosphorylation readouts in podocytes","pmids":["12832477"],"confidence":"High","gaps":["Stoichiometry of nephrin/podocin/CD2AP/PI3K complex unresolved"]},{"year":2003,"claim":"Established CD2AP as an endosomal trafficking adaptor by mapping interactions with Rab4, c-Cbl, and endophilin/cortactin that route activated receptors toward degradation.","evidence":"Yeast two-hybrid, in vitro binding, truncation mutants, and PDGFR/EGFR degradation assays","pmids":["12559036","12672817"],"confidence":"High","gaps":["Direct demonstration of CD2AP on the degradative carriers limited to marker co-localization"]},{"year":2004,"claim":"Demonstrated a Flt-1/c-Cbl/CD2AP ternary complex required for VEGFR-1 internalization and ubiquitination, generalizing the receptor-downregulation function to angiogenic receptors.","evidence":"Co-IP, dominant-negative CD2AP, and endocytosis/ubiquitination assays","pmids":["15001553"],"confidence":"Medium","gaps":["Relies on overexpression and dominant-negative; endogenous requirement untested"]},{"year":2005,"claim":"Pinpointed the essential, life-sustaining function of CD2AP to podocytes via tissue-specific transgenic rescue, separating its renal role from immune functions.","evidence":"Podocyte-specific transgenic rescue of CD2AP-null mice with histology and proteinuria readouts","pmids":["15951437"],"confidence":"High","gaps":["Molecular basis of podocyte specificity not addressed","Testicular phenotype mechanism unexplored"]},{"year":2006,"claim":"Showed differential adaptor partnering of TβRI (CD2AP vs TAB1) routes TGF-β signaling through distinct MAPK outputs, introducing CD2AP as a TGF-β signaling determinant.","evidence":"Co-IP and in vivo TGF-β3 administration with p38/ERK readouts in Sertoli cells","pmids":["16617054"],"confidence":"Medium","gaps":["Direct CD2AP–TβRI binding interface not mapped in this study"]},{"year":2007,"claim":"Defined the CD2AP/CIN85 balance as a rheostat for podocyte RTK signaling and identified dendrin as a CD2AP-bound proapoptotic slit-diaphragm factor.","evidence":"CD2AP-/- podocytes with growth-factor stimulation and CIN85-knockdown rescue; co-IP and nuclear translocation assays for dendrin","pmids":["17213204","17537921"],"confidence":"Medium","gaps":["Mechanism by which CIN85 upregulation terminates RTK signaling not fully resolved"]},{"year":2008,"claim":"Extended the receptor-degradation role to neuronal Ret and revealed activity-dependent association/dissociation, establishing CD2AP as a negative regulator of GDNF/Ret survival signaling.","evidence":"Reciprocal co-IP, gain- and loss-of-function in sympathetic neurons with Ret degradation and survival assays","pmids":["18753381"],"confidence":"High","gaps":["Isoform selectivity of Ret regulation not yet examined here"]},{"year":2008,"claim":"Used the Drosophila ortholog Cindr to show evolutionary conservation of CD2AP as a bridge between cadherin junctions and actin capping proteins controlling tissue patterning.","evidence":"Drosophila cindr genetics, co-IP, and epistasis in developing retina","pmids":["18362180"],"confidence":"Medium","gaps":["Mammalian junctional capping role not yet demonstrated biochemically"]},{"year":2009,"claim":"Established CD2AP requirements in immune effector function, including NK-cell cytotoxicity through FasL-granule polarization.","evidence":"siRNA knockdown in NK92 cells, cytotoxicity/conjugate/degranulation assays, and CD2AP–FasL co-IP","pmids":["19945749"],"confidence":"Medium","gaps":["Direct binding interface and reciprocal validation absent","Single lab"]},{"year":2009,"claim":"Resolved a direct, kinase-dependent CD2AP–TβRI interaction that recruits PI3K to activate antiapoptotic AKT independently of Smad, explaining CD2AP-loss hypersensitivity to TGF-β.","evidence":"Direct binding assay, CD2AP-/- and Smad-/- podocytes, apoptosis assay, and TGF-β1 transgenic mice","pmids":["19679673"],"confidence":"High","gaps":["Phosphorylation event controlling the interaction not identified"]},{"year":2010,"claim":"Identified CD2AP as a Rac1-specific effector recruited to cell-cell contacts that links Rac1 to capping protein and cortactin for epithelial barrier control.","evidence":"Peptide pulldown/MS, domain mapping, siRNA, constitutively active Rac1, and barrier assays","pmids":["20404345"],"confidence":"Medium","gaps":["Whether Rac1 binding is direct in cells vs via complexes not fully resolved"]},{"year":2011,"claim":"Defined the dendrin–cathepsin L cascade through which CD2AP gates actin-remodeling proteolysis, with CD2AP as both a regulator and a substrate in a feedforward loop.","evidence":"CD2AP KO podocytes and mice, nuclear fractionation, cathepsin L activity, and proteolysis assays","pmids":["21911934"],"confidence":"High","gaps":["Trigger linking CD2AP loss to dendrin release not fully defined"]},{"year":2011,"claim":"Revealed CD2AP-dependent SUMOylation of its paralog CIN85 at Lys598 as a switch controlling competition for nephrin binding.","evidence":"SUMOylation assays, K598R mutagenesis, and binding assays in WT vs CD2AP-/- podocytes","pmids":["22203040"],"confidence":"High","gaps":["SUMO E3 ligase and how CD2AP enhances SUMOylation unidentified"]},{"year":2011,"claim":"Provided NMR solution structures of all three SH3 domains, identifying the exceptionally stable N-terminal SH3 as a determinant of target recruitment.","evidence":"NMR, differential scanning calorimetry, and FoldX thermodynamic analysis","pmids":["21519904"],"confidence":"Medium","gaps":["Functional consequence of stability inferred, not directly tested"]},{"year":2012,"claim":"Demonstrated CD2AP is required to colocalize capping protein with cortactin and to build lamellipodial branched actin for cell migration.","evidence":"siRNA, super-resolution microscopy, migration assay, and co-IP","pmids":["23090967"],"confidence":"Medium","gaps":["Direct simultaneous binding of CP and cortactin by one CD2AP molecule not shown"]},{"year":2012,"claim":"Connected CD2AP/nephrin complexes to septin 7 and GLUT4-vesicle trafficking, implicating CD2AP in metabolic vesicle regulation in podocytes.","evidence":"Co-IP, siRNA, fractionation, and glucose uptake assays","pmids":["22809625"],"confidence":"Medium","gaps":["Direct CD2AP–septin 7 interaction interface unmapped"]},{"year":2012,"claim":"Defined CD2AP/SHIP1 as positive regulators of BDCA2/FcεR1γ ITAM signaling that restrain Cbl-mediated degradation in plasmacytoid dendritic cells.","evidence":"Co-IP/MS, siRNA, ubiquitination and IFN assays, and membrane recruitment imaging","pmids":["22706086"],"confidence":"High","gaps":["Structural basis of CD2AP–SHIP1–Cbl assembly not resolved"]},{"year":2013,"claim":"Established CD2AP as a bona fide barbed-end actin-capping protein that stabilizes adherens-junction actin under mechanical stress through in vitro reconstitution.","evidence":"In vitro reconstitution, barbed-end capping assay, siRNA, and mechanical-stress barrier assays","pmids":["24322428"],"confidence":"High","gaps":["Regulation of capping activity in cells (on/off switch) not defined"]},{"year":2013,"claim":"Characterized the multimeric SH3 dimerization modes of CD2AP with CD2 and Cbl-b, explaining how the adaptor diversifies signaling complex assembly.","evidence":"NMR, isothermal titration calorimetry, and small-angle X-ray scattering","pmids":["23663663"],"confidence":"High","gaps":["Cellular relevance of specific dimer modes not tested in vivo"]},{"year":2014,"claim":"Mapped isoform-selective Ret51 ubiquitination driven by CD2AP SH3 domains and Cbl-3/c, with Ret-induced CD2AP degradation as negative feedback.","evidence":"Co-IP, siRNA, ubiquitination assays, domain deletions, and substrate lysine mutagenesis","pmids":["24425877"],"confidence":"High","gaps":["Mechanism of Ret9 vs Ret51 discrimination not fully explained"]},{"year":2015,"claim":"Defined the SH3 binding motif (Px(P/A)xPR) and solved high-resolution structures with RIN3 epitopes, showing RIN3 recruits CD2AP to Rab5+ early endosomes.","evidence":"Crystal structures, peptide arrays, ITC, co-IP, and immunofluorescence","pmids":["26296892"],"confidence":"High","gaps":["Full repertoire of physiological motif-bearing partners not enumerated"]},{"year":2015,"claim":"Demonstrated CD2AP is required for blood-brain barrier integrity independently of nephrotic illness, broadening its barrier-maintenance role beyond the kidney.","evidence":"Fluorescein extravasation, EEG/behavior, in kidney-rescued CD2AP-/- mice","pmids":["26358779"],"confidence":"Medium","gaps":["Molecular mechanism of CD2AP action in brain endothelium undefined"]},{"year":2015,"claim":"Established CD2AP control of GLUT4 storage-vesicle trafficking via GGA2 and clathrin–actin connection, linking it to insulin-responsive glucose uptake.","evidence":"CD2AP-/- podocytes, live imaging, fractionation, and co-IP","pmids":["26546360"],"confidence":"High","gaps":["Direct vs indirect nature of CD2AP–GGA2 association unclear"]},{"year":2016,"claim":"Revealed CD2AP as a TrkA/p85 scaffold that promotes long-range NGF–AKT signaling endosomes and axon growth in sensory neurons.","evidence":"Co-IP, gain/loss-of-function, neurite morphology, AKT/ERK, and endosome imaging","pmids":["27076424"],"confidence":"Medium","gaps":["Selectivity for AKT over ERK mechanism not explained"]},{"year":2016,"claim":"Connected CD2AP to tankyrase-regulated Wnt/β-catenin signaling in podocytes, with CD2AP loss elevating β-catenin activity and kidney injury.","evidence":"Co-IP, CD2AP-/- podocytes, XAV939, zebrafish KD, and β-catenin readouts","pmids":["27441654"],"confidence":"Medium","gaps":["Direct biochemical link between CD2AP and tankyrase PARylation undefined"]},{"year":2017,"claim":"Showed CD2AP binds ICAM-1 and is a mechanosensitive node coupling endothelial ICAM-1 to PI3K/cortactin/Rac1 to govern neutrophil transmigration route.","evidence":"Co-IP, siRNA, transmigration, PI3K/Rac1 activation assays, and force application","pmids":["28484057"],"confidence":"High","gaps":["Force-dependent conformational basis of CD2AP–ICAM-1 release not structurally resolved"]},{"year":2018,"claim":"Identified CD2AP as a host factor exploited by alphavirus nsP3 via cooperative bivalent SH3 binding, with redundancy among CD2AP/BIN1/SH3KBP1 in replication initiation.","evidence":"Quantitative proteomics, NMR, nsP3 mutagenesis, and viral replication assays","pmids":["29702546","31493651"],"confidence":"Medium","gaps":["Cellular pathway co-opted by the CD2AP–nsP3 interaction not fully defined"]},{"year":2018,"claim":"Showed CD2AP restrains TCR signaling duration in CD4 T cells, limiting follicular helper differentiation during chronic infection.","evidence":"CD4-specific CD2AP KO, LCMV model, flow cytometry, and TCR signaling assays","pmids":["29734372"],"confidence":"Medium","gaps":["Molecular target of CD2AP that shortens TCR signaling not identified"]},{"year":2019,"claim":"Demonstrated that VEGF-A-driven Y10 phosphorylation in SH3-1 tunes nephrin-binding affinity, with cross-species rescue showing this fine-tuning is functionally indispensable for the filtration barrier.","evidence":"Isoelectric focusing, mutagenesis, phospho-antibodies, and zebrafish/Drosophila rescue with filtration readouts","pmids":["31235616"],"confidence":"High","gaps":["Kinase responsible for Y10 phosphorylation not definitively assigned"]},{"year":2019,"claim":"Defined a conserved CD2AP role in endosomal sorting of APP toward lysosomal degradation, linking CD2AP trafficking activity to APP processing.","evidence":"Gain/loss-of-function in cell lines and neurons, Rab5/Rab7 co-localization, and APP degradation assays","pmids":["31138646"],"confidence":"Medium","gaps":["Direct effect on amyloidogenic vs non-amyloidogenic cleavage not resolved"]},{"year":2019,"claim":"Established a conserved synaptic role for CD2AP/Cindr in synapse maturation and proteostasis via 14-3-3ζ and the ubiquitin-proteasome system, validated in null mice.","evidence":"Drosophila cindr genetics, synaptic physiology, Cindr–14-3-3ζ co-IP, and CD2AP null mouse analysis","pmids":["31412248"],"confidence":"High","gaps":["Direct substrates of CD2AP-regulated synaptic proteostasis incompletely defined"]},{"year":2020,"claim":"Identified a CD2AP–PI3K positive-feedback loop at lateral membranes that sets epithelial lateral membrane proportions through F-actin and PI3K activity.","evidence":"siRNA, PI3K inhibition, membrane-tethered domain rescue, and F-actin imaging in MDCK cells","pmids":["31723006"],"confidence":"High","gaps":["How SH3-bound PI3K is locally activated mechanistically not fully resolved"]},{"year":2024,"claim":"Placed CD2AP upstream of p38 MAPK in neurons, where its loss promotes tau phosphorylation and cognitive decline, reversible by p38 inhibition.","evidence":"Neuron-specific Cd2ap KO in APP/PS1 mice, electrophysiology, behavior, and p38 inhibitor rescue","pmids":["39696695"],"confidence":"High","gaps":["Direct molecular link from CD2AP loss to p38 activation not identified"]},{"year":2024,"claim":"Showed CD2AP can promote glioblastoma progression through a TRIM5–NF-κB axis, revealing a context-dependent pro-tumor role.","evidence":"Co-IP, gain/loss-of-function, NF-κB reporter, TRIM5-knockdown epistasis, and in vivo tumorigenesis","pmids":["39353894"],"confidence":"Medium","gaps":["Mechanism of CD2AP-dependent TRIM5 stabilization undefined"]},{"year":null,"claim":"How CD2AP's actin-capping activity, receptor-degradation function, and PI3K/AKT scaffolding are coordinately switched by phosphorylation and partner availability in each tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating capping, trafficking, and signaling roles","Upstream kinases controlling CD2AP phosphostate largely unidentified","Quantitative competition among nephrin, CIN85, and other SH3/C-terminal partners not mapped in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,5,24,31,41]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[22,25,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8,15,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,24,41]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,8,28,37]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,3,22,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,17,33,41]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,8,27,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,24,35,43]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,27,20]}],"complexes":["slit diaphragm complex","GLUT4 storage vesicle"],"partners":["NPHS1","CBL","RAB4A","CTTN","RAC1","TGFBR1","SH3KBP1","PSTPIP1"],"other_free_text":[]}},"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; 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Basic to translational science","url":"https://pubmed.ncbi.nlm.nih.gov/38984045","citation_count":13,"is_preprint":false},{"pmid":"31810186","id":"PMC_31810186","title":"Integrated Methylome and Transcriptome Analysis between the CMS-D2 Line ZBA and Its Maintainer Line ZB in Upland Cotton.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31810186","citation_count":13,"is_preprint":false},{"pmid":"33719006","id":"PMC_33719006","title":"Anthracycline-Induced Cardiotoxicity: Molecular Insights Obtained from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs).","date":"2021","source":"The AAPS journal","url":"https://pubmed.ncbi.nlm.nih.gov/33719006","citation_count":13,"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":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":"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":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":"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":"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":"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":12,"is_preprint":false},{"pmid":"39035791","id":"PMC_39035791","title":"Upregulation of utrophin improves the phenotype of Duchenne muscular dystrophy hiPSC-derived CMs.","date":"2024","source":"Molecular therapy. 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The C-terminal coiled-coil domain mediates homodimerization. CD2AP colocalizes with F-actin and p130(Cas) at membrane ruffles and leading edges, and ectopic expression alters actin cytoskeleton organization.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, immunofluorescence, ectopic expression in COS-7 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays, domain mapping, and functional overexpression phenotype in a single study\",\n      \"pmids\": [\"10339567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD2AP binds the proto-oncogenic protein c-Cbl through its second SH3 domain interacting with the carboxyl terminus of c-Cbl; this interaction is dependent on tyrosine phosphorylation of CMS/CD2AP and is induced upon stimulation of cell-surface receptors (e.g., EGF). Both proteins colocalize at lamellipodia and leading edges of cells.\",\n      \"method\": \"SH3 domain binding assays, co-immunoprecipitation, immunofluorescence, EGF stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped binding, phosphorylation-dependence demonstrated, colocalization confirmed, single lab\",\n      \"pmids\": [\"11067845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD2AP localizes to the slit diaphragm of podocytes (demonstrated by immunoelectron microscopy), co-immunoprecipitates with nephrin from a podocyte cell line, and interacts with the cytoplasmic C-terminal domain of nephrin via a novel C-terminal domain of CD2AP.\",\n      \"method\": \"Immunoelectron microscopy, co-immunoprecipitation, domain mapping studies\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — immunoelectron microscopy for localization, reciprocal co-IP, domain mapping; confirmed by multiple independent studies\",\n      \"pmids\": [\"11733379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In cultured podocytes, CD2AP colocalizes with F-actin at lamellipodia leading edges and in small spots associated with the Arp2/3 complex and cortactin (sites of dynamic actin assembly), whereas p130Cas localizes to focal adhesions. CD2AP thus associates with dynamic rather than stable actin structures in podocyte foot processes.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy, co-localization with Arp2/3 and cortactin markers\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with multiple markers, single lab\",\n      \"pmids\": [\"11553524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Both nephrin and CD2AP interact with the p85 regulatory subunit of PI3K in vivo, recruit PI3K to the plasma membrane, and together with podocin stimulate PI3K-dependent AKT signaling in podocytes. AKT mediates phosphorylation of Bad, protecting podocytes from detachment-induced cell death.\",\n      \"method\": \"Co-immunoprecipitation in vivo, PI3K recruitment assay, AKT signaling readouts, phosphoserine 2D gel analysis, podocyte cell culture\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo co-IP, functional PI3K/AKT signaling assay, multiple downstream readouts, replicated concept across labs\",\n      \"pmids\": [\"12832477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD2AP interacts constitutively with endophilin; EGF stimulation induces transient association of Cbl and EGFR with the CD2AP-endophilin complex. CD2AP binds cortactin via its second proline-rich region, and cortactin binds CD2AP through its SH3 domain. This links EGFR endocytosis to actin polymerization via the Arp2/3 complex. CD2AP and cortactin co-localize in EGF-induced membrane ruffles.\",\n      \"method\": \"Proteomics-based co-purification, co-immunoprecipitation at endogenous levels, domain mapping, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP, domain mapping, EGF-stimulated complex formation, single lab\",\n      \"pmids\": [\"12672817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD2AP/CMS interacts with GTP-bound Rab4 (Rab4-Q67L) via yeast two-hybrid and in vitro binding. Co-expression of Rab4-Q67L with CD2AP induces enlargement of EEA1-positive early endosomes. CD2AP also interacts with c-Cbl, and early endosome enlargement requires CD2AP to interact with both Rab4 and c-Cbl. A truncated CD2AP that binds Rab4 but not c-Cbl inhibits PDGF receptor degradation, placing CD2AP in the early-to-late endosome trafficking/degradative pathway.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-expression, truncation mutant analysis, fluorescence microscopy, PDGF receptor degradation assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding, yeast two-hybrid, domain requirement established by truncation mutants with functional readout (receptor degradation)\",\n      \"pmids\": [\"12559036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD2AP functions downstream of CD2 and the PSTPIP1 adaptor to promote formation of the immunological synapse; PSTPIP1 coiled-coil domain binds both CD2 and CD2AP, and the PSTPIP1 proline-rich region interacts with WASp. Expression of coiled-coil domain-deleted PSTPIP1 disrupts co-localization at the synapse and CD2-induced actin polymerization in WASp-deficient T cells is impaired.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative PSTPIP1 expression, T cell:APC conjugate formation assay, immunofluorescence\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by dominant-negative, co-IP, functional synapse formation assay, single lab\",\n      \"pmids\": [\"12530983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VEGF stimulation induces formation of a ternary complex of Flt-1 (VEGFR-1), c-Cbl, and CD2AP in endocytic vesicles. Wild-type CD2AP enhances VEGF-stimulated internalization and ubiquitination of Flt-1, whereas dominant-negative CD2AP or mutated c-Cbl fails to do so, demonstrating that the c-Cbl/CD2AP complex is required for Flt-1 endocytosis and degradation.\",\n      \"method\": \"Co-immunoprecipitation, transient expression, immunofluorescence colocalization, endocytosis assay, ubiquitination assay, dominant-negative CD2AP\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative and functional endocytosis/ubiquitination assays, single lab\",\n      \"pmids\": [\"15001553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Podocyte-specific expression of CD2AP in CD2AP-null mice rescues lethality and prevents proteinuria, demonstrating that the essential function of CD2AP for survival is specifically in podocytes and not in immune or other renal cells. CD2AP-deficient mice show age-related testicular abnormalities.\",\n      \"method\": \"Transgenic rescue with podocyte-specific promoter, histological and functional analysis of CD2AP-null mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiment with tissue-specific transgene, definitive functional localization to podocytes\",\n      \"pmids\": [\"15951437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In living podocytes, CD2AP localizes to dynamic, motile actin-rich spots (≤0.5 μm) that are frequently associated with vesicles. These spots are enriched for cortactin and F-actin, belong to a Rab4-positive late endosomal compartment, and their motility depends on actin polymerization. CD2AP has a high turnover rate (FRAP half-time <10 s) in these spots.\",\n      \"method\": \"Confocal time-lapse microscopy (GFP-CD2AP), FRAP, G-actin microinjection, jasplakinolide treatment, marker co-localization\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with FRAP and pharmacological perturbation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15956777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"VEGF-A signaling in podocytes induces upregulation of podocin and increases the interaction between podocin and CD2AP, linking VEGFR2 signaling to modulation of the slit diaphragm complex composition.\",\n      \"method\": \"Co-immunoprecipitation, VEGFR2 neutralizing antibody, recombinant VEGF165 treatment, Western blot\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP assay, one lab, limited mechanistic follow-up\",\n      \"pmids\": [\"16597608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD2AP forms a complex with TGF-beta receptor type I (TβRI) in Sertoli cells; when TβRI preferentially associates with CD2AP (rather than TAB1), only Sertoli-germ cell adhesion is disrupted without compromising the blood-testis barrier. This differential adaptor association routes TGF-β3 signaling selectively through p38 MAPK or ERK.\",\n      \"method\": \"Co-immunoprecipitation, in vivo TGF-β3 administration, p38/ERK signaling readouts, overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating complex, in vivo functional readout, pathway epistasis, single lab\",\n      \"pmids\": [\"16617054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dendrin is a constituent of the slit diaphragm complex that directly binds both nephrin and CD2AP. In experimental glomerulonephritis and under high-dose TGF-β1 stimulation, dendrin translocates from the slit diaphragm to the podocyte nucleus, where it promotes apoptosis. CD2AP can repress this proapoptotic TGF-β signaling.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, nuclear translocation assay, TGF-β1 stimulation, apoptosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by co-IP, functional nuclear translocation assay, single lab\",\n      \"pmids\": [\"17537921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD2AP deficiency in podocytes leads to diminished signaling initiation and termination of receptor tyrosine kinase (RTK) pathways (IGF-1, VEGF, FGF), with decreased PI3K/AKT and ERK signaling. CIN85, upregulated in CD2AP-deficient podocytes, contributes to RTK signaling termination; repression of CIN85 restores the RTK signaling response, indicating that CD2AP/CIN85 balance regulates podocyte RTK signaling.\",\n      \"method\": \"CD2AP-/- mouse podocytes, growth factor stimulation, Western blot for p-AKT/p-ERK, CIN85 knockdown rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with defined signaling phenotype, rescue by paralog knockdown, single lab\",\n      \"pmids\": [\"17213204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD2AP associates with Ret receptor tyrosine kinase under basal (unstimulated) conditions in sympathetic neurons and dissociates upon GDNF-induced Ret activation. CD2AP also forms a complex with Cbl-3/c upon GDNF stimulation. CD2AP overexpression enhances Ret degradation and inhibits GDNF-dependent survival; CD2AP knockdown blocks Ret degradation and promotes survival, identifying CD2AP as a regulator of Ret downregulation.\",\n      \"method\": \"Co-immunoprecipitation from neurons, CD2AP overexpression and siRNA knockdown, Ret degradation assay, neuronal survival assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, gain- and loss-of-function with functional readouts (receptor degradation, survival), two orthogonal perturbations\",\n      \"pmids\": [\"18753381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Drosophila CD2AP/CIN85 ortholog Cindr links E-cadherin at cell junctions to multiple actin cytoskeleton components including capping protein alpha and capping protein beta. Reducing cindr activity causes defects in cell movement and tissue patterning. Cindr physically and functionally connects junction proteins and actin regulators.\",\n      \"method\": \"Drosophila genetics (cindr reduction), co-immunoprecipitation, genetic epistasis, fluorescence microscopy in developing retina\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila ortholog, physical interaction and genetic epistasis, defined cellular phenotype, single lab\",\n      \"pmids\": [\"18362180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD2AP interacts directly with the cytoplasmic tail of TGF-beta receptor type I (TβRI) in a kinase-dependent manner, and this interaction is required for TβRI to recruit the p85 subunit of PI3K, thereby activating the antiapoptotic PI3K/AKT pathway independently of Smad2/3 signaling. CD2AP-deficient podocytes are hypersensitive to TGF-β-induced apoptosis, while Smad3 deficiency is protective.\",\n      \"method\": \"Direct binding assay (C-terminal CD2AP with TβRI cytoplasmic tail), co-immunoprecipitation, CD2AP-/- and Smad-/- podocytes, apoptosis assay, TGF-β1 transgenic mouse model\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct interaction mapped by domain experiments, KO cells, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"19679673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD2AP specifically interacts with the C-terminal hypervariable domain of Rac1 (but not other Rho family members), requiring both the proline-rich domain and the poly-basic region of Rac1 and at least two of the three N-terminal SH3 domains of CD2AP. Constitutively active Rac1 recruits CD2AP to cell-cell contacts in epithelial cells, where CD2AP controls epithelial barrier function and links Rac1 to CAPZ and cortactin.\",\n      \"method\": \"Peptide-based pulldown with mass spectrometry, co-immunoprecipitation, siRNA knockdown, constitutively active Rac1 expression, barrier function assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide pulldown + MS identification, domain mapping, functional barrier assay, single lab\",\n      \"pmids\": [\"20404345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD2AP regulates the TGF-β1-dependent translocation of dendrin from the slit diaphragm to the podocyte nucleus. Nuclear dendrin acts as a transcription factor promoting expression of cytosolic cathepsin L (CatL), which proteolytically cleaves dynamin and synaptopodin, reorganizing the podocyte actin cytoskeleton. CD2AP itself is a CatL substrate, creating a feedforward loop. Loss of CD2AP increases apoptotic susceptibility to TGF-β1.\",\n      \"method\": \"CD2AP KO mouse and human podocytes, nuclear fractionation, transcription factor reporter assay, cathepsin L activity assay, proteolysis assays, mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic cascade established in KO cells and mice with biochemical reconstitution elements, multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"21911934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD2AP regulates SUMOylation of its paralog CIN85 in podocytes: full-length CIN85 is SUMOylated by SUMO-1, -2, and -3 in wild-type podocytes and this SUMOylation is enhanced in the presence of CD2AP. SUMOylation at Lys598 prevents CIN85 from binding nephrin; K598R mutation abolishes SUMOylation and increases CIN85-nephrin binding.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assay, site-directed mutagenesis (K598R), Western blot in CD2AP-/- vs WT podocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis defines SUMO site, functional consequence on nephrin binding shown, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22203040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD2AP NMR solution structures of all three SH3 domains were determined. The N-terminal SH3 domain of CD2AP (and CIN85) is the most stable SH3 domain characterized, driven by an extensive intramolecular interaction network; this high stability is proposed to be critical for maintaining the conformation needed for target recruitment.\",\n      \"method\": \"NMR spectroscopy, differential scanning calorimetry (DSC), FoldX structure-based thermodynamic analysis\",\n      \"journal\": \"Journal of biomolecular NMR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure with thermodynamic validation, but functional consequence inferred rather than directly tested\",\n      \"pmids\": [\"21519904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD2AP links cortactin and actin capping protein (CP) at the cell periphery; loss of CD2AP reduces colocalization of CP and cortactin and impairs formation of short branched actin filaments characteristic of lamellipodia, resulting in defective cell migration. Super-resolution microscopy confirmed that CD2AP is required for efficient colocalization of CP and cortactin.\",\n      \"method\": \"siRNA knockdown, super-resolution fluorescence microscopy, cell migration assay, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined phenotype, super-resolution microscopy, co-IP, single lab\",\n      \"pmids\": [\"23090967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Septin 7 forms a complex with CD2AP and nephrin (co-immunoprecipitation) and also with VAMP2. The filamentous localization of septin 7 depends on CD2AP and intact actin. Knockdown of septin 7 facilitates glucose uptake and increases the interaction of VAMP2 with nephrin and syntaxin 4, suggesting septin 7 (in a CD2AP-containing complex) hinders GLUT4 storage vesicle trafficking.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, 2-deoxy-D-glucose uptake assay, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP complex, KD functional assay, subcellular fractionation, single lab\",\n      \"pmids\": [\"22809625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD2AP positively regulates BDCA2/FcεR1γ receptor signaling in plasmacytoid dendritic cells by forming a complex with SHIP1 that inhibits the E3 ubiquitin ligase Cbl. CD2AP/SHIP1 knockdown reduces ITAM signaling, enhances ubiquitination and degradation of Syk and FcεR1γ, and blocks inhibition of TLR9-mediated type I IFN production. Upon BDCA2 cross-linking, the CD2AP/SHIP1/Cbl complex recruits to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, siRNA knockdown, ubiquitination assay, IFN production assay, immunofluorescence\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP + MS identification of SHIP1, KD with multiple functional readouts (signaling, ubiquitination, IFN), plasma membrane recruitment shown\",\n      \"pmids\": [\"22706086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD2AP (FSGS3) is a barbed-end actin capping protein that stabilizes actin at the adherens junction. Identified by in vitro reconstitution biochemistry with cross-linking approach; CD2AP colocalizes with E-cadherin and α-actinin-4 at the apical junction of MDCK cells. CD2AP knockdown reduces actin accumulation and stability at the adherens junction and compromises adhesive strength and barrier function under mechanical stress.\",\n      \"method\": \"In vitro reconstitution, actin barbed-end capping assay, siRNA knockdown, mechanical stress apparatus, barrier function assay, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution biochemistry establishing capping activity, functional KD phenotype with mechanical readout\",\n      \"pmids\": [\"24322428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD2AP SH3-A forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b, as characterized by NMR, isothermal titration calorimetry (ITC), and small-angle X-ray scattering. This multimeric binding mode enables high diversity in signaling complex assembly.\",\n      \"method\": \"NMR, isothermal titration calorimetry, small-angle X-ray scattering\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple structural/biophysical methods (NMR, ITC, SAXS) establishing binding modes in a single rigorous study\",\n      \"pmids\": [\"23663663\"],\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 to drive Cbl-3/c-dependent Ret51 ubiquitination; the coiled-coil domain of CD2AP is dispensable. Two major ubiquitination sites in Ret51 are Lys1060 and Lys1107. Activated Ret induces CD2AP degradation as a negative feedback.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, domain deletion mutants, site-directed mutagenesis of Ret lysines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain-requirement mapping, site-directed mutagenesis of substrate ubiquitination sites, functional ubiquitination/degradation assay\",\n      \"pmids\": [\"24425877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD2AP SH3 domains 1 and 2 show similar binding preferences; SH3-3 binds more weakly and recognizes an extended sequence in ALIX. Preferred binding motif is Px(P/A)xPR. Crystal structures of SH3-1 and SH3-2 in complex with RIN3 epitopes determined at 1.65 Å and 1.11 Å resolution. RIN3 recruits CD2AP to RAB5a-positive early endosomes via two SH3-binding sites.\",\n      \"method\": \"Crystal structure determination, peptide array screen, isothermal titration calorimetry, permutation arrays, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures combined with ITC and functional localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26296892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD2AP is required for blood-brain barrier integrity in mice: CD2AP-deficient mice show increased sodium fluorescein extravasation (reduced BBB integrity) independent of nephrotic syndrome severity, and CD2AP is expressed in brain-adjacent endothelial cells. CD2AP-/- mice also show shorter latency to pentylenetetrazol-induced seizures.\",\n      \"method\": \"Sodium fluorescein extravasation assay, EEG, behavioral testing, CD2AP-/- mice with kidney-specific CD2AP rescue transgene\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct BBB integrity assay with genetic controls dissociating systemic illness, single lab\",\n      \"pmids\": [\"26358779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD2AP deficiency in podocytes disrupts GLUT4 (SLC2A4) trafficking: CD2AP-/- podocytes fail to increase glucose uptake in response to insulin, and HA-Glut4-GFP clusters perinuclearly rather than trafficking dynamically. CD2AP co-fractionates with GLUT4, IRAP, and sortilin on GLUT4 storage vesicles (GSVs), forms a complex with GGA2 (a clathrin adaptor sorting Glut4 to GSVs), and connects clathrin to actin in the perinuclear region.\",\n      \"method\": \"CD2AP-/- podocytes, live-cell imaging (HA-Glut4-GFP), 2-deoxy-D-glucose uptake assay, subcellular fractionation, co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with direct functional assay, live imaging, fractionation, co-IP complex identification, multiple orthogonal methods\",\n      \"pmids\": [\"26546360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD2AP adaptor protein forms a novel complex with the NGF receptor TrkA and the PI3K regulatory subunit p85 in sensory neurons; CD2AP levels positively regulate the degree of TrkA:p85 association. CD2AP regulates NGF signaling through AKT (but not ERK) and regulates long-range NGF signaling through TrkA+/RAB5+ signaling endosomes. CD2AP functions as a positive regulator of axon growth and neurite complexity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown and overexpression, neurite morphology assay, AKT/ERK signaling assays, endosome imaging\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel co-IP complex, gain/loss-of-function with defined signaling and morphological readouts, single lab\",\n      \"pmids\": [\"27076424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD2AP mediates internalization of the exosome cargo protein GPRC5B following cell surface delivery, contributing to Golgi accumulation of GPRC5B in parallel with biosynthetic trafficking.\",\n      \"method\": \"Inducible GPRC5B expression system, GPRC5B trafficking assay, siRNA knockdown of CD2AP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment, limited mechanistic follow-up for CD2AP specifically\",\n      \"pmids\": [\"27765817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In endothelial cells, CD2AP interacts with ICAM-1 and limits ICAM-1 clustering dynamics. Loss of CD2AP increases ICAM-1 complex formation, increases neutrophil adhesion, decreases crawling, and shifts neutrophil transmigration preference from paracellular to transcellular. Mechanistically, CD2AP is required for ICAM-1-mediated PI3K activation, cortactin/F-actin recruitment, and Rac1 recruitment and activation downstream of ICAM-1. Mechanical force on ICAM-1 impairs CD2AP binding to ICAM-1.\",\n      \"method\": \"Co-immunoprecipitation, CD2AP siRNA knockdown, neutrophil adhesion/transmigration assay, PI3K activation assay, Rac1 activation assay, mechanical force application\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding identified, KD with multiple mechanistic readouts (PI3K, cortactin, Rac1, transmigration), force-response assay\",\n      \"pmids\": [\"28484057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Alphavirus (CHIKV) nsP3 HVD binds CD2AP via its SH3 domains; the interaction site was mapped to the second SH3-ligand-like element in nsP3 HVD. Mutation of the CD2AP-binding motif in nsP3 attenuates viral replication and abolishes co-localization of CD2AP with nsP3 and replication complexes. CD2AP binds nsP3 HVDs from many New and Old World alphaviruses.\",\n      \"method\": \"Quantitative proteomics, site-directed mutagenesis of nsP3, viral replication assay, immunofluorescence colocalization\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding site mapped by mutagenesis, functional viral replication readout, single lab\",\n      \"pmids\": [\"29702546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD2AP inactivation in CD4 T cells promotes follicular helper T cell (Tfh) differentiation during chronic LCMV infection, associated with extended TCR signaling duration and enhanced cytokine production specifically under TH1 conditions. CD2AP-deficient CD4 T cells show enhanced germinal center responses.\",\n      \"method\": \"CD4 T cell-specific CD2AP knockout, LCMV infection model, flow cytometry, TCR signaling duration assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular differentiation and signaling phenotype, in vivo infection model, single lab\",\n      \"pmids\": [\"29734372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAWS1 (FAM83G) interacts dynamically with CD2AP at lamellae. PAWS1 knockout causes F-actin disorganization, lamellipodial defects, and impaired cell migration. CD2AP knockout in U2OS cells produces similar actin and migration defects, consistent with the two proteins acting in the same cytoskeletal pathway.\",\n      \"method\": \"CRISPR/Cas9 knockout of PAWS1 and CD2AP, confocal microscopy, live-cell actin imaging, co-immunoprecipitation (interaction with CD2AP)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO, live imaging, defined actin and migration phenotype, interaction with CD2AP shown, single lab\",\n      \"pmids\": [\"29175910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD2AP overexpression accelerates transfer of APP from Rab5-positive early endosomes to Rab7-positive late endosomes, stimulating lysosomal APP degradation. CD2AP knockdown has the opposite effect. This trafficking role is conserved in primary cortical neurons from mice.\",\n      \"method\": \"CD2AP overexpression and siRNA knockdown in COS-7, HEK293 cells, and primary cortical neurons; Rab5/Rab7 co-localization; APP degradation assay; nutrient starvation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with subcellular localization readout and degradation assay, replicated in neurons, single lab\",\n      \"pmids\": [\"31138646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VEGF-A stimulation induces tyrosine phosphorylation of CD2AP in podocytes. Phosphorylation of Y10 in the SH3-1 domain is indispensable for CD2AP function in vivo: the Y10 phosphorylation increases nephrin binding affinity to CD2AP, but this enhanced affinity paradoxically impairs glomerular filtration barrier function rather than stabilizing it, as demonstrated by cross-species rescue in cd2ap-knockdown zebrafish and Drosophila cindr mutants.\",\n      \"method\": \"Isoelectric focusing, site-directed mutagenesis, phospho-CD2AP antibodies, zebrafish cd2ap KD rescue, Drosophila cindr mutant rescue\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis defines phosphorylation site, cross-species in vivo rescue, functional filtration barrier readout, multiple orthogonal methods\",\n      \"pmids\": [\"31235616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NMR structural analysis of CHIKV nsP3 HVD shows two SH3-binding sites; CD2AP interacts with HVD using its SH3-A and SH3-C domains, leaving SH3-B available for other partners. The cooperative bivalent interaction increases binding affinity. BIN1, CD2AP, and SH3KBP1 play redundant roles in initiation of CHIKV replication.\",\n      \"method\": \"NMR spectroscopy, chemical shift perturbation, point mutations in HVD binding sites, viral replication assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization of binding mode, domain identification, mutagenesis with functional replication readout, single lab\",\n      \"pmids\": [\"31493651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The Drosophila CD2AP ortholog Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and synaptic vesicle recycling/release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and PMCA. Loss of cindr elevates PMCA levels and reduces cytosolic calcium. CD2AP null mice show conserved synaptic proteostasis defects.\",\n      \"method\": \"Drosophila cindr mutant analysis, synaptic physiology assays, co-immunoprecipitation (Cindr–14-3-3ζ), ubiquitin-proteasome assay, CD2AP null mouse analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Drosophila ortholog genetics, electrophysiology, biochemical interaction, and mammalian KO validation across two model systems\",\n      \"pmids\": [\"31412248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD2AP is a critical determinant of epithelial lateral membrane proportions: depletion of CD2AP or PI3K inhibition causes loss of F-actin and expansion of apical-basal domains at the expense of lateral membrane height in MDCK cells. The SH3 domains of CD2AP bind PI3K and are necessary for PI3K activity along lateral membranes. Tethering CD2AP SH3 domains or p110γ to the membrane rescues CD2AP-KD phenotypes. CD2AP and PI3K form a positive feedback loop linking actin assembly to PI3K activation at lateral membranes.\",\n      \"method\": \"siRNA knockdown, PI3K inhibition, domain rescue experiments (membrane-tethered SH3/p110γ), F-actin imaging in MDCK cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain-specific rescue experiments, pharmacological and genetic perturbation, defined morphological phenotype with mechanistic interpretation\",\n      \"pmids\": [\"31723006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD2AP inhibits gastric cancer cell metastasis by promoting cellular adhesion and cytoskeletal assembly; interaction with the F-actin capping protein CAPZA1 was demonstrated by immunofluorescence and is proposed as a mechanistic basis for CD2AP effects on cytoskeleton.\",\n      \"method\": \"CD2AP overexpression and knockdown in GC cells, migration/invasion assay, immunofluorescence showing CAPZA1 interaction, IHC of patient samples\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell assay and co-localization but interaction with CAPZA1 not confirmed by co-IP, limited mechanistic follow-up\",\n      \"pmids\": [\"31989722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD2AP is indispensable for NK cell cytotoxicity: CD2AP knockdown reduces NK92 cell cytotoxicity, impairs conjugate formation with target cells, and prevents FasL-bearing granule polarization toward the contact site. CD2AP associates with FasL by co-immunoprecipitation and colocalizes with FasL-bearing granules near the cell contact site during killing.\",\n      \"method\": \"siRNA knockdown in NK92 cells, cytotoxicity assay, conjugate formation assay, degranulation assay, co-immunoprecipitation (CD2AP–FasL), immunofluorescence\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple functional readouts, co-IP identifying FasL interaction, single lab\",\n      \"pmids\": [\"19945749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tankyrases interact with CD2AP and regulate Wnt/β-catenin signaling in podocytes. In the absence of CD2AP, tankyrase-mediated PARylation is increased and β-catenin activity is elevated. CD2AP-deficient podocytes show upregulation of LEF1 and fibronectin, downstream targets of Wnt/β-catenin. In zebrafish, tankyrase inhibition in CD2AP-depleted larvae aggravates kidney injury.\",\n      \"method\": \"Co-immunoprecipitation (tankyrase–CD2AP), CD2AP-/- podocytes, tankyrase inhibitor XAV939, zebrafish cd2ap knockdown model, β-catenin activity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, KO cells, in vivo zebrafish model, multiple signaling readouts, single lab\",\n      \"pmids\": [\"27441654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neuronal knockout of Cd2ap in APP/PS1 mice activates p38 MAPK signaling, leading to increased tau phosphorylation, synaptic injury, neuronal apoptosis, and cognitive impairment. Treatment with a p38 MAPK inhibitor ameliorates these phenotypes, placing CD2AP upstream of p38 MAPK in a pathway regulating tau pathology.\",\n      \"method\": \"Neuron-specific Cd2ap knockout in APP/PS1 mice, immunoblotting, immunofluorescence, electrophysiology, behavioral tests, p38 MAPK inhibitor treatment, stable CD2AP-KD SH-SY5Y cells\",\n      \"journal\": \"Translational neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with rescue by pharmacological inhibitor, multiple readouts (tau phosphorylation, synaptic physiology, behavior), two model systems\",\n      \"pmids\": [\"39696695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD2AP promotes glioblastoma progression by interacting with TRIM5, an NF-κB modulator. CD2AP overexpression increases TRIM5 levels and NF-κB activity; CD2AP knockdown has opposite effects. Downregulation of TRIM5 reverses elevated NF-κB activity in CD2AP-overexpressing cells, and NF-κB inhibition attenuates malignant features induced by CD2AP overexpression.\",\n      \"method\": \"Co-immunoprecipitation (CD2AP–TRIM5), CD2AP overexpression and knockdown in GBM cells, NF-κB reporter assay, TRIM5 knockdown epistasis, in vivo tumorigenesis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, gain/loss-of-function, genetic epistasis (TRIM5 KD rescue), in vivo tumor model, single lab\",\n      \"pmids\": [\"39353894\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD2AP is a multifunctional scaffolding adaptor protein containing three SH3 domains, a proline-rich region, and a coiled-coil domain that assembles multiprotein complexes at the plasma membrane and endosomes: in podocytes, it localizes to the slit diaphragm where it directly binds nephrin (via its C-terminal domain) and TGF-β receptor type I (via its C-terminus), recruits PI3K/AKT pro-survival signaling, gates cathepsin L-dependent cytoskeletal remodeling, and controls SUMOylation of its paralog CIN85; it acts as a barbed-end actin capping protein that stabilizes adherens junction actin and, via its SH3 domains, links cortactin and capping protein CP at lamellipodia; it regulates receptor tyrosine kinase downregulation (EGFR, Ret, Flt-1) by forming complexes with c-Cbl/Cbl-3 and endophilin; it regulates endosomal sorting through interaction with Rab4; in the nervous system it coordinates NGF/TrkA–p85–PI3K–AKT signaling endosomes and, through 14-3-3ζ, regulates synaptic proteostasis; and tyrosine phosphorylation (at Y10 of SH3-1 by VEGF-A/RTK signaling) fine-tunes its interaction affinity with nephrin to control slit diaphragm stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD2AP is a multivalent scaffolding adaptor built from three N-terminal SH3 domains, a proline-rich region, and a C-terminal coiled-coil that homodimerizes, assembling signaling and cytoskeletal complexes at the plasma membrane, cell junctions, and endosomes [#0, #21, #26]. Its SH3 domains recognize a Px(P/A)xPR motif and engage diverse partners — Src-family kinases, the PI3K p85 subunit, Grb2, c-Cbl, and cortactin — and can form type I and type II dimeric complexes that diversify the architecture of the assemblies it nucleates [#0, #26, #28]. A dominant function is the coupling of actin dynamics to membrane organization: CD2AP is a barbed-end actin-capping protein that stabilizes junctional actin and bridges cortactin to capping protein at lamellipodia, sustaining branched-filament assembly required for cell migration and epithelial barrier and lateral-membrane integrity, in part through a CD2AP–PI3K positive feedback loop [#22, #25, #41]. CD2AP also drives receptor tyrosine kinase downregulation by partnering with c-Cbl/Cbl-3 and endophilin and with Rab4 to route activated receptors — EGFR, Flt-1, Ret51, and PDGFR — through the endosomal degradative pathway [#5, #6, #8, #27]. In podocytes it localizes to the slit diaphragm, binds the cytoplasmic tail of nephrin through a C-terminal domain, and recruits PI3K/AKT pro-survival signaling alongside nephrin and podocin [#2, #4]; its tissue-specific requirement in podocytes is essential for survival and prevention of proteinuria [#9]. CD2AP gates TGF-\\u03b2 signaling by binding T\\u03b2RI to activate antiapoptotic PI3K/AKT independently of Smad and by restraining dendrin-driven, cathepsin L-dependent cytoskeletal proteolysis, with CD2AP itself a cathepsin L substrate in a feedforward loop [#17, #19]. Beyond the kidney, CD2AP functions in immune-cell adhesion and synapse formation, endothelial barrier and neutrophil transmigration, neuronal NGF/TrkA–p85–PI3K signaling endosomes, and synaptic proteostasis via 14-3-3\\u03b6, and neuronal loss of CD2AP drives p38 MAPK-dependent tau pathology in an Alzheimer's model [#7, #31, #33, #40, #45].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined CD2AP as an SH3-and-coiled-coil adaptor that physically links signaling kinases to the actin cytoskeleton, establishing its core architecture and biochemical logic.\",\n      \"evidence\": \"Co-IP, domain mapping, and immunofluorescence of ectopically expressed CMS/CD2AP in COS-7 cells\",\n      \"pmids\": [\"10339567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of each interaction not tested in physiological cells\", \"No endogenous-level validation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed CD2AP binds c-Cbl in a tyrosine-phosphorylation- and receptor-stimulation-dependent manner, linking the adaptor to receptor signaling at the leading edge.\",\n      \"evidence\": \"SH3 domain binding assays, co-IP, and EGF stimulation with immunofluorescence\",\n      \"pmids\": [\"11067845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in receptor downregulation not yet established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed CD2AP at the podocyte slit diaphragm as a direct nephrin partner, defining its central role in glomerular filtration barrier architecture.\",\n      \"evidence\": \"Immunoelectron microscopy, reciprocal co-IP, and domain mapping in a podocyte cell line\",\n      \"pmids\": [\"11733379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from the nephrin–CD2AP complex not yet defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked the nephrin–CD2AP complex to PI3K/AKT pro-survival signaling, explaining how slit-diaphragm assembly protects podocytes from detachment-induced death.\",\n      \"evidence\": \"In vivo co-IP, PI3K recruitment and AKT/Bad phosphorylation readouts in podocytes\",\n      \"pmids\": [\"12832477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of nephrin/podocin/CD2AP/PI3K complex unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established CD2AP as an endosomal trafficking adaptor by mapping interactions with Rab4, c-Cbl, and endophilin/cortactin that route activated receptors toward degradation.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, truncation mutants, and PDGFR/EGFR degradation assays\",\n      \"pmids\": [\"12559036\", \"12672817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of CD2AP on the degradative carriers limited to marker co-localization\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated a Flt-1/c-Cbl/CD2AP ternary complex required for VEGFR-1 internalization and ubiquitination, generalizing the receptor-downregulation function to angiogenic receptors.\",\n      \"evidence\": \"Co-IP, dominant-negative CD2AP, and endocytosis/ubiquitination assays\",\n      \"pmids\": [\"15001553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relies on overexpression and dominant-negative; endogenous requirement untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Pinpointed the essential, life-sustaining function of CD2AP to podocytes via tissue-specific transgenic rescue, separating its renal role from immune functions.\",\n      \"evidence\": \"Podocyte-specific transgenic rescue of CD2AP-null mice with histology and proteinuria readouts\",\n      \"pmids\": [\"15951437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of podocyte specificity not addressed\", \"Testicular phenotype mechanism unexplored\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed differential adaptor partnering of T\\u03b2RI (CD2AP vs TAB1) routes TGF-\\u03b2 signaling through distinct MAPK outputs, introducing CD2AP as a TGF-\\u03b2 signaling determinant.\",\n      \"evidence\": \"Co-IP and in vivo TGF-\\u03b23 administration with p38/ERK readouts in Sertoli cells\",\n      \"pmids\": [\"16617054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CD2AP–T\\u03b2RI binding interface not mapped in this study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the CD2AP/CIN85 balance as a rheostat for podocyte RTK signaling and identified dendrin as a CD2AP-bound proapoptotic slit-diaphragm factor.\",\n      \"evidence\": \"CD2AP-/- podocytes with growth-factor stimulation and CIN85-knockdown rescue; co-IP and nuclear translocation assays for dendrin\",\n      \"pmids\": [\"17213204\", \"17537921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CIN85 upregulation terminates RTK signaling not fully resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended the receptor-degradation role to neuronal Ret and revealed activity-dependent association/dissociation, establishing CD2AP as a negative regulator of GDNF/Ret survival signaling.\",\n      \"evidence\": \"Reciprocal co-IP, gain- and loss-of-function in sympathetic neurons with Ret degradation and survival assays\",\n      \"pmids\": [\"18753381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform selectivity of Ret regulation not yet examined here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Used the Drosophila ortholog Cindr to show evolutionary conservation of CD2AP as a bridge between cadherin junctions and actin capping proteins controlling tissue patterning.\",\n      \"evidence\": \"Drosophila cindr genetics, co-IP, and epistasis in developing retina\",\n      \"pmids\": [\"18362180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian junctional capping role not yet demonstrated biochemically\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established CD2AP requirements in immune effector function, including NK-cell cytotoxicity through FasL-granule polarization.\",\n      \"evidence\": \"siRNA knockdown in NK92 cells, cytotoxicity/conjugate/degranulation assays, and CD2AP–FasL co-IP\",\n      \"pmids\": [\"19945749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface and reciprocal validation absent\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved a direct, kinase-dependent CD2AP–T\\u03b2RI interaction that recruits PI3K to activate antiapoptotic AKT independently of Smad, explaining CD2AP-loss hypersensitivity to TGF-\\u03b2.\",\n      \"evidence\": \"Direct binding assay, CD2AP-/- and Smad-/- podocytes, apoptosis assay, and TGF-\\u03b21 transgenic mice\",\n      \"pmids\": [\"19679673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation event controlling the interaction not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified CD2AP as a Rac1-specific effector recruited to cell-cell contacts that links Rac1 to capping protein and cortactin for epithelial barrier control.\",\n      \"evidence\": \"Peptide pulldown/MS, domain mapping, siRNA, constitutively active Rac1, and barrier assays\",\n      \"pmids\": [\"20404345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Rac1 binding is direct in cells vs via complexes not fully resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the dendrin–cathepsin L cascade through which CD2AP gates actin-remodeling proteolysis, with CD2AP as both a regulator and a substrate in a feedforward loop.\",\n      \"evidence\": \"CD2AP KO podocytes and mice, nuclear fractionation, cathepsin L activity, and proteolysis assays\",\n      \"pmids\": [\"21911934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger linking CD2AP loss to dendrin release not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed CD2AP-dependent SUMOylation of its paralog CIN85 at Lys598 as a switch controlling competition for nephrin binding.\",\n      \"evidence\": \"SUMOylation assays, K598R mutagenesis, and binding assays in WT vs CD2AP-/- podocytes\",\n      \"pmids\": [\"22203040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase and how CD2AP enhances SUMOylation unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided NMR solution structures of all three SH3 domains, identifying the exceptionally stable N-terminal SH3 as a determinant of target recruitment.\",\n      \"evidence\": \"NMR, differential scanning calorimetry, and FoldX thermodynamic analysis\",\n      \"pmids\": [\"21519904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of stability inferred, not directly tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated CD2AP is required to colocalize capping protein with cortactin and to build lamellipodial branched actin for cell migration.\",\n      \"evidence\": \"siRNA, super-resolution microscopy, migration assay, and co-IP\",\n      \"pmids\": [\"23090967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct simultaneous binding of CP and cortactin by one CD2AP molecule not shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected CD2AP/nephrin complexes to septin 7 and GLUT4-vesicle trafficking, implicating CD2AP in metabolic vesicle regulation in podocytes.\",\n      \"evidence\": \"Co-IP, siRNA, fractionation, and glucose uptake assays\",\n      \"pmids\": [\"22809625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CD2AP–septin 7 interaction interface unmapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined CD2AP/SHIP1 as positive regulators of BDCA2/Fc\\u03b5R1\\u03b3 ITAM signaling that restrain Cbl-mediated degradation in plasmacytoid dendritic cells.\",\n      \"evidence\": \"Co-IP/MS, siRNA, ubiquitination and IFN assays, and membrane recruitment imaging\",\n      \"pmids\": [\"22706086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CD2AP–SHIP1–Cbl assembly not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established CD2AP as a bona fide barbed-end actin-capping protein that stabilizes adherens-junction actin under mechanical stress through in vitro reconstitution.\",\n      \"evidence\": \"In vitro reconstitution, barbed-end capping assay, siRNA, and mechanical-stress barrier assays\",\n      \"pmids\": [\"24322428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of capping activity in cells (on/off switch) not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterized the multimeric SH3 dimerization modes of CD2AP with CD2 and Cbl-b, explaining how the adaptor diversifies signaling complex assembly.\",\n      \"evidence\": \"NMR, isothermal titration calorimetry, and small-angle X-ray scattering\",\n      \"pmids\": [\"23663663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular relevance of specific dimer modes not tested in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped isoform-selective Ret51 ubiquitination driven by CD2AP SH3 domains and Cbl-3/c, with Ret-induced CD2AP degradation as negative feedback.\",\n      \"evidence\": \"Co-IP, siRNA, ubiquitination assays, domain deletions, and substrate lysine mutagenesis\",\n      \"pmids\": [\"24425877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Ret9 vs Ret51 discrimination not fully explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the SH3 binding motif (Px(P/A)xPR) and solved high-resolution structures with RIN3 epitopes, showing RIN3 recruits CD2AP to Rab5+ early endosomes.\",\n      \"evidence\": \"Crystal structures, peptide arrays, ITC, co-IP, and immunofluorescence\",\n      \"pmids\": [\"26296892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of physiological motif-bearing partners not enumerated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated CD2AP is required for blood-brain barrier integrity independently of nephrotic illness, broadening its barrier-maintenance role beyond the kidney.\",\n      \"evidence\": \"Fluorescein extravasation, EEG/behavior, in kidney-rescued CD2AP-/- mice\",\n      \"pmids\": [\"26358779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of CD2AP action in brain endothelium undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established CD2AP control of GLUT4 storage-vesicle trafficking via GGA2 and clathrin–actin connection, linking it to insulin-responsive glucose uptake.\",\n      \"evidence\": \"CD2AP-/- podocytes, live imaging, fractionation, and co-IP\",\n      \"pmids\": [\"26546360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of CD2AP–GGA2 association unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed CD2AP as a TrkA/p85 scaffold that promotes long-range NGF–AKT signaling endosomes and axon growth in sensory neurons.\",\n      \"evidence\": \"Co-IP, gain/loss-of-function, neurite morphology, AKT/ERK, and endosome imaging\",\n      \"pmids\": [\"27076424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for AKT over ERK mechanism not explained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CD2AP to tankyrase-regulated Wnt/\\u03b2-catenin signaling in podocytes, with CD2AP loss elevating \\u03b2-catenin activity and kidney injury.\",\n      \"evidence\": \"Co-IP, CD2AP-/- podocytes, XAV939, zebrafish KD, and \\u03b2-catenin readouts\",\n      \"pmids\": [\"27441654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between CD2AP and tankyrase PARylation undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed CD2AP binds ICAM-1 and is a mechanosensitive node coupling endothelial ICAM-1 to PI3K/cortactin/Rac1 to govern neutrophil transmigration route.\",\n      \"evidence\": \"Co-IP, siRNA, transmigration, PI3K/Rac1 activation assays, and force application\",\n      \"pmids\": [\"28484057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Force-dependent conformational basis of CD2AP–ICAM-1 release not structurally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified CD2AP as a host factor exploited by alphavirus nsP3 via cooperative bivalent SH3 binding, with redundancy among CD2AP/BIN1/SH3KBP1 in replication initiation.\",\n      \"evidence\": \"Quantitative proteomics, NMR, nsP3 mutagenesis, and viral replication assays\",\n      \"pmids\": [\"29702546\", \"31493651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular pathway co-opted by the CD2AP–nsP3 interaction not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CD2AP restrains TCR signaling duration in CD4 T cells, limiting follicular helper differentiation during chronic infection.\",\n      \"evidence\": \"CD4-specific CD2AP KO, LCMV model, flow cytometry, and TCR signaling assays\",\n      \"pmids\": [\"29734372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of CD2AP that shortens TCR signaling not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that VEGF-A-driven Y10 phosphorylation in SH3-1 tunes nephrin-binding affinity, with cross-species rescue showing this fine-tuning is functionally indispensable for the filtration barrier.\",\n      \"evidence\": \"Isoelectric focusing, mutagenesis, phospho-antibodies, and zebrafish/Drosophila rescue with filtration readouts\",\n      \"pmids\": [\"31235616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Y10 phosphorylation not definitively assigned\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a conserved CD2AP role in endosomal sorting of APP toward lysosomal degradation, linking CD2AP trafficking activity to APP processing.\",\n      \"evidence\": \"Gain/loss-of-function in cell lines and neurons, Rab5/Rab7 co-localization, and APP degradation assays\",\n      \"pmids\": [\"31138646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect on amyloidogenic vs non-amyloidogenic cleavage not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a conserved synaptic role for CD2AP/Cindr in synapse maturation and proteostasis via 14-3-3\\u03b6 and the ubiquitin-proteasome system, validated in null mice.\",\n      \"evidence\": \"Drosophila cindr genetics, synaptic physiology, Cindr–14-3-3\\u03b6 co-IP, and CD2AP null mouse analysis\",\n      \"pmids\": [\"31412248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates of CD2AP-regulated synaptic proteostasis incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a CD2AP–PI3K positive-feedback loop at lateral membranes that sets epithelial lateral membrane proportions through F-actin and PI3K activity.\",\n      \"evidence\": \"siRNA, PI3K inhibition, membrane-tethered domain rescue, and F-actin imaging in MDCK cells\",\n      \"pmids\": [\"31723006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SH3-bound PI3K is locally activated mechanistically not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed CD2AP upstream of p38 MAPK in neurons, where its loss promotes tau phosphorylation and cognitive decline, reversible by p38 inhibition.\",\n      \"evidence\": \"Neuron-specific Cd2ap KO in APP/PS1 mice, electrophysiology, behavior, and p38 inhibitor rescue\",\n      \"pmids\": [\"39696695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from CD2AP loss to p38 activation not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed CD2AP can promote glioblastoma progression through a TRIM5–NF-\\u03baB axis, revealing a context-dependent pro-tumor role.\",\n      \"evidence\": \"Co-IP, gain/loss-of-function, NF-\\u03baB reporter, TRIM5-knockdown epistasis, and in vivo tumorigenesis\",\n      \"pmids\": [\"39353894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CD2AP-dependent TRIM5 stabilization undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD2AP's actin-capping activity, receptor-degradation function, and PI3K/AKT scaffolding are coordinately switched by phosphorylation and partner availability in each tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating capping, trafficking, and signaling roles\", \"Upstream kinases controlling CD2AP phosphostate largely unidentified\", \"Quantitative competition among nephrin, CIN85, and other SH3/C-terminal partners not mapped in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 5, 24, 31, 41]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [22, 25, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8, 15, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 24, 41]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 8, 28, 37]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 22, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 17, 33, 41]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 8, 27, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 24, 35, 43]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 27, 20]}\n    ],\n    \"complexes\": [\"slit diaphragm complex\", \"GLUT4 storage vesicle\"],\n    \"partners\": [\"NPHS1\", \"CBL\", \"RAB4A\", \"CTTN\", \"RAC1\", \"TGFBR1\", \"SH3KBP1\", \"PSTPIP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"CD2AP","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 28484057"},"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}