{"gene":"SRCIN1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2000,"finding":"SNIP (p140Cap/SRCIN1) was identified as a novel SNAP-25-interacting protein. Biochemical and deletion analysis demonstrated that the SNIP-SNAP-25 association is mediated via coiled-coil interactions. SNIP co-localizes with SNAP-25 and the cortical actin cytoskeleton, suggesting it serves as a linker between SNAP-25 and the submembranous cytoskeleton. Overexpression of SNIP or its SNAP-25-interacting domain inhibits Ca2+-dependent exocytosis from PC12 cells.","method":"Co-immunoprecipitation, deletion analysis, subcellular fractionation, immunofluorescence, overexpression in PC12 cells with exocytosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding mapped by deletion analysis, functional consequence demonstrated by overexpression inhibiting Ca2+-dependent exocytosis, multiple orthogonal methods","pmids":["10625663"],"is_preprint":false},{"year":2003,"finding":"p140Cap was identified as a novel p130Cas-associated protein by affinity chromatography of human ECV304 cell extracts on an MBP-p130Cas column followed by mass spectrometry. Endogenous and transfected p140Cap co-immunoprecipitate with p130Cas and associate through their carboxy-terminal region. p140Cap co-distributes with cortical actin and actin stress fibers but not focal adhesions. p140Cap is tyrosine-phosphorylated within 15 min of cell adhesion to integrin ligands and in response to EGF via an EGFR-dependent mechanism. Expression of p140Cap delays cell spreading in the early phases of adhesion to fibronectin.","method":"Affinity chromatography, mass spectrometry, co-immunoprecipitation, immunofluorescence, subcellular fractionation, overexpression in NIH3T3 and ECV304 cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — affinity chromatography + MS identification, reciprocal co-IP, functional cell spreading assay, multiple orthogonal methods in single study","pmids":["14657239"],"is_preprint":false},{"year":2007,"finding":"p140Cap was characterized as a novel Src-binding protein that regulates Src activation via C-terminal Src kinase (Csk). p140Cap silencing increases cell spreading, migration rate and Src kinase activity. Increased p140Cap expression activates Csk, leading to inhibition of Src and downstream signaling, as well as inhibition of cell motility and invasion. High levels of p140Cap strongly impair cell proliferation and in vivo breast cancer cell growth.","method":"RNA silencing, overexpression, Src kinase activity assay, cell migration/invasion assays, in vivo tumor growth assay, co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain and loss-of-function experiments with defined molecular readouts (Src kinase activity, Csk activation), in vivo validation","pmids":["17525734"],"is_preprint":false},{"year":2008,"finding":"p140Cap is expressed in rat brain in a developmental stage-dependent manner and is relatively abundant in the synaptic plasma membrane fraction in adults. Electron microscopy revealed localization at pre- and post-synapses. The third SH3 domain of vinexin interacts with the C-terminal Pro-rich motif of p140Cap; this interaction was confirmed by co-immunoprecipitation in COS7 cells and rat brain. Additionally, the pre-synaptic protein synaptophysin interacts with p140Cap.","method":"Subcellular fractionation, immunohistochemistry, electron microscopy, co-immunoprecipitation, pulldown/binding domain mapping","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, EM, co-IP, domain mapping) in single study; interactions validated in both cell line and brain tissue","pmids":["18662323"],"is_preprint":false},{"year":2010,"finding":"p140Cap immobilizes E-cadherin at the cell membrane and inhibits EGFR and Erk1/2 signaling, blocking scatter and proliferation of cancer cells. p140Cap-dependent regulation of E-cadherin/EGFR cross-talk and cell motility is due to inhibition of Src kinase. Additionally, p140Cap impairs Erk1/2 phosphorylation by affecting Ras activity downstream of EGFR, independent of Src activity restoration.","method":"Gain and loss-of-function approaches in breast and colon cancer cells, Western blotting for phospho-EGFR/Erk1/2, Ras activity assay, cell motility assays, co-immunoprecipitation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function, multiple signaling readouts, epistasis (Src rescue insufficient for Erk1/2 restoration establishes dual pathway control)","pmids":["20453886"],"is_preprint":false},{"year":2011,"finding":"p140Cap suppresses invasive properties of highly metastatic breast carcinoma cells by inhibiting cortactin-dependent cell motility. p140Cap over-expression causes ~80% inhibition of lung metastasis in orthotopic transplantation. p140Cap associates with cortactin via its second proline-rich domain binding to the cortactin SH3 domain, and inhibits cortactin tyrosine phosphorylation in response to EGF. The phosphomimetic cortactin Y421 mutant rescues migration and invasion in p140Cap-overexpressing cells.","method":"Orthotopic transplantation in mice, directional migration assay, 3D invasion assay, co-immunoprecipitation, Western blotting, rescue with phosphomimetic cortactin mutant","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo metastasis assay, domain-level interaction mapping, phosphomimetic rescue establishing mechanistic causality, multiple orthogonal methods","pmids":["21725361"],"is_preprint":false},{"year":2013,"finding":"SNAP-25 regulates spine morphogenesis through postsynaptic binding to p140Cap. Acute reduction of SNAP-25 leads to immature dendritic spine phenotype; overexpression increases density of mature PSD-95-positive spines. The regulation depends on SNAP-25's ability to bind both the plasma membrane and p140Cap. SNAP-25 recruits and stabilizes p140Cap, which is a key regulator of actin cytoskeleton and spine formation.","method":"shRNA knockdown, overexpression, immunofluorescence, spine morphology analysis, co-immunoprecipitation, live imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE), defined spine morphology readout, co-IP validating interaction, functional dependence demonstrated","pmids":["23868368"],"is_preprint":false},{"year":2013,"finding":"Mass spectrometry identified that p140Cap is in vivo phosphorylated on tyrosine within the EGLYA motif (GEGLpYADPYGLLHEGR) as well as on three serine residues. Site-specific mutagenesis of the EPLYA/EGLYA tyrosines to phenylalanine abolishes p140Cap tyrosine phosphorylation and eliminates its ability to bind Csk. Abl kinase was identified as the major kinase responsible for p140Cap tyrosine phosphorylation on EPLYA and EGLYA sequences both in vitro and in HEK-293 cells.","method":"Mass spectrometry, site-directed mutagenesis, Far Western analysis, in vitro kinase assay, co-immunoprecipitation in HEK-293 cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo MS identification of phosphosite, mutagenesis establishing requirement for Csk binding, in vitro kinase assay identifying Abl; multiple orthogonal methods","pmids":["23383002"],"is_preprint":false},{"year":2013,"finding":"Two domains of p140Cap, TER (Tyrosine Enriched Region containing EPLYA and EGLYA motifs) and CT (Carboxy Terminal with proline-rich sequence), each independently associate with Csk and Src, inhibit Src activation and FAK phosphorylation, and impair in vitro and in vivo tumor cell growth and directional migration. The ability to act as negative regulators mainly resides on the two tyrosines in EPLYA/EGLYA (TER) and the second proline-rich stretch (CT).","method":"Stable cell lines expressing domain fragments, kinase activity assays, point mutation/deletion mutagenesis, in vitro migration/proliferation assays, in vivo tumor assay","journal":"American journal of cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis with defined functional readouts in vitro and in vivo, domain-level dissection of mechanistic requirements","pmids":["23841028"],"is_preprint":false},{"year":2014,"finding":"p140Cap knockout mice are impaired in object recognition and show deficits in LTP and LTD. Primary neurons from p140Cap-/- mice show reduced mushroom spines and abnormal F-actin organization. These phenotypes are caused by reduced inhibitory control of RhoA and cortactin toward cofilin. p140Cap acts through direct inhibition of Src kinase activation and through binding to the scaffold protein Citron-N to control spine actin organization.","method":"Knockout mouse model, behavioral tests (object recognition), LTP/LTD electrophysiology, spine morphology analysis, F-actin staining, co-immunoprecipitation with Citron-N, RhoA/cofilin activity assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with multiple orthogonal readouts (behavior, electrophysiology, morphology, biochemistry), interaction validated by co-IP","pmids":["24453341"],"is_preprint":false},{"year":2015,"finding":"Endophilin A1 localizes to dendritic spines and regulates spine morphogenesis through p140Cap as a downstream effector. Disruption of the endophilin A1–p140Cap interaction impairs spine formation and maturation. Endophilin A1 regulates the distribution of p140Cap and its downstream effector cortactin, as well as F-actin enrichment in dendritic spines. Knockdown of either endophilin A1 or p140Cap impairs spine stabilization and synaptic function.","method":"Co-immunoprecipitation, shRNA knockdown, immunofluorescence, spine morphology analysis, electrophysiology","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal KD experiments, co-IP validating direct interaction, multiple functional readouts (morphology + electrophysiology)","pmids":["25771685"],"is_preprint":false},{"year":2017,"finding":"Presynaptic β-catenin expression upregulates excitatory synaptic transmission and dendritic spine density. p140Cap is a newly identified β-catenin-interacting protein required in the presynaptic locus for mediating these effects on synapse stabilization and spinogenesis in neocortex.","method":"Conditional viral expression of stabilized β-catenin in defined neuron layers, electrophysiology, spine density analysis, co-immunoprecipitation identifying p140Cap as β-catenin interactor","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific manipulation with defined pre- vs. postsynaptic dissection, co-IP validation of interaction, multiple functional readouts","pmids":["28641114"],"is_preprint":false},{"year":2017,"finding":"p140Cap dampens ERBB2-positive tumor cell progression by interfering with ERBB2-dependent activation of Rac GTPase-controlled circuitries. p140Cap impairs tumor onset and growth in the NeuT mouse model and counteracts EMT, resulting in decreased metastasis formation.","method":"NeuT transgenic mouse model, gain/loss of function in ERBB2-positive cell lines, Rac GTPase activity assays, EMT marker analysis, in vivo tumor growth and metastasis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model, defined molecular mechanism (Rac GTPase circuitry), multiple orthogonal methods including biochemical and functional assays","pmids":["28300085"],"is_preprint":false},{"year":2017,"finding":"p140Cap synaptic interactome isolated by co-immunoprecipitation from mouse synaptosomes and mass spectrometry identified 351 p140Cap interactors clustering to postsynaptic density sub-complexes. Interactors converge on synaptic transmission, actin cytoskeleton remodeling, and cell-cell junction organization.","method":"Co-immunoprecipitation from crude mouse synaptosomes, mass spectrometry-based proteomics, gene co-expression analysis","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome from native tissue; single lab, limited individual validation of specific interactions","pmids":["28713243"],"is_preprint":false},{"year":2019,"finding":"p140Cap regulates GABAergic synaptogenesis and hippocampal inhibitory circuits. p140Cap is present in presynaptic GABAergic terminals; its genetic depletion results in higher frequency of mIPSCs without amplitude change, a larger synaptic vesicle readily releasable pool, increased number of inhibitory synapses, increased parvalbumin- and somatostatin-expressing interneurons, and enhanced susceptibility to kainate-induced seizures. Specific deletion of p140Cap in forebrain interneurons recapitulates these effects.","method":"p140Cap-/- knockout mice, cell-type-specific conditional knockout (forebrain interneurons), patch-clamp electrophysiology (mIPSC, RRP analysis), immunohistochemistry, in vitro/in vivo seizure assays","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Strong — global and cell-type-specific KO with multiple orthogonal functional readouts; presynaptic mechanism established by RRP analysis","pmids":["29161354"],"is_preprint":false},{"year":2019,"finding":"p140Cap negatively regulates Src and STAT3 signaling in neuroblastoma cells, affects anchorage-independent growth and migration, impairs in vivo tumor growth and spontaneous lung metastasis formation, and increases sensitivity to doxorubicin, etoposide, and Src inhibitors.","method":"Gain and loss of function experiments, Src and STAT3 activity assays, anchorage-independent growth assay, migration assay, xenograft mouse model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function, defined molecular pathway readouts (Src, STAT3), in vivo validation","pmids":["31285546"],"is_preprint":false},{"year":2020,"finding":"The N-terminal domain of p140Cap (amino acids 1–287) is sufficient to associate with full-length Tiam1 and the truncated catalytic domain of Tiam1, causing a decrease in Tiam1 activity. p140Cap expression causes Tiam1 redistribution along the apicobasal junctional axis and p140Cap, Tiam1, and E-cadherin co-interact, with increased E-cadherin at the cell membrane.","method":"Biochemical domain mapping, co-immunoprecipitation, Tiam1 GEF activity assay, immunofluorescence, E-cadherin membrane localization analysis","journal":"American journal of cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain-level biochemical mapping, GEF activity assay demonstrating functional inhibition, co-IP validating interaction, single lab but multiple orthogonal methods","pmids":["33415001"],"is_preprint":false},{"year":2022,"finding":"p140Cap directly binds the GluN2A subunit of NMDAR. In p140Cap KO mice, GluN2A is less associated with PSD95 in ex vivo synaptosomes and cultured hippocampal neurons; p140Cap re-expression rescues GluN2A/PSD95 colocalization. p140Cap associates with synaptic lipid rafts and controls selective recruitment of GluN2A and PSD95 to lipid raft domains in an activity-dependent fashion. p140Cap is required for embedding GluN2A clusters in lipid rafts.","method":"Co-immunoprecipitation, KO mouse model, rescue experiments by transfection, subcellular fractionation (lipid raft isolation), gated-STED microscopy, electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction demonstrated by co-IP, KO + rescue establishes causality, STED microscopy for spatial validation, lipid raft fractionation; multiple orthogonal methods","pmids":["35953295"],"is_preprint":false},{"year":2022,"finding":"p140Cap loss-of-function in female mice leads to severe hypofertility, delayed puberty, altered estrus cycle, reduced ovulation, and defective LH/estradiol production. Adult p140Cap KO mice show loss of GnRH-immunoreactive neurons and reduced GnRH/LH mRNAs. The glutamatergic circuitry (VGLUT-ir punctae) in the preoptic area and on GnRH neurons is significantly reduced in p140Cap KO mice, indicating p140Cap controls female fertility via glutamatergic afference on hypothalamic GnRH neurons.","method":"p140Cap KO mouse model, immunohistochemistry for GnRH/kisspeptin/VGLUT, hormone measurements, in vivo KP stimulation assay","journal":"Frontiers in neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple orthogonal readouts (endocrine, neuroanatomical, functional KP stimulation), mechanistic pathway established","pmids":["35237119"],"is_preprint":false},{"year":2023,"finding":"p140Cap inhibits β-Catenin by localizing in and stabilizing the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Through upstream inhibition of β-Catenin, p140Cap restricts tumorigenicity and self-renewal of tumor-initiating cells, limiting release of inflammatory cytokine G-CSF, which is required for polymorphonuclear myeloid-derived suppressor cells to create an immunosuppressive tumor-promoting environment.","method":"Transcriptomic analysis, co-immunoprecipitation with β-Catenin destruction complex components, loss-of-function/gain-of-function experiments, G-CSF measurement, in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP establishing destruction complex localization, functional rescue experiments, integrative transcriptomic + preclinical in vivo validation","pmids":["37169737"],"is_preprint":false},{"year":2023,"finding":"p140Cap positively regulates HMGCR (the pace-maker enzyme of the mevalonate pathway) via transcriptional and post-translational mechanisms, increasing flux through the MVA pathway. Higher cholesterol synthesis is paralleled with enhanced cholesterol efflux. p140Cap promotes increased cholesterol localization in the plasma membrane, reduces lipid raft-associated Rac1 signaling, and impairs cell membrane fluidity and cell migration in a cholesterol-dependent manner.","method":"In vitro and in vivo p140Cap expression models, HMGCR activity/expression analysis, cholesterol flux assays, lipid raft fractionation, Rac1 activity assay, migration assays, statin sensitivity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods but single lab; cholesterol-dependence established by pharmacological rescue","pmids":["38123597"],"is_preprint":false},{"year":2023,"finding":"SNX17 interacts with p140Cap (identified by GST pulldown and interactome analysis). This interaction is crucial for dendritic spine maturation. Snx17 haploinsufficiency leads to impaired synaptic transmission and reduced spine maturation, phenocopying p140Cap loss.","method":"GST pulldown, interactome analysis, Snx17 knockout mice, spine morphology analysis, electrophysiology","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — GST pulldown identifies interaction, KO mouse model establishes functional consequence; interaction with p140Cap validated in vivo","pmids":["37704928"],"is_preprint":false},{"year":2025,"finding":"BIN1 SH3 domain interacts with p140Cap through two class II proline-rich motifs (but not a class I motif) in p140Cap, with biologically relevant affinity (KD = 7.7 μM). A rare BIN1 coding variant (rs138047593) significantly reduces p140Cap and tau binding. BIN1 and p140Cap colocalize within molecular distance in cultured cells and mouse brain.","method":"Surface plasmon resonance, alanine-scanning mutagenesis, co-immunoprecipitation, GST pulldown, confocal microscopy, proximity ligation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR provides binding affinity, mutagenesis maps binding motifs, co-IP and PLA confirm interaction in cells and brain; multiple orthogonal methods in single rigorous study","pmids":["40889683"],"is_preprint":false},{"year":2025,"finding":"p140Cap (and its paralog KIAA1217/SKT) localizes to centrosomes and regulates ciliogenesis through Src family signaling. Loss of p140Cap impairs ciliogenesis in RPE-1 cells. Defects caused by p140Cap loss are rescued by inhibiting actin polymerization or Src activity, establishing that p140Cap regulates actin polymerization through Src family kinase activity at centrosomes/cilia.","method":"BioID proximity labeling, loss-of-function (siRNA/KO), ciliogenesis assay (cilia number/length), rescue with actin polymerization inhibitors and Src inhibitors","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype and pharmacological epistasis rescue; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.10.30.685566"],"is_preprint":true}],"current_model":"SRCIN1/p140Cap is an adaptor/scaffold protein that functions as a negative regulator of Src kinase activity by recruiting and activating Csk (via phosphorylation of EPLYA/EGLYA motifs by Abl kinase), while also suppressing cancer progression through inhibition of Rac GTPase (via Tiam1), stabilization of E-cadherin/adherens junctions, inhibition of Ras/EGFR signaling, stabilization of the β-Catenin destruction complex, and modulation of the mevalonate/cholesterol pathway; in neurons, p140Cap acts as a postsynaptic hub that directly binds SNAP-25, GluN2A (NMDAR), β-catenin, cortactin, Citron-N, endophilin A1, vinexin, and SNX17 to regulate dendritic spine maturation, synaptic plasticity (LTP/LTD), GABAergic synaptogenesis, and female fertility via hypothalamic glutamatergic circuits, with its centrosomal localization also linking it to ciliogenesis through Src-dependent actin regulation."},"narrative":{"mechanistic_narrative":"SRCIN1 (p140Cap/SNIP) is a multidomain adaptor/scaffold protein that integrates Src-family kinase signaling with actin cytoskeletal remodeling to control cell adhesion, motility, tumor progression, and synaptic organization [PMID:17525734, PMID:24453341]. Its core biochemical function is negative regulation of Src: p140Cap recruits and activates C-terminal Src kinase (Csk), and this depends on Abl-mediated tyrosine phosphorylation of its EPLYA/EGLYA motifs, mutation of which abolishes Csk binding [PMID:17525734, PMID:23383002]. Two independent regions—a tyrosine-enriched region carrying the EPLYA/EGLYA tyrosines and a C-terminal proline-rich region—each suffice to bind Csk and Src, dampen Src activation and FAK phosphorylation, and impair tumor cell growth and migration [PMID:23841028]. In cancer, p140Cap acts as a broad suppressor of progression by immobilizing E-cadherin and inhibiting EGFR/Ras/Erk1/2 signaling [PMID:20453886], by binding cortactin to block invasion and metastasis [PMID:21725361], by inhibiting Tiam1-driven Rac GTPase circuitry [PMID:33415001, PMID:28300085], by stabilizing the β-catenin destruction complex to limit tumor-initiating-cell self-renewal and an immunosuppressive microenvironment [PMID:37169737], and by upregulating HMGCR to remodel membrane cholesterol and reduce raft-associated Rac1 signaling [PMID:38123597]. In neurons, p140Cap is a postsynaptic and presynaptic hub that, through binding to SNAP-25, GluN2A, β-catenin, cortactin, Citron-N, endophilin A1, and SNX17, governs dendritic spine maturation, actin organization, synaptic plasticity, and GABAergic synaptogenesis, with knockout mice showing impaired LTP/LTD, abnormal spine morphology, altered inhibitory circuits, and seizure susceptibility [PMID:23868368, PMID:24453341, PMID:35953295, PMID:29161354]. Loss of p140Cap in female mice also causes hypofertility via reduced glutamatergic input onto hypothalamic GnRH neurons [PMID:35237119].","teleology":[{"year":2000,"claim":"Establishing the first molecular partner defined SRCIN1 as a SNAP-25-binding linker to the cortical cytoskeleton with a functional role in regulated exocytosis.","evidence":"Co-IP, deletion mapping, and exocytosis assays in PC12 cells","pmids":["10625663"],"confidence":"High","gaps":["Did not identify catalytic activity or kinase-regulatory function","Coiled-coil binding mode not structurally resolved"]},{"year":2003,"claim":"Identification as a p130Cas-associated, adhesion- and EGF-induced tyrosine-phosphorylated protein linked SRCIN1 to integrin/EGFR signaling and cortical actin.","evidence":"Affinity chromatography/MS, reciprocal co-IP, cell spreading assays in NIH3T3/ECV304","pmids":["14657239"],"confidence":"High","gaps":["Kinase responsible for phosphorylation not yet identified","Functional consequence limited to spreading delay"]},{"year":2007,"claim":"Defining p140Cap as a Csk-activating, Src-inhibiting protein established its central mechanism and its tumor-suppressive consequences.","evidence":"RNAi/overexpression, Src kinase assays, migration/invasion and in vivo breast tumor growth assays","pmids":["17525734"],"confidence":"High","gaps":["Did not define how p140Cap engages Csk at the residue level","Csk recruitment mechanism unresolved"]},{"year":2010,"claim":"Showing p140Cap immobilizes E-cadherin and suppresses EGFR/Ras/Erk1/2 separated its adhesion-stabilizing and Ras-modulating roles from pure Src inhibition.","evidence":"Gain/loss-of-function, Ras activity assays, Src-rescue epistasis in breast/colon cancer cells","pmids":["20453886"],"confidence":"High","gaps":["Direct mechanism of Ras inhibition not defined","Link between E-cadherin immobilization and Src inhibition mechanistically incomplete"]},{"year":2011,"claim":"Mapping the cortactin interaction and demonstrating phosphomimetic rescue established a causal actin/invasion axis for metastasis suppression.","evidence":"Orthotopic metastasis model, domain mapping, cortactin Y421 phosphomimetic rescue","pmids":["21725361"],"confidence":"High","gaps":["Whether cortactin regulation is fully Src-dependent not isolated","In vivo cell-autonomy of effect not fully dissected"]},{"year":2013,"claim":"Identifying Abl-mediated EPLYA/EGLYA tyrosine phosphorylation as required for Csk binding, and mapping two independent inhibitory domains, defined the structural logic of Src regulation.","evidence":"In vivo MS phosphosite mapping, site-directed mutagenesis, in vitro kinase assays, domain-fragment cell lines with tumor assays","pmids":["23383002","23841028"],"confidence":"High","gaps":["Stoichiometry and order of Abl/Csk/Src assembly unresolved","Role of the three serine phosphosites not characterized"]},{"year":2013,"claim":"Establishing SNAP-25-dependent recruitment of p140Cap to spines placed it as a postsynaptic regulator of actin and spine maturation.","evidence":"shRNA/overexpression, spine morphology, co-IP and live imaging in neurons","pmids":["23868368"],"confidence":"High","gaps":["Downstream actin effectors at spines not fully mapped here","Synaptic plasticity readouts not yet tested"]},{"year":2014,"claim":"p140Cap knockout mice connected the protein to learning, LTP/LTD, and spine actin via Src inhibition and Citron-N binding, establishing physiological neuronal function.","evidence":"KO mouse behavior, LTP/LTD electrophysiology, spine/F-actin analysis, RhoA/cofilin assays, Citron-N co-IP","pmids":["24453341"],"confidence":"High","gaps":["Relative contributions of Src vs Citron-N pathways not quantified","Cell-type specificity of behavioral deficit not resolved"]},{"year":2015,"claim":"Defining endophilin A1 as an upstream regulator that positions p140Cap and cortactin extended the spine actin regulatory pathway.","evidence":"Co-IP, reciprocal shRNA knockdown, spine morphology and electrophysiology","pmids":["25771685"],"confidence":"High","gaps":["Direct vs indirect nature of endophilin A1 binding not fully established","Molecular trigger for the interaction unknown"]},{"year":2017,"claim":"Multiple studies expanded p140Cap's roles: presynaptic β-catenin partnership in spinogenesis, ERBB2/Rac-dependent tumor suppression, and a 351-protein synaptic interactome converging on transmission and actin.","evidence":"Conditional viral β-catenin expression with co-IP; NeuT mouse model with Rac assays; synaptosome co-IP/MS proteomics","pmids":["28641114","28300085","28713243"],"confidence":"High","gaps":["Most interactome partners individually unvalidated","Mechanism linking β-catenin binding to presynaptic stabilization not defined"]},{"year":2019,"claim":"Cell-type-specific studies established a presynaptic GABAergic role controlling inhibitory circuits and seizure susceptibility, and extended tumor suppression to neuroblastoma via Src/STAT3.","evidence":"Global and interneuron-specific conditional KO with patch-clamp/RRP analysis and seizure assays; neuroblastoma gain/loss-of-function with xenografts","pmids":["29161354","31285546"],"confidence":"High","gaps":["Molecular target controlling RRP size at GABAergic terminals not identified","Mechanism of STAT3 regulation not defined"]},{"year":2020,"claim":"Mapping the N-terminal Tiam1 interaction and demonstrating GEF inhibition mechanistically linked p140Cap to Rac suppression and E-cadherin stabilization.","evidence":"Domain mapping, co-IP, Tiam1 GEF activity assay, E-cadherin localization","pmids":["33415001"],"confidence":"High","gaps":["Structural basis of Tiam1 inhibition not resolved","Single-lab validation"]},{"year":2022,"claim":"Demonstrating direct GluN2A binding and activity-dependent recruitment of GluN2A/PSD95 to lipid rafts defined a specific postsynaptic receptor-organizing function, and a parallel study tied p140Cap to female fertility via hypothalamic glutamatergic input.","evidence":"Co-IP, KO+rescue, lipid raft fractionation, STED microscopy, electrophysiology; KO endocrine/neuroanatomical analysis with KP stimulation","pmids":["35953295","35237119"],"confidence":"High","gaps":["Mechanism coupling p140Cap to raft partitioning unresolved","Direct vs circuit-level cause of GnRH neuron loss not separated"]},{"year":2023,"claim":"Three studies added β-catenin destruction-complex stabilization with immunomodulatory consequences, HMGCR/mevalonate-pathway control of membrane cholesterol, and an SNX17 interaction required for spine maturation.","evidence":"Co-IP with destruction complex and G-CSF/in vivo tumor models; HMGCR/cholesterol flux and Rac1 assays with statin rescue; GST pulldown and Snx17 KO mouse","pmids":["37169737","38123597","37704928"],"confidence":"High","gaps":["How p140Cap physically stabilizes the destruction complex unresolved","Transcriptional mechanism of HMGCR upregulation not defined","SNX17 interaction directness needs reciprocal validation"]},{"year":2025,"claim":"An affinity-quantified BIN1 interaction (and an AD-associated variant that weakens it) plus a centrosomal ciliogenesis role broadened p140Cap's adaptor functions into neurodegeneration-relevant and ciliary contexts.","evidence":"SPR, alanine-scanning, co-IP/PLA for BIN1; BioID, loss-of-function and pharmacological epistasis (actin/Src inhibitors) for ciliogenesis (one preprint)","pmids":["40889683","bio_10.1101_2025.10.30.685566"],"confidence":"Medium","gaps":["Functional consequence of BIN1 binding in disease not established","Ciliogenesis findings are preprint and not peer-reviewed","Centrosomal Src target at cilia not identified"]},{"year":null,"claim":"How p140Cap's many distinct interaction modules are coordinated—whether tumor-suppressive and synaptic functions reflect a shared Src/actin core or context-specific assemblies—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating the multiple binding domains","Determinants of context-specific partner selection unknown","Quantitative hierarchy among Src, Rac/Tiam1, and β-catenin axes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,11,17,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7,16]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,17,20]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,12,16]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,9,14,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,15,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20]}],"complexes":["β-Catenin destruction complex","postsynaptic density"],"partners":["SNAP25","CSK","SRC","CTTN","TIAM1","GRIN2A","CTNNB1","BIN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C0H9","full_name":"SRC kinase signaling inhibitor 1","aliases":["SNAP-25-interacting protein","SNIP","p130Cas-associated protein","p140Cap"],"length_aa":1183,"mass_kda":127.1,"function":"Acts as a negative regulator of SRC by activating CSK which inhibits SRC activity and downstream signaling, leading to impaired cell spreading and migration. Regulates dendritic spine morphology. Involved in calcium-dependent exocytosis. 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Biochemical and deletion analysis demonstrated that the SNIP-SNAP-25 association is mediated via coiled-coil interactions. SNIP co-localizes with SNAP-25 and the cortical actin cytoskeleton, suggesting it serves as a linker between SNAP-25 and the submembranous cytoskeleton. Overexpression of SNIP or its SNAP-25-interacting domain inhibits Ca2+-dependent exocytosis from PC12 cells.\",\n      \"method\": \"Co-immunoprecipitation, deletion analysis, subcellular fractionation, immunofluorescence, overexpression in PC12 cells with exocytosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding mapped by deletion analysis, functional consequence demonstrated by overexpression inhibiting Ca2+-dependent exocytosis, multiple orthogonal methods\",\n      \"pmids\": [\"10625663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p140Cap was identified as a novel p130Cas-associated protein by affinity chromatography of human ECV304 cell extracts on an MBP-p130Cas column followed by mass spectrometry. Endogenous and transfected p140Cap co-immunoprecipitate with p130Cas and associate through their carboxy-terminal region. p140Cap co-distributes with cortical actin and actin stress fibers but not focal adhesions. p140Cap is tyrosine-phosphorylated within 15 min of cell adhesion to integrin ligands and in response to EGF via an EGFR-dependent mechanism. Expression of p140Cap delays cell spreading in the early phases of adhesion to fibronectin.\",\n      \"method\": \"Affinity chromatography, mass spectrometry, co-immunoprecipitation, immunofluorescence, subcellular fractionation, overexpression in NIH3T3 and ECV304 cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — affinity chromatography + MS identification, reciprocal co-IP, functional cell spreading assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"14657239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p140Cap was characterized as a novel Src-binding protein that regulates Src activation via C-terminal Src kinase (Csk). p140Cap silencing increases cell spreading, migration rate and Src kinase activity. Increased p140Cap expression activates Csk, leading to inhibition of Src and downstream signaling, as well as inhibition of cell motility and invasion. High levels of p140Cap strongly impair cell proliferation and in vivo breast cancer cell growth.\",\n      \"method\": \"RNA silencing, overexpression, Src kinase activity assay, cell migration/invasion assays, in vivo tumor growth assay, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain and loss-of-function experiments with defined molecular readouts (Src kinase activity, Csk activation), in vivo validation\",\n      \"pmids\": [\"17525734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p140Cap is expressed in rat brain in a developmental stage-dependent manner and is relatively abundant in the synaptic plasma membrane fraction in adults. Electron microscopy revealed localization at pre- and post-synapses. The third SH3 domain of vinexin interacts with the C-terminal Pro-rich motif of p140Cap; this interaction was confirmed by co-immunoprecipitation in COS7 cells and rat brain. Additionally, the pre-synaptic protein synaptophysin interacts with p140Cap.\",\n      \"method\": \"Subcellular fractionation, immunohistochemistry, electron microscopy, co-immunoprecipitation, pulldown/binding domain mapping\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, EM, co-IP, domain mapping) in single study; interactions validated in both cell line and brain tissue\",\n      \"pmids\": [\"18662323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p140Cap immobilizes E-cadherin at the cell membrane and inhibits EGFR and Erk1/2 signaling, blocking scatter and proliferation of cancer cells. p140Cap-dependent regulation of E-cadherin/EGFR cross-talk and cell motility is due to inhibition of Src kinase. Additionally, p140Cap impairs Erk1/2 phosphorylation by affecting Ras activity downstream of EGFR, independent of Src activity restoration.\",\n      \"method\": \"Gain and loss-of-function approaches in breast and colon cancer cells, Western blotting for phospho-EGFR/Erk1/2, Ras activity assay, cell motility assays, co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function, multiple signaling readouts, epistasis (Src rescue insufficient for Erk1/2 restoration establishes dual pathway control)\",\n      \"pmids\": [\"20453886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p140Cap suppresses invasive properties of highly metastatic breast carcinoma cells by inhibiting cortactin-dependent cell motility. p140Cap over-expression causes ~80% inhibition of lung metastasis in orthotopic transplantation. p140Cap associates with cortactin via its second proline-rich domain binding to the cortactin SH3 domain, and inhibits cortactin tyrosine phosphorylation in response to EGF. The phosphomimetic cortactin Y421 mutant rescues migration and invasion in p140Cap-overexpressing cells.\",\n      \"method\": \"Orthotopic transplantation in mice, directional migration assay, 3D invasion assay, co-immunoprecipitation, Western blotting, rescue with phosphomimetic cortactin mutant\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo metastasis assay, domain-level interaction mapping, phosphomimetic rescue establishing mechanistic causality, multiple orthogonal methods\",\n      \"pmids\": [\"21725361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNAP-25 regulates spine morphogenesis through postsynaptic binding to p140Cap. Acute reduction of SNAP-25 leads to immature dendritic spine phenotype; overexpression increases density of mature PSD-95-positive spines. The regulation depends on SNAP-25's ability to bind both the plasma membrane and p140Cap. SNAP-25 recruits and stabilizes p140Cap, which is a key regulator of actin cytoskeleton and spine formation.\",\n      \"method\": \"shRNA knockdown, overexpression, immunofluorescence, spine morphology analysis, co-immunoprecipitation, live imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE), defined spine morphology readout, co-IP validating interaction, functional dependence demonstrated\",\n      \"pmids\": [\"23868368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mass spectrometry identified that p140Cap is in vivo phosphorylated on tyrosine within the EGLYA motif (GEGLpYADPYGLLHEGR) as well as on three serine residues. Site-specific mutagenesis of the EPLYA/EGLYA tyrosines to phenylalanine abolishes p140Cap tyrosine phosphorylation and eliminates its ability to bind Csk. Abl kinase was identified as the major kinase responsible for p140Cap tyrosine phosphorylation on EPLYA and EGLYA sequences both in vitro and in HEK-293 cells.\",\n      \"method\": \"Mass spectrometry, site-directed mutagenesis, Far Western analysis, in vitro kinase assay, co-immunoprecipitation in HEK-293 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo MS identification of phosphosite, mutagenesis establishing requirement for Csk binding, in vitro kinase assay identifying Abl; multiple orthogonal methods\",\n      \"pmids\": [\"23383002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Two domains of p140Cap, TER (Tyrosine Enriched Region containing EPLYA and EGLYA motifs) and CT (Carboxy Terminal with proline-rich sequence), each independently associate with Csk and Src, inhibit Src activation and FAK phosphorylation, and impair in vitro and in vivo tumor cell growth and directional migration. The ability to act as negative regulators mainly resides on the two tyrosines in EPLYA/EGLYA (TER) and the second proline-rich stretch (CT).\",\n      \"method\": \"Stable cell lines expressing domain fragments, kinase activity assays, point mutation/deletion mutagenesis, in vitro migration/proliferation assays, in vivo tumor assay\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis with defined functional readouts in vitro and in vivo, domain-level dissection of mechanistic requirements\",\n      \"pmids\": [\"23841028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p140Cap knockout mice are impaired in object recognition and show deficits in LTP and LTD. Primary neurons from p140Cap-/- mice show reduced mushroom spines and abnormal F-actin organization. These phenotypes are caused by reduced inhibitory control of RhoA and cortactin toward cofilin. p140Cap acts through direct inhibition of Src kinase activation and through binding to the scaffold protein Citron-N to control spine actin organization.\",\n      \"method\": \"Knockout mouse model, behavioral tests (object recognition), LTP/LTD electrophysiology, spine morphology analysis, F-actin staining, co-immunoprecipitation with Citron-N, RhoA/cofilin activity assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with multiple orthogonal readouts (behavior, electrophysiology, morphology, biochemistry), interaction validated by co-IP\",\n      \"pmids\": [\"24453341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endophilin A1 localizes to dendritic spines and regulates spine morphogenesis through p140Cap as a downstream effector. Disruption of the endophilin A1–p140Cap interaction impairs spine formation and maturation. Endophilin A1 regulates the distribution of p140Cap and its downstream effector cortactin, as well as F-actin enrichment in dendritic spines. Knockdown of either endophilin A1 or p140Cap impairs spine stabilization and synaptic function.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, immunofluorescence, spine morphology analysis, electrophysiology\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal KD experiments, co-IP validating direct interaction, multiple functional readouts (morphology + electrophysiology)\",\n      \"pmids\": [\"25771685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Presynaptic β-catenin expression upregulates excitatory synaptic transmission and dendritic spine density. p140Cap is a newly identified β-catenin-interacting protein required in the presynaptic locus for mediating these effects on synapse stabilization and spinogenesis in neocortex.\",\n      \"method\": \"Conditional viral expression of stabilized β-catenin in defined neuron layers, electrophysiology, spine density analysis, co-immunoprecipitation identifying p140Cap as β-catenin interactor\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific manipulation with defined pre- vs. postsynaptic dissection, co-IP validation of interaction, multiple functional readouts\",\n      \"pmids\": [\"28641114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p140Cap dampens ERBB2-positive tumor cell progression by interfering with ERBB2-dependent activation of Rac GTPase-controlled circuitries. p140Cap impairs tumor onset and growth in the NeuT mouse model and counteracts EMT, resulting in decreased metastasis formation.\",\n      \"method\": \"NeuT transgenic mouse model, gain/loss of function in ERBB2-positive cell lines, Rac GTPase activity assays, EMT marker analysis, in vivo tumor growth and metastasis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model, defined molecular mechanism (Rac GTPase circuitry), multiple orthogonal methods including biochemical and functional assays\",\n      \"pmids\": [\"28300085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p140Cap synaptic interactome isolated by co-immunoprecipitation from mouse synaptosomes and mass spectrometry identified 351 p140Cap interactors clustering to postsynaptic density sub-complexes. Interactors converge on synaptic transmission, actin cytoskeleton remodeling, and cell-cell junction organization.\",\n      \"method\": \"Co-immunoprecipitation from crude mouse synaptosomes, mass spectrometry-based proteomics, gene co-expression analysis\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome from native tissue; single lab, limited individual validation of specific interactions\",\n      \"pmids\": [\"28713243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p140Cap regulates GABAergic synaptogenesis and hippocampal inhibitory circuits. p140Cap is present in presynaptic GABAergic terminals; its genetic depletion results in higher frequency of mIPSCs without amplitude change, a larger synaptic vesicle readily releasable pool, increased number of inhibitory synapses, increased parvalbumin- and somatostatin-expressing interneurons, and enhanced susceptibility to kainate-induced seizures. Specific deletion of p140Cap in forebrain interneurons recapitulates these effects.\",\n      \"method\": \"p140Cap-/- knockout mice, cell-type-specific conditional knockout (forebrain interneurons), patch-clamp electrophysiology (mIPSC, RRP analysis), immunohistochemistry, in vitro/in vivo seizure assays\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — global and cell-type-specific KO with multiple orthogonal functional readouts; presynaptic mechanism established by RRP analysis\",\n      \"pmids\": [\"29161354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p140Cap negatively regulates Src and STAT3 signaling in neuroblastoma cells, affects anchorage-independent growth and migration, impairs in vivo tumor growth and spontaneous lung metastasis formation, and increases sensitivity to doxorubicin, etoposide, and Src inhibitors.\",\n      \"method\": \"Gain and loss of function experiments, Src and STAT3 activity assays, anchorage-independent growth assay, migration assay, xenograft mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function, defined molecular pathway readouts (Src, STAT3), in vivo validation\",\n      \"pmids\": [\"31285546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The N-terminal domain of p140Cap (amino acids 1–287) is sufficient to associate with full-length Tiam1 and the truncated catalytic domain of Tiam1, causing a decrease in Tiam1 activity. p140Cap expression causes Tiam1 redistribution along the apicobasal junctional axis and p140Cap, Tiam1, and E-cadherin co-interact, with increased E-cadherin at the cell membrane.\",\n      \"method\": \"Biochemical domain mapping, co-immunoprecipitation, Tiam1 GEF activity assay, immunofluorescence, E-cadherin membrane localization analysis\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain-level biochemical mapping, GEF activity assay demonstrating functional inhibition, co-IP validating interaction, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33415001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p140Cap directly binds the GluN2A subunit of NMDAR. In p140Cap KO mice, GluN2A is less associated with PSD95 in ex vivo synaptosomes and cultured hippocampal neurons; p140Cap re-expression rescues GluN2A/PSD95 colocalization. p140Cap associates with synaptic lipid rafts and controls selective recruitment of GluN2A and PSD95 to lipid raft domains in an activity-dependent fashion. p140Cap is required for embedding GluN2A clusters in lipid rafts.\",\n      \"method\": \"Co-immunoprecipitation, KO mouse model, rescue experiments by transfection, subcellular fractionation (lipid raft isolation), gated-STED microscopy, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction demonstrated by co-IP, KO + rescue establishes causality, STED microscopy for spatial validation, lipid raft fractionation; multiple orthogonal methods\",\n      \"pmids\": [\"35953295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p140Cap loss-of-function in female mice leads to severe hypofertility, delayed puberty, altered estrus cycle, reduced ovulation, and defective LH/estradiol production. Adult p140Cap KO mice show loss of GnRH-immunoreactive neurons and reduced GnRH/LH mRNAs. The glutamatergic circuitry (VGLUT-ir punctae) in the preoptic area and on GnRH neurons is significantly reduced in p140Cap KO mice, indicating p140Cap controls female fertility via glutamatergic afference on hypothalamic GnRH neurons.\",\n      \"method\": \"p140Cap KO mouse model, immunohistochemistry for GnRH/kisspeptin/VGLUT, hormone measurements, in vivo KP stimulation assay\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple orthogonal readouts (endocrine, neuroanatomical, functional KP stimulation), mechanistic pathway established\",\n      \"pmids\": [\"35237119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p140Cap inhibits β-Catenin by localizing in and stabilizing the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Through upstream inhibition of β-Catenin, p140Cap restricts tumorigenicity and self-renewal of tumor-initiating cells, limiting release of inflammatory cytokine G-CSF, which is required for polymorphonuclear myeloid-derived suppressor cells to create an immunosuppressive tumor-promoting environment.\",\n      \"method\": \"Transcriptomic analysis, co-immunoprecipitation with β-Catenin destruction complex components, loss-of-function/gain-of-function experiments, G-CSF measurement, in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing destruction complex localization, functional rescue experiments, integrative transcriptomic + preclinical in vivo validation\",\n      \"pmids\": [\"37169737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p140Cap positively regulates HMGCR (the pace-maker enzyme of the mevalonate pathway) via transcriptional and post-translational mechanisms, increasing flux through the MVA pathway. Higher cholesterol synthesis is paralleled with enhanced cholesterol efflux. p140Cap promotes increased cholesterol localization in the plasma membrane, reduces lipid raft-associated Rac1 signaling, and impairs cell membrane fluidity and cell migration in a cholesterol-dependent manner.\",\n      \"method\": \"In vitro and in vivo p140Cap expression models, HMGCR activity/expression analysis, cholesterol flux assays, lipid raft fractionation, Rac1 activity assay, migration assays, statin sensitivity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods but single lab; cholesterol-dependence established by pharmacological rescue\",\n      \"pmids\": [\"38123597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNX17 interacts with p140Cap (identified by GST pulldown and interactome analysis). This interaction is crucial for dendritic spine maturation. Snx17 haploinsufficiency leads to impaired synaptic transmission and reduced spine maturation, phenocopying p140Cap loss.\",\n      \"method\": \"GST pulldown, interactome analysis, Snx17 knockout mice, spine morphology analysis, electrophysiology\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — GST pulldown identifies interaction, KO mouse model establishes functional consequence; interaction with p140Cap validated in vivo\",\n      \"pmids\": [\"37704928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BIN1 SH3 domain interacts with p140Cap through two class II proline-rich motifs (but not a class I motif) in p140Cap, with biologically relevant affinity (KD = 7.7 μM). A rare BIN1 coding variant (rs138047593) significantly reduces p140Cap and tau binding. BIN1 and p140Cap colocalize within molecular distance in cultured cells and mouse brain.\",\n      \"method\": \"Surface plasmon resonance, alanine-scanning mutagenesis, co-immunoprecipitation, GST pulldown, confocal microscopy, proximity ligation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR provides binding affinity, mutagenesis maps binding motifs, co-IP and PLA confirm interaction in cells and brain; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"40889683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"p140Cap (and its paralog KIAA1217/SKT) localizes to centrosomes and regulates ciliogenesis through Src family signaling. Loss of p140Cap impairs ciliogenesis in RPE-1 cells. Defects caused by p140Cap loss are rescued by inhibiting actin polymerization or Src activity, establishing that p140Cap regulates actin polymerization through Src family kinase activity at centrosomes/cilia.\",\n      \"method\": \"BioID proximity labeling, loss-of-function (siRNA/KO), ciliogenesis assay (cilia number/length), rescue with actin polymerization inhibitors and Src inhibitors\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype and pharmacological epistasis rescue; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.30.685566\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SRCIN1/p140Cap is an adaptor/scaffold protein that functions as a negative regulator of Src kinase activity by recruiting and activating Csk (via phosphorylation of EPLYA/EGLYA motifs by Abl kinase), while also suppressing cancer progression through inhibition of Rac GTPase (via Tiam1), stabilization of E-cadherin/adherens junctions, inhibition of Ras/EGFR signaling, stabilization of the β-Catenin destruction complex, and modulation of the mevalonate/cholesterol pathway; in neurons, p140Cap acts as a postsynaptic hub that directly binds SNAP-25, GluN2A (NMDAR), β-catenin, cortactin, Citron-N, endophilin A1, vinexin, and SNX17 to regulate dendritic spine maturation, synaptic plasticity (LTP/LTD), GABAergic synaptogenesis, and female fertility via hypothalamic glutamatergic circuits, with its centrosomal localization also linking it to ciliogenesis through Src-dependent actin regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRCIN1 (p140Cap/SNIP) is a multidomain adaptor/scaffold protein that integrates Src-family kinase signaling with actin cytoskeletal remodeling to control cell adhesion, motility, tumor progression, and synaptic organization [#2, #9]. Its core biochemical function is negative regulation of Src: p140Cap recruits and activates C-terminal Src kinase (Csk), and this depends on Abl-mediated tyrosine phosphorylation of its EPLYA/EGLYA motifs, mutation of which abolishes Csk binding [#2, #7]. Two independent regions—a tyrosine-enriched region carrying the EPLYA/EGLYA tyrosines and a C-terminal proline-rich region—each suffice to bind Csk and Src, dampen Src activation and FAK phosphorylation, and impair tumor cell growth and migration [#8]. In cancer, p140Cap acts as a broad suppressor of progression by immobilizing E-cadherin and inhibiting EGFR/Ras/Erk1/2 signaling [#4], by binding cortactin to block invasion and metastasis [#5], by inhibiting Tiam1-driven Rac GTPase circuitry [#16, #12], by stabilizing the β-catenin destruction complex to limit tumor-initiating-cell self-renewal and an immunosuppressive microenvironment [#19], and by upregulating HMGCR to remodel membrane cholesterol and reduce raft-associated Rac1 signaling [#20]. In neurons, p140Cap is a postsynaptic and presynaptic hub that, through binding to SNAP-25, GluN2A, β-catenin, cortactin, Citron-N, endophilin A1, and SNX17, governs dendritic spine maturation, actin organization, synaptic plasticity, and GABAergic synaptogenesis, with knockout mice showing impaired LTP/LTD, abnormal spine morphology, altered inhibitory circuits, and seizure susceptibility [#6, #9, #17, #14]. Loss of p140Cap in female mice also causes hypofertility via reduced glutamatergic input onto hypothalamic GnRH neurons [#18].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the first molecular partner defined SRCIN1 as a SNAP-25-binding linker to the cortical cytoskeleton with a functional role in regulated exocytosis.\",\n      \"evidence\": \"Co-IP, deletion mapping, and exocytosis assays in PC12 cells\",\n      \"pmids\": [\"10625663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify catalytic activity or kinase-regulatory function\", \"Coiled-coil binding mode not structurally resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification as a p130Cas-associated, adhesion- and EGF-induced tyrosine-phosphorylated protein linked SRCIN1 to integrin/EGFR signaling and cortical actin.\",\n      \"evidence\": \"Affinity chromatography/MS, reciprocal co-IP, cell spreading assays in NIH3T3/ECV304\",\n      \"pmids\": [\"14657239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for phosphorylation not yet identified\", \"Functional consequence limited to spreading delay\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining p140Cap as a Csk-activating, Src-inhibiting protein established its central mechanism and its tumor-suppressive consequences.\",\n      \"evidence\": \"RNAi/overexpression, Src kinase assays, migration/invasion and in vivo breast tumor growth assays\",\n      \"pmids\": [\"17525734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how p140Cap engages Csk at the residue level\", \"Csk recruitment mechanism unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing p140Cap immobilizes E-cadherin and suppresses EGFR/Ras/Erk1/2 separated its adhesion-stabilizing and Ras-modulating roles from pure Src inhibition.\",\n      \"evidence\": \"Gain/loss-of-function, Ras activity assays, Src-rescue epistasis in breast/colon cancer cells\",\n      \"pmids\": [\"20453886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of Ras inhibition not defined\", \"Link between E-cadherin immobilization and Src inhibition mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping the cortactin interaction and demonstrating phosphomimetic rescue established a causal actin/invasion axis for metastasis suppression.\",\n      \"evidence\": \"Orthotopic metastasis model, domain mapping, cortactin Y421 phosphomimetic rescue\",\n      \"pmids\": [\"21725361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cortactin regulation is fully Src-dependent not isolated\", \"In vivo cell-autonomy of effect not fully dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying Abl-mediated EPLYA/EGLYA tyrosine phosphorylation as required for Csk binding, and mapping two independent inhibitory domains, defined the structural logic of Src regulation.\",\n      \"evidence\": \"In vivo MS phosphosite mapping, site-directed mutagenesis, in vitro kinase assays, domain-fragment cell lines with tumor assays\",\n      \"pmids\": [\"23383002\", \"23841028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and order of Abl/Csk/Src assembly unresolved\", \"Role of the three serine phosphosites not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing SNAP-25-dependent recruitment of p140Cap to spines placed it as a postsynaptic regulator of actin and spine maturation.\",\n      \"evidence\": \"shRNA/overexpression, spine morphology, co-IP and live imaging in neurons\",\n      \"pmids\": [\"23868368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream actin effectors at spines not fully mapped here\", \"Synaptic plasticity readouts not yet tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"p140Cap knockout mice connected the protein to learning, LTP/LTD, and spine actin via Src inhibition and Citron-N binding, establishing physiological neuronal function.\",\n      \"evidence\": \"KO mouse behavior, LTP/LTD electrophysiology, spine/F-actin analysis, RhoA/cofilin assays, Citron-N co-IP\",\n      \"pmids\": [\"24453341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of Src vs Citron-N pathways not quantified\", \"Cell-type specificity of behavioral deficit not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining endophilin A1 as an upstream regulator that positions p140Cap and cortactin extended the spine actin regulatory pathway.\",\n      \"evidence\": \"Co-IP, reciprocal shRNA knockdown, spine morphology and electrophysiology\",\n      \"pmids\": [\"25771685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of endophilin A1 binding not fully established\", \"Molecular trigger for the interaction unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies expanded p140Cap's roles: presynaptic β-catenin partnership in spinogenesis, ERBB2/Rac-dependent tumor suppression, and a 351-protein synaptic interactome converging on transmission and actin.\",\n      \"evidence\": \"Conditional viral β-catenin expression with co-IP; NeuT mouse model with Rac assays; synaptosome co-IP/MS proteomics\",\n      \"pmids\": [\"28641114\", \"28300085\", \"28713243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Most interactome partners individually unvalidated\", \"Mechanism linking β-catenin binding to presynaptic stabilization not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cell-type-specific studies established a presynaptic GABAergic role controlling inhibitory circuits and seizure susceptibility, and extended tumor suppression to neuroblastoma via Src/STAT3.\",\n      \"evidence\": \"Global and interneuron-specific conditional KO with patch-clamp/RRP analysis and seizure assays; neuroblastoma gain/loss-of-function with xenografts\",\n      \"pmids\": [\"29161354\", \"31285546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target controlling RRP size at GABAergic terminals not identified\", \"Mechanism of STAT3 regulation not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the N-terminal Tiam1 interaction and demonstrating GEF inhibition mechanistically linked p140Cap to Rac suppression and E-cadherin stabilization.\",\n      \"evidence\": \"Domain mapping, co-IP, Tiam1 GEF activity assay, E-cadherin localization\",\n      \"pmids\": [\"33415001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Tiam1 inhibition not resolved\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating direct GluN2A binding and activity-dependent recruitment of GluN2A/PSD95 to lipid rafts defined a specific postsynaptic receptor-organizing function, and a parallel study tied p140Cap to female fertility via hypothalamic glutamatergic input.\",\n      \"evidence\": \"Co-IP, KO+rescue, lipid raft fractionation, STED microscopy, electrophysiology; KO endocrine/neuroanatomical analysis with KP stimulation\",\n      \"pmids\": [\"35953295\", \"35237119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling p140Cap to raft partitioning unresolved\", \"Direct vs circuit-level cause of GnRH neuron loss not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Three studies added β-catenin destruction-complex stabilization with immunomodulatory consequences, HMGCR/mevalonate-pathway control of membrane cholesterol, and an SNX17 interaction required for spine maturation.\",\n      \"evidence\": \"Co-IP with destruction complex and G-CSF/in vivo tumor models; HMGCR/cholesterol flux and Rac1 assays with statin rescue; GST pulldown and Snx17 KO mouse\",\n      \"pmids\": [\"37169737\", \"38123597\", \"37704928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How p140Cap physically stabilizes the destruction complex unresolved\", \"Transcriptional mechanism of HMGCR upregulation not defined\", \"SNX17 interaction directness needs reciprocal validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An affinity-quantified BIN1 interaction (and an AD-associated variant that weakens it) plus a centrosomal ciliogenesis role broadened p140Cap's adaptor functions into neurodegeneration-relevant and ciliary contexts.\",\n      \"evidence\": \"SPR, alanine-scanning, co-IP/PLA for BIN1; BioID, loss-of-function and pharmacological epistasis (actin/Src inhibitors) for ciliogenesis (one preprint)\",\n      \"pmids\": [\"40889683\", \"bio_10.1101_2025.10.30.685566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of BIN1 binding in disease not established\", \"Ciliogenesis findings are preprint and not peer-reviewed\", \"Centrosomal Src target at cilia not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How p140Cap's many distinct interaction modules are coordinated—whether tumor-suppressive and synaptic functions reflect a shared Src/actin core or context-specific assemblies—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating the multiple binding domains\", \"Determinants of context-specific partner selection unknown\", \"Quantitative hierarchy among Src, Rac/Tiam1, and β-catenin axes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 11, 17, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7, 16]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 17, 20]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 12, 16]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 9, 14, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 15, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"\\u03b2-Catenin destruction complex\",\n      \"postsynaptic density\"\n    ],\n    \"partners\": [\n      \"SNAP25\",\n      \"CSK\",\n      \"SRC\",\n      \"CTTN\",\n      \"TIAM1\",\n      \"GRIN2A\",\n      \"CTNNB1\",\n      \"BIN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}