{"gene":"SRCIN1","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2000,"finding":"SRCIN1/p140Cap (identified as SNIP) was discovered as a novel SNAP-25-interacting protein; the interaction is mediated via coiled-coil domains, and overexpression of SNIP or its SNAP-25-interacting domain inhibits Ca2+-dependent exocytosis from PC12 cells. SNIP co-localizes with SNAP-25 and cortical actin cytoskeleton, suggesting it links SNAP-25 to the submembranous cytoskeleton.","method":"Yeast two-hybrid / biochemical pulldown, deletion analysis, co-localization by immunofluorescence, Ca2+-dependent exocytosis assay in PC12 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — functional reconstitution in PC12 cells with domain mapping and multiple orthogonal methods in a single study","pmids":["10625663"],"is_preprint":false},{"year":2003,"finding":"p140Cap (SRCIN1) was identified as a p130Cas-associated protein that is tyrosine-phosphorylated upon integrin-mediated cell adhesion and EGF stimulation; it co-immunoprecipitates with p130Cas via its carboxy-terminal region, co-localizes with cortical actin and actin stress fibers (but not focal adhesions), and its expression delays cell spreading on fibronectin.","method":"Affinity chromatography, mass spectrometry, co-immunoprecipitation, immunofluorescence, cell spreading assay on fibronectin","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — original identification by affinity chromatography/MS, validated by co-IP, localization, and functional spreading assay","pmids":["14657239"],"is_preprint":false},{"year":2007,"finding":"p140Cap/SRCIN1 was characterized as a novel Src-binding protein that inhibits Src kinase activity through activation of C-terminal Src kinase (Csk). p140Cap silencing increases cell spreading, migration, and Src activity; increased p140Cap expression activates Csk, inhibits Src and downstream signaling, impairs cell motility/invasion, and suppresses in vivo breast cancer cell growth.","method":"RNAi silencing, overexpression, kinase activity assays, co-immunoprecipitation, in vivo tumor growth assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — gain and loss of function with enzymatic activity readout and in vivo validation, replicated across multiple cell lines","pmids":["17525734"],"is_preprint":false},{"year":2008,"finding":"p140Cap is expressed in rat brain in a developmentally regulated manner, enriched in the synaptic plasma membrane fraction, localizes to pre- and post-synaptic sites by electron microscopy, and forms a complex with vinexin (via its third SH3 domain binding to the C-terminal Pro-rich motif of p140Cap) and with synaptophysin, suggesting roles in neurotransmitter release and synapse formation.","method":"Subcellular fractionation, immunohistochemistry, electron microscopy, co-immunoprecipitation from COS7 cells and rat brain, interaction domain mapping","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including EM localization and reciprocal co-IP with domain mapping","pmids":["18662323"],"is_preprint":false},{"year":2010,"finding":"p140Cap/SRCIN1 immobilizes E-cadherin at the cell membrane and inhibits EGFR and Erk1/2 signaling, blocking scatter and proliferation of cancer cells; this E-cadherin/EGFR cross-talk regulation is dependent on Src kinase inhibition. Additionally, p140Cap impairs Erk1/2 phosphorylation independently of Src by affecting Ras activity downstream of EGFR.","method":"Gain and loss of function (overexpression and silencing), western blotting for signaling molecules, cell motility assays, Ras activity assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches in breast and colon cancer cells establishing dual mechanistic control of Src and Ras","pmids":["20453886"],"is_preprint":false},{"year":2011,"finding":"p140Cap suppresses metastasis in vivo (80% reduction in lung metastases) and inhibits directional migration by associating with cortactin via its second proline-rich domain binding to the cortactin SH3 domain, inhibiting cortactin tyrosine phosphorylation (Y421) in response to EGF; a phosphomimetic cortactin Y421 mutant rescues migration in p140Cap-overexpressing cells.","method":"Orthotopic transplantation in Rag2-/-γc-/- mice, co-immunoprecipitation, domain binding mapping, EGF stimulation/phosphorylation assays, rescue with phosphomimetic mutant","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic rescue experiment with phosphomimetic mutant, in vivo metastasis model, and co-IP domain mapping","pmids":["21725361"],"is_preprint":false},{"year":2013,"finding":"SNAP-25 binds p140Cap at the plasma membrane in postsynaptic compartments, and this interaction is required for spine morphogenesis; acute reduction of SNAP-25 leads to immature dendritic spines, while overexpression increases density of mature PSD-95-positive spines in a manner dependent on SNAP-25 binding to both the plasma membrane and p140Cap.","method":"shRNA knockdown, overexpression, immunofluorescence, co-localization, spine morphology analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — functional genetic epistasis with spine morphology readout, mechanistic link to p140Cap interaction established","pmids":["23868368"],"is_preprint":false},{"year":2013,"finding":"p140Cap is phosphorylated in vivo on tyrosine within the EGLYA motif (by mass spectrometry); mutagenesis of both EPLYA/EGLYA tyrosines abolishes tyrosine phosphorylation and eliminates binding to Csk. The Abelson (Abl) kinase is identified as the major kinase phosphorylating p140Cap on EPLYA and EGLYA sequences both in vitro and in HEK-293 cells.","method":"Mass spectrometry phosphoproteomics, site-directed mutagenesis, in vitro kinase assay, co-immunoprecipitation, Far Western analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — in vivo phosphosite identification by MS with mutagenesis validation and in vitro kinase reconstitution","pmids":["23383002"],"is_preprint":false},{"year":2013,"finding":"The TER (Tyrosine Enriched Region) and CT (Carboxy Terminal) domains of p140Cap are each sufficient to associate with Csk and Src, inhibit Src activation, inhibit FAK phosphorylation, and impair in vitro and in vivo tumor cell migration and proliferation; the functional activity resides specifically on the two EPLYA/EGLYA tyrosines in TER and the second proline-rich stretch in CT.","method":"Stable cell line expression of truncation/point-mutant constructs, co-immunoprecipitation, kinase activity assays, in vitro migration assays, in vivo tumor growth","journal":"American journal of cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — domain and point mutant analysis with multiple functional readouts","pmids":["23841028"],"is_preprint":false},{"year":2014,"finding":"p140Cap knockout mice show impaired object recognition, LTP, and LTD; p140Cap-/- primary neurons have reduced mushroom spines and abnormal F-actin. p140Cap regulates spine actin organization through local inhibition of RhoA and cortactin/cofilin signaling, mediated by its ability to directly inhibit Src kinase activation and by binding to the scaffold protein Citron-N.","method":"Knockout mouse model, behavioral tests (object recognition), electrophysiology (LTP/LTD), phalloidin staining of F-actin, co-immunoprecipitation with Citron-N, kinase activity assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO with multiple orthogonal phenotypic and molecular readouts, direct binding to Citron-N established","pmids":["24453341"],"is_preprint":false},{"year":2015,"finding":"Endophilin A1 localizes to dendritic spines and regulates spine morphogenesis through a direct downstream interaction with p140Cap; disruption of endophilin A1-p140Cap interaction impairs spine formation and maturation. Endophilin A1 regulates the distribution of p140Cap and its effector cortactin, as well as F-actin enrichment in spines.","method":"GST pulldown, co-immunoprecipitation, shRNA knockdown, immunofluorescence, spine morphology analysis, synaptic function assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — direct binding identified by GST pulldown, functional epistasis established by knockdown and interaction disruption","pmids":["25771685"],"is_preprint":false},{"year":2017,"finding":"Presynaptic β-catenin expression stabilizes functional synapses and spines via anterograde signaling; p140Cap was identified as a β-catenin-interacting protein required in the presynaptic locus for mediating enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated release probability of glutamatergic synapses.","method":"Co-immunoprecipitation, conditional expression of stabilized β-catenin in specific neuron layers, electrophysiology, spine density analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — co-IP identifies p140Cap as β-catenin partner; cell-type-specific expression with electrophysiological and morphological readouts","pmids":["28641114"],"is_preprint":false},{"year":2017,"finding":"p140Cap/SRCIN1 dampens ERBB2-positive tumor cell progression by interfering with ERBB2-dependent activation of Rac GTPase-controlled circuitries, impairing tumor onset and growth in the NeuT mouse model and counteracting EMT to decrease metastasis formation.","method":"NeuT mouse tumor model, gain/loss of function, Rac1 activity assays, EMT markers, in vivo tumor growth and metastasis assessment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo preclinical model with mechanistic pathway identification (Rac GTPase circuitry), replicated across multiple readouts","pmids":["28300085"],"is_preprint":false},{"year":2017,"finding":"p140Cap synaptic interactome (351 proteins) identified by co-immunoprecipitation from mouse synaptosomes followed by mass spectrometry; interactors cluster to postsynaptic density sub-complexes involved in synaptic transmission, actin cytoskeleton remodeling, and cell-cell junction organization.","method":"Co-immunoprecipitation from crude synaptosomes, mass spectrometry-based proteomics, bioinformatics network analysis","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — systematic unbiased interactome from native synaptic tissue with MS validation","pmids":["28713243"],"is_preprint":false},{"year":2019,"finding":"p140Cap/SRCIN1 negatively regulates Src and STAT3 signaling in neuroblastoma, suppresses anchorage-independent growth and migration, inhibits in vivo tumor growth and spontaneous lung metastasis formation, and increases sensitivity to doxorubicin/etoposide and Src inhibitors.","method":"Gain/loss of function (SRCIN1 overexpression and silencing), in vivo xenograft and spontaneous metastasis models, kinase activity assays (Src, STAT3), drug sensitivity assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — in vivo tumor and metastasis models with mechanistic pathway (Src/STAT3) and drug sensitivity validation","pmids":["31285546"],"is_preprint":false},{"year":2019,"finding":"p140Cap/SRCIN1 regulates GABAergic synaptogenesis: p140Cap is present in presynaptic GABAergic terminals, and its genetic depletion results in a larger synaptic vesicle readily releasable pool, increased mIPSC frequency without amplitude change, premature/enhanced network synchronization, increased susceptibility to seizures, and increased number of inhibitory synapses and parvalbumin/somatostatin interneurons. Specific deletion in forebrain interneurons recapitulates these phenotypes.","method":"p140Cap knockout mice, whole-cell patch-clamp electrophysiology, synaptic vesicle pool assays, in vitro and in vivo seizure models, immunohistochemistry, conditional interneuron-specific KO","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with multiple electrophysiological and in vivo phenotypic readouts establishing presynaptic GABAergic function","pmids":["29161354"],"is_preprint":false},{"year":2020,"finding":"The N-terminal domain of p140Cap (residues 1-287) is sufficient to interact with Tiam1 (full-length and truncated catalytic domain), causing Tiam1 redistribution to apicobasal junctions and decreased Tiam1 GEF activity toward Rac1, with concomitant increase of E-cadherin at the cell membrane.","method":"Co-immunoprecipitation, domain truncation/deletion analysis, GEF activity assay for Tiam1/Rac1, immunofluorescence of E-cadherin localization","journal":"American journal of cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — domain mapping with biochemical GEF activity assay and localization readout","pmids":["33415001"],"is_preprint":false},{"year":2022,"finding":"p140Cap directly binds the GluN2A subunit of NMDA receptors and modulates the GluN2A-associated molecular network; in p140Cap KO mice, GluN2A association with PSD95 is reduced in synaptosomes and hippocampal neurons, and GluN2A/PSD95 are less recruited into synaptic lipid rafts. p140Cap KO rescue experiments restore GluN2A-PSD95 colocalization.","method":"Co-immunoprecipitation, synaptosome fractionation, lipid raft isolation, gated-STED microscopy, KO rescue, electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding shown by co-IP, mechanistic rescue in KO neurons, super-resolution microscopy, multiple orthogonal methods","pmids":["35953295"],"is_preprint":false},{"year":2022,"finding":"p140Cap KO female mice exhibit severe hypofertility, delayed puberty, altered estrus cycle, reduced ovulation, and defective LH/estradiol production during proestrus; adult KO mice show loss of GnRH-ir neurons and reduced GnRH projections to the median eminence, without changes in kisspeptin signaling, but with significantly reduced density of glutamatergic (VGLUT-ir) synapses on GnRH neurons, indicating p140Cap controls female fertility via glutamatergic input to hypothalamic GnRH neurons.","method":"p140Cap KO mouse model, immunohistochemistry, hormone measurements (LH, estradiol), in vivo kisspeptin challenge, VGLUT immunostaining, GnRH neuron counting","journal":"Frontiers in neuroscience","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with systematic neuroanatomical and endocrine dissection of mechanism, epistasis with glutamatergic vs. kisspeptin pathways","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, thereby restricting tumorigenicity and self-renewal of tumor-initiating cells, limiting G-CSF release, and impairing polymorphonuclear myeloid-derived suppressor cell function.","method":"Transcriptomic analysis, co-immunoprecipitation of destruction complex components, β-Catenin activity reporter assays, in vivo preclinical models, cytokine measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — mechanistic co-IP of destruction complex with functional readouts (reporter, G-CSF, in vivo tumor), multiple orthogonal methods","pmids":["37169737"],"is_preprint":false},{"year":2023,"finding":"p140Cap promotes increased flux through the mevalonate pathway by positively regulating HMGCR via transcriptional and post-translational mechanisms; this leads to enhanced cholesterol efflux, increased cholesterol in the plasma membrane, reduction of lipid raft-associated Rac1 signaling, impaired membrane fluidity and cell migration in a cholesterol-dependent manner.","method":"In vitro and in vivo metabolic flux analysis, HMGCR expression/activity assays, cholesterol localization imaging, lipid raft fractionation, Rac1 activity assay, statin sensitivity assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo evidence with mechanistic cholesterol pathway dissection and Rac1 signaling readout","pmids":["38123597"],"is_preprint":false},{"year":2023,"finding":"SNX17 interacts with p140Cap (identified by GST pulldown and interactome analysis); this interaction is required for dendritic spine maturation, as Snx17 haploinsufficiency reduces spine maturation and impairs synaptic transmission.","method":"GST pulldown, interactome analysis, Snx17 knockout/haploinsufficient mice, spine morphology analysis, electrophysiology","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — GST pulldown identifies interaction, functional consequence shown in vivo by haploinsufficiency but direct mechanistic link requires further validation","pmids":["37704928"],"is_preprint":false},{"year":2025,"finding":"BIN1 SH3 domain directly binds p140Cap via two class II proline-rich motifs (KD = 7.7 μM by surface plasmon resonance); alanine-scanning mutagenesis maps the binding residues. BIN1 and p140Cap colocalize and are within molecular distance in cultured cells and mouse brain by confocal microscopy and proximity ligation assay. A rare BIN1 coding variant (rs138047593) significantly reduces p140Cap (and tau) binding.","method":"Surface plasmon resonance, alanine-scanning mutagenesis, confocal microscopy, proximity ligation assay, co-immunoprecipitation, GST pulldown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — binding affinity by SPR with mutagenesis mapping, validated by multiple orthogonal methods in cells and mouse brain","pmids":["40889683"],"is_preprint":false},{"year":2025,"finding":"p140Cap and its paralog KIAA1217/SKT are centrosomal proteins; loss of p140Cap or KIAA1217 impairs ciliogenesis (fewer and shorter cilia), and these defects are rescued by inhibiting actin polymerization or Src family kinase activity, indicating p140Cap regulates ciliogenesis through Src-dependent actin remodeling.","method":"BioID proximity labeling, ciliogenesis assays, actin polymerization inhibitors, Src inhibitors, domain mapping for centrosomal targeting","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue with pharmacological inhibitors establishes pathway placement; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.30.685566"],"is_preprint":true}],"current_model":"SRCIN1/p140Cap is a multidomain adaptor/scaffold protein that acts as a hub inhibiting Src kinase activity through Csk recruitment (via EPLYA/EGLYA tyrosine motifs phosphorylated by Abl kinase), suppressing downstream signaling cascades (Rac1/Tiam1, Ras/Erk, STAT3, β-Catenin destruction complex, and NMDAR/PSD95 assembly in lipid rafts), regulating actin cytoskeleton organization through cortactin, cofilin/RhoA, and the mevalonate/cholesterol pathway, and controlling synaptic function—including GABA release, glutamatergic input to GnRH neurons, and dendritic spine maturation—through interactions with SNAP-25, Citron-N, endophilin A1, SNX17, β-catenin, and GluN2A, collectively establishing p140Cap as a tumor suppressor and synaptic organizer that coordinates Src-dependent signaling, cytoskeletal dynamics, and membrane organization."},"narrative":{"teleology":[{"year":2000,"claim":"The initial discovery that p140Cap/SNIP directly binds SNAP-25 via coiled-coil domains and inhibits Ca²⁺-dependent exocytosis established it as a regulator linking exocytic machinery to the cortical actin cytoskeleton, opening the question of its broader signaling roles.","evidence":"Yeast two-hybrid, biochemical pulldown, deletion mapping, and Ca²⁺-dependent exocytosis assay in PC12 cells","pmids":["10625663"],"confidence":"High","gaps":["Whether SNAP-25 interaction is relevant in neurons in vivo was untested","Mechanism of actin cytoskeleton linkage undefined","No kinase regulatory function yet identified"]},{"year":2003,"claim":"Identification of p140Cap as a tyrosine-phosphorylated p130Cas-associated protein that delays cell spreading on fibronectin linked it to integrin/growth factor signaling and cytoskeletal regulation, beyond its exocytic role.","evidence":"Affinity chromatography, mass spectrometry identification, co-immunoprecipitation, cell spreading assay on fibronectin","pmids":["14657239"],"confidence":"High","gaps":["Kinase responsible for tyrosine phosphorylation unknown","Direct mechanism of spreading inhibition unresolved"]},{"year":2007,"claim":"Demonstration that p140Cap inhibits Src kinase activity by activating Csk, with silencing increasing and overexpression decreasing Src-dependent migration/invasion and in vivo tumor growth, established the central tumor-suppressive mechanism.","evidence":"RNAi and overexpression in multiple breast cancer lines, kinase activity assays, co-IP, in vivo xenograft tumor growth","pmids":["17525734"],"confidence":"High","gaps":["Phosphorylation sites mediating Csk recruitment not yet mapped","Src-independent tumor suppressive mechanisms not addressed"]},{"year":2008,"claim":"Localization of p140Cap to pre- and postsynaptic sites in brain and identification of vinexin as a synaptic partner extended the protein's function from cancer biology into neurobiology.","evidence":"Subcellular fractionation, electron microscopy, co-IP from rat brain synaptosomes with domain mapping","pmids":["18662323"],"confidence":"High","gaps":["Functional synaptic consequence of p140Cap loss not yet tested","Relationship between Src inhibition and synaptic function unclear"]},{"year":2010,"claim":"Showing that p140Cap stabilizes E-cadherin at the membrane and independently inhibits both Src-dependent EGFR signaling and Ras/Erk pathway activation revealed dual control over epithelial cell proliferation and scattering.","evidence":"Gain/loss of function in breast and colon cancer cells, Ras activity assay, Erk phosphorylation, E-cadherin localization","pmids":["20453886"],"confidence":"High","gaps":["Mechanism of Src-independent Ras inhibition not fully resolved","Direct versus indirect E-cadherin stabilization unclear"]},{"year":2011,"claim":"Mapping the cortactin SH3 domain as the direct binding interface and showing that p140Cap suppresses cortactin Y421 phosphorylation—with rescue by a phosphomimetic mutant—defined the molecular basis for metastasis suppression (80% reduction in lung metastases).","evidence":"Orthotopic transplantation in immunodeficient mice, co-IP, domain mapping, EGF-stimulated phosphorylation, phosphomimetic rescue","pmids":["21725361"],"confidence":"High","gaps":["Whether cortactin inhibition operates through Src or an alternative kinase in vivo not fully distinguished"]},{"year":2013,"claim":"Identification of Abl as the kinase phosphorylating the EPLYA/EGLYA motifs and demonstration that these phosphotyrosines are required for Csk binding resolved how p140Cap activates Csk to inhibit Src, completing the upstream regulatory circuit.","evidence":"In vivo mass spectrometry phosphosite mapping, site-directed mutagenesis, in vitro kinase assay with Abl, Far Western, co-IP in HEK-293 cells","pmids":["23383002","23841028"],"confidence":"High","gaps":["Whether Abl phosphorylation of p140Cap is regulated by specific upstream signals in tumors is undefined","Structural basis of p140Cap–Csk interaction unknown"]},{"year":2013,"claim":"Discovery that postsynaptic SNAP-25 binding to p140Cap is required for dendritic spine morphogenesis established a neuronal function beyond the original exocytosis role.","evidence":"shRNA knockdown and overexpression in neurons, spine morphology quantification, co-localization with PSD-95","pmids":["23868368"],"confidence":"High","gaps":["Downstream signaling from SNAP-25–p140Cap to actin in spines not elucidated"]},{"year":2014,"claim":"p140Cap knockout mice showed impaired LTP/LTD, reduced mushroom spines, and disrupted object recognition; mechanistically, p140Cap locally inhibits RhoA and cortactin/cofilin through Src inhibition and Citron-N scaffolding, establishing it as a master organizer of synaptic actin dynamics.","evidence":"KO mouse model, behavioral testing, electrophysiology, phalloidin staining, co-IP with Citron-N, kinase assays","pmids":["24453341"],"confidence":"High","gaps":["Relative contribution of Src-dependent versus Src-independent pathways in spine regulation not quantified","Role at presynaptic terminals in excitatory synapses not addressed"]},{"year":2015,"claim":"Identification of endophilin A1 as a direct upstream partner that regulates p140Cap distribution into spines revealed how p140Cap is recruited to postsynaptic sites to control cortactin and F-actin.","evidence":"GST pulldown, co-IP, shRNA knockdown with spine morphology and synaptic function readouts","pmids":["25771685"],"confidence":"High","gaps":["Structural determinants of endophilin A1–p140Cap binding not resolved","Whether endophilin A1 also modulates p140Cap in non-neuronal cells unknown"]},{"year":2017,"claim":"Three parallel advances—(i) p140Cap dampening ERBB2/Rac1 signaling to suppress EMT and metastasis in vivo, (ii) presynaptic β-catenin requiring p140Cap to enhance excitatory transmission, and (iii) a synaptic interactome of 351 proteins—broadened p140Cap's role to Rac GTPase control in cancer and trans-synaptic signaling in brain.","evidence":"NeuT mouse model with Rac1 assays; conditional β-catenin expression with electrophysiology; co-IP/MS from synaptosomes","pmids":["28300085","28641114","28713243"],"confidence":"High","gaps":["Mechanism linking presynaptic β-catenin–p140Cap to vesicle release probability not defined","Which of the 351 synaptic interactors are functionally required is unknown"]},{"year":2019,"claim":"Extension of the Src/STAT3 inhibitory mechanism to neuroblastoma, with demonstration that p140Cap increases chemosensitivity, generalized the tumor-suppressive activity beyond breast cancer and identified STAT3 as an additional downstream effector.","evidence":"SRCIN1 overexpression/silencing in neuroblastoma cells, xenograft models, Src/STAT3 activity assays, drug sensitivity assays","pmids":["31285546"],"confidence":"High","gaps":["Whether p140Cap-mediated chemosensitization is solely through Src/STAT3 or involves additional pathways not resolved"]},{"year":2019,"claim":"Conditional knockout showed p140Cap is present in presynaptic GABAergic terminals and restrains inhibitory synaptogenesis and vesicle release, with loss causing increased seizure susceptibility, revealing a previously unknown role in inhibitory circuit homeostasis.","evidence":"Global and interneuron-specific conditional KO mice, patch-clamp electrophysiology, vesicle pool assays, seizure models, immunohistochemistry","pmids":["29161354"],"confidence":"High","gaps":["Molecular target through which p140Cap restricts GABA vesicle release probability not identified","Whether Src inhibition mediates the presynaptic GABAergic phenotype untested"]},{"year":2020,"claim":"Mapping the N-terminal domain (1–287) as sufficient to bind Tiam1 and directly inhibit its GEF activity toward Rac1 provided a Src-independent mechanism for p140Cap's suppression of Rac1 signaling and E-cadherin stabilization.","evidence":"Domain truncation analysis, co-IP, Tiam1 GEF activity assay, E-cadherin immunofluorescence","pmids":["33415001"],"confidence":"High","gaps":["Whether the Tiam1-binding and Csk-binding functions are coordinately regulated is unknown","No structural data for the N-terminal domain"]},{"year":2022,"claim":"Demonstrating that p140Cap directly binds GluN2A and is required for GluN2A/PSD-95 assembly in synaptic lipid rafts, with rescue in KO neurons, established a postsynaptic scaffolding function for NMDAR organization that explains the LTP/LTD deficits.","evidence":"Co-IP, synaptosome and lipid raft fractionation, gated-STED super-resolution microscopy, KO rescue, electrophysiology","pmids":["35953295"],"confidence":"High","gaps":["How p140Cap promotes lipid raft recruitment of GluN2A/PSD-95 mechanistically is unclear","Relationship between cholesterol regulation (mevalonate pathway) and raft organization in neurons not tested"]},{"year":2022,"claim":"KO female mice showed severe hypofertility with reduced GnRH neurons and diminished glutamatergic synapses onto GnRH neurons, extending p140Cap's synaptic function to neuroendocrine reproductive control.","evidence":"KO mouse, immunohistochemistry for GnRH/VGLUT, hormone measurements, kisspeptin challenge","pmids":["35237119"],"confidence":"High","gaps":["Whether p140Cap acts cell-autonomously in GnRH neurons or in their presynaptic partners is unresolved","Mechanism of GnRH neuron loss not determined"]},{"year":2023,"claim":"Two new tumor-suppressive mechanisms were defined: p140Cap stabilizes the β-catenin destruction complex to restrict tumor-initiating cell self-renewal and immunosuppressive G-CSF release, and it promotes mevalonate pathway flux to increase membrane cholesterol, reducing lipid raft Rac1 signaling and migration.","evidence":"Co-IP of destruction complex, β-catenin reporter, in vivo models, HMGCR activity/expression assays, cholesterol imaging, lipid raft fractionation, Rac1 assay","pmids":["37169737","38123597"],"confidence":"High","gaps":["Whether β-catenin destruction complex stabilization and mevalonate regulation are mechanistically linked is unknown","Transcriptional versus post-translational contribution to HMGCR regulation not fully separated"]},{"year":2023,"claim":"Identification of SNX17 as a p140Cap interactor required for dendritic spine maturation added an endosomal trafficking component to the synaptic scaffold network.","evidence":"GST pulldown, interactome analysis, Snx17 haploinsufficient mice, spine morphology, electrophysiology","pmids":["37704928"],"confidence":"Medium","gaps":["Direct mechanistic link between SNX17–p140Cap and spine actin remodeling not established","Whether SNX17 regulates p140Cap trafficking or vice versa is unclear"]},{"year":2025,"claim":"Quantitative biophysical mapping of the BIN1 SH3 domain–p140Cap interaction (KD 7.7 µM) and demonstration that a rare BIN1 coding variant disrupts this binding connected p140Cap to Alzheimer's disease-associated BIN1 biology.","evidence":"Surface plasmon resonance, alanine-scanning mutagenesis, proximity ligation assay in mouse brain, co-IP, confocal microscopy","pmids":["40889683"],"confidence":"High","gaps":["Functional consequence of BIN1–p140Cap interaction at synapses not yet demonstrated","Whether the rare BIN1 variant affects synaptic p140Cap function in vivo is untested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of p140Cap's multivalent scaffold function, whether its cholesterol/mevalonate regulation in cancer cells operates in neurons to control lipid raft NMDAR assembly, and whether Src-dependent actin remodeling underlies its putative role in ciliogenesis.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure for any p140Cap domain or complex","Integration of mevalonate/cholesterol regulation with synaptic lipid raft function untested","Ciliogenesis role reported only in a preprint and not independently validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7,8,14,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6,9,10,11,17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6,17]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,5,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,7,12,14,16,19,20]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,6,9,11,15,17]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,16,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20]}],"complexes":["β-catenin destruction complex"],"partners":["SNAP25","CSK","CTTN","CIT","TIAM1","GRIN2A","CTNNB1","BIN1"],"other_free_text":[]},"mechanistic_narrative":"SRCIN1 (p140Cap) is a multidomain scaffold protein that coordinates Src family kinase inhibition, actin cytoskeleton remodeling, and membrane organization in both epithelial cells and neurons. In cancer cells, p140Cap recruits and activates Csk through Abl-phosphorylated EPLYA/EGLYA tyrosine motifs, thereby inhibiting Src and downstream Ras/Erk, STAT3, and Rac1/Tiam1 signaling; it additionally stabilizes the β-catenin destruction complex and promotes mevalonate pathway flux to modulate cholesterol-dependent membrane dynamics, collectively suppressing tumor growth, invasion, and metastasis [PMID:17525734, PMID:23383002, PMID:37169737, PMID:38123597]. At synapses, p140Cap localizes to both pre- and postsynaptic compartments where it controls dendritic spine maturation through interactions with SNAP-25, cortactin, Citron-N, endophilin A1, and SNX17, organizes GluN2A/PSD-95 complexes into lipid rafts, and restrains GABAergic vesicle release; loss of p140Cap in mice impairs LTP/LTD, object recognition, and female fertility through reduced glutamatergic innervation of GnRH neurons [PMID:24453341, PMID:35953295, PMID:29161354, PMID:35237119]."},"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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SNIP co-localizes with SNAP-25 and cortical actin cytoskeleton, suggesting it links SNAP-25 to the submembranous cytoskeleton.\",\n      \"method\": \"Yeast two-hybrid / biochemical pulldown, deletion analysis, co-localization by immunofluorescence, Ca2+-dependent exocytosis assay in PC12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional reconstitution in PC12 cells with domain mapping and multiple orthogonal methods in a single study\",\n      \"pmids\": [\"10625663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p140Cap (SRCIN1) was identified as a p130Cas-associated protein that is tyrosine-phosphorylated upon integrin-mediated cell adhesion and EGF stimulation; it co-immunoprecipitates with p130Cas via its carboxy-terminal region, co-localizes with cortical actin and actin stress fibers (but not focal adhesions), and its expression delays cell spreading on fibronectin.\",\n      \"method\": \"Affinity chromatography, mass spectrometry, co-immunoprecipitation, immunofluorescence, cell spreading assay on fibronectin\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original identification by affinity chromatography/MS, validated by co-IP, localization, and functional spreading assay\",\n      \"pmids\": [\"14657239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p140Cap/SRCIN1 was characterized as a novel Src-binding protein that inhibits Src kinase activity through activation of C-terminal Src kinase (Csk). p140Cap silencing increases cell spreading, migration, and Src activity; increased p140Cap expression activates Csk, inhibits Src and downstream signaling, impairs cell motility/invasion, and suppresses in vivo breast cancer cell growth.\",\n      \"method\": \"RNAi silencing, overexpression, kinase activity assays, co-immunoprecipitation, in vivo tumor growth assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — gain and loss of function with enzymatic activity readout and in vivo validation, replicated across multiple cell lines\",\n      \"pmids\": [\"17525734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p140Cap is expressed in rat brain in a developmentally regulated manner, enriched in the synaptic plasma membrane fraction, localizes to pre- and post-synaptic sites by electron microscopy, and forms a complex with vinexin (via its third SH3 domain binding to the C-terminal Pro-rich motif of p140Cap) and with synaptophysin, suggesting roles in neurotransmitter release and synapse formation.\",\n      \"method\": \"Subcellular fractionation, immunohistochemistry, electron microscopy, co-immunoprecipitation from COS7 cells and rat brain, interaction domain mapping\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including EM localization and reciprocal co-IP with domain mapping\",\n      \"pmids\": [\"18662323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p140Cap/SRCIN1 immobilizes E-cadherin at the cell membrane and inhibits EGFR and Erk1/2 signaling, blocking scatter and proliferation of cancer cells; this E-cadherin/EGFR cross-talk regulation is dependent on Src kinase inhibition. Additionally, p140Cap impairs Erk1/2 phosphorylation independently of Src by affecting Ras activity downstream of EGFR.\",\n      \"method\": \"Gain and loss of function (overexpression and silencing), western blotting for signaling molecules, cell motility assays, Ras activity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches in breast and colon cancer cells establishing dual mechanistic control of Src and Ras\",\n      \"pmids\": [\"20453886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p140Cap suppresses metastasis in vivo (80% reduction in lung metastases) and inhibits directional migration by associating with cortactin via its second proline-rich domain binding to the cortactin SH3 domain, inhibiting cortactin tyrosine phosphorylation (Y421) in response to EGF; a phosphomimetic cortactin Y421 mutant rescues migration in p140Cap-overexpressing cells.\",\n      \"method\": \"Orthotopic transplantation in Rag2-/-γc-/- mice, co-immunoprecipitation, domain binding mapping, EGF stimulation/phosphorylation assays, rescue with phosphomimetic mutant\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic rescue experiment with phosphomimetic mutant, in vivo metastasis model, and co-IP domain mapping\",\n      \"pmids\": [\"21725361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNAP-25 binds p140Cap at the plasma membrane in postsynaptic compartments, and this interaction is required for spine morphogenesis; acute reduction of SNAP-25 leads to immature dendritic spines, while overexpression increases density of mature PSD-95-positive spines in a manner dependent on SNAP-25 binding to both the plasma membrane and p140Cap.\",\n      \"method\": \"shRNA knockdown, overexpression, immunofluorescence, co-localization, spine morphology analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional genetic epistasis with spine morphology readout, mechanistic link to p140Cap interaction established\",\n      \"pmids\": [\"23868368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p140Cap is phosphorylated in vivo on tyrosine within the EGLYA motif (by mass spectrometry); mutagenesis of both EPLYA/EGLYA tyrosines abolishes tyrosine phosphorylation and eliminates binding to Csk. The Abelson (Abl) kinase is identified as the major kinase phosphorylating p140Cap on EPLYA and EGLYA sequences both in vitro and in HEK-293 cells.\",\n      \"method\": \"Mass spectrometry phosphoproteomics, site-directed mutagenesis, in vitro kinase assay, co-immunoprecipitation, Far Western analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo phosphosite identification by MS with mutagenesis validation and in vitro kinase reconstitution\",\n      \"pmids\": [\"23383002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The TER (Tyrosine Enriched Region) and CT (Carboxy Terminal) domains of p140Cap are each sufficient to associate with Csk and Src, inhibit Src activation, inhibit FAK phosphorylation, and impair in vitro and in vivo tumor cell migration and proliferation; the functional activity resides specifically on the two EPLYA/EGLYA tyrosines in TER and the second proline-rich stretch in CT.\",\n      \"method\": \"Stable cell line expression of truncation/point-mutant constructs, co-immunoprecipitation, kinase activity assays, in vitro migration assays, in vivo tumor growth\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain and point mutant analysis with multiple functional readouts\",\n      \"pmids\": [\"23841028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p140Cap knockout mice show impaired object recognition, LTP, and LTD; p140Cap-/- primary neurons have reduced mushroom spines and abnormal F-actin. p140Cap regulates spine actin organization through local inhibition of RhoA and cortactin/cofilin signaling, mediated by its ability to directly inhibit Src kinase activation and by binding to the scaffold protein Citron-N.\",\n      \"method\": \"Knockout mouse model, behavioral tests (object recognition), electrophysiology (LTP/LTD), phalloidin staining of F-actin, co-immunoprecipitation with Citron-N, kinase activity assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO with multiple orthogonal phenotypic and molecular readouts, direct binding to Citron-N established\",\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 a direct downstream interaction with p140Cap; disruption of endophilin A1-p140Cap interaction impairs spine formation and maturation. Endophilin A1 regulates the distribution of p140Cap and its effector cortactin, as well as F-actin enrichment in spines.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, shRNA knockdown, immunofluorescence, spine morphology analysis, synaptic function assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding identified by GST pulldown, functional epistasis established by knockdown and interaction disruption\",\n      \"pmids\": [\"25771685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Presynaptic β-catenin expression stabilizes functional synapses and spines via anterograde signaling; p140Cap was identified as a β-catenin-interacting protein required in the presynaptic locus for mediating enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated release probability of glutamatergic synapses.\",\n      \"method\": \"Co-immunoprecipitation, conditional expression of stabilized β-catenin in specific neuron layers, electrophysiology, spine density analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP identifies p140Cap as β-catenin partner; cell-type-specific expression with electrophysiological and morphological readouts\",\n      \"pmids\": [\"28641114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p140Cap/SRCIN1 dampens ERBB2-positive tumor cell progression by interfering with ERBB2-dependent activation of Rac GTPase-controlled circuitries, impairing tumor onset and growth in the NeuT mouse model and counteracting EMT to decrease metastasis formation.\",\n      \"method\": \"NeuT mouse tumor model, gain/loss of function, Rac1 activity assays, EMT markers, in vivo tumor growth and metastasis assessment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo preclinical model with mechanistic pathway identification (Rac GTPase circuitry), replicated across multiple readouts\",\n      \"pmids\": [\"28300085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p140Cap synaptic interactome (351 proteins) identified by co-immunoprecipitation from mouse synaptosomes followed by mass spectrometry; interactors cluster to postsynaptic density sub-complexes involved in synaptic transmission, actin cytoskeleton remodeling, and cell-cell junction organization.\",\n      \"method\": \"Co-immunoprecipitation from crude synaptosomes, mass spectrometry-based proteomics, bioinformatics network analysis\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic unbiased interactome from native synaptic tissue with MS validation\",\n      \"pmids\": [\"28713243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p140Cap/SRCIN1 negatively regulates Src and STAT3 signaling in neuroblastoma, suppresses anchorage-independent growth and migration, inhibits in vivo tumor growth and spontaneous lung metastasis formation, and increases sensitivity to doxorubicin/etoposide and Src inhibitors.\",\n      \"method\": \"Gain/loss of function (SRCIN1 overexpression and silencing), in vivo xenograft and spontaneous metastasis models, kinase activity assays (Src, STAT3), drug sensitivity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo tumor and metastasis models with mechanistic pathway (Src/STAT3) and drug sensitivity validation\",\n      \"pmids\": [\"31285546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p140Cap/SRCIN1 regulates GABAergic synaptogenesis: p140Cap is present in presynaptic GABAergic terminals, and its genetic depletion results in a larger synaptic vesicle readily releasable pool, increased mIPSC frequency without amplitude change, premature/enhanced network synchronization, increased susceptibility to seizures, and increased number of inhibitory synapses and parvalbumin/somatostatin interneurons. Specific deletion in forebrain interneurons recapitulates these phenotypes.\",\n      \"method\": \"p140Cap knockout mice, whole-cell patch-clamp electrophysiology, synaptic vesicle pool assays, in vitro and in vivo seizure models, immunohistochemistry, conditional interneuron-specific KO\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with multiple electrophysiological and in vivo phenotypic readouts establishing presynaptic GABAergic function\",\n      \"pmids\": [\"29161354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The N-terminal domain of p140Cap (residues 1-287) is sufficient to interact with Tiam1 (full-length and truncated catalytic domain), causing Tiam1 redistribution to apicobasal junctions and decreased Tiam1 GEF activity toward Rac1, with concomitant increase of E-cadherin at the cell membrane.\",\n      \"method\": \"Co-immunoprecipitation, domain truncation/deletion analysis, GEF activity assay for Tiam1/Rac1, immunofluorescence of E-cadherin localization\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mapping with biochemical GEF activity assay and localization readout\",\n      \"pmids\": [\"33415001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p140Cap directly binds the GluN2A subunit of NMDA receptors and modulates the GluN2A-associated molecular network; in p140Cap KO mice, GluN2A association with PSD95 is reduced in synaptosomes and hippocampal neurons, and GluN2A/PSD95 are less recruited into synaptic lipid rafts. p140Cap KO rescue experiments restore GluN2A-PSD95 colocalization.\",\n      \"method\": \"Co-immunoprecipitation, synaptosome fractionation, lipid raft isolation, gated-STED microscopy, KO rescue, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding shown by co-IP, mechanistic rescue in KO neurons, super-resolution microscopy, multiple orthogonal methods\",\n      \"pmids\": [\"35953295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p140Cap KO female mice exhibit severe hypofertility, delayed puberty, altered estrus cycle, reduced ovulation, and defective LH/estradiol production during proestrus; adult KO mice show loss of GnRH-ir neurons and reduced GnRH projections to the median eminence, without changes in kisspeptin signaling, but with significantly reduced density of glutamatergic (VGLUT-ir) synapses on GnRH neurons, indicating p140Cap controls female fertility via glutamatergic input to hypothalamic GnRH neurons.\",\n      \"method\": \"p140Cap KO mouse model, immunohistochemistry, hormone measurements (LH, estradiol), in vivo kisspeptin challenge, VGLUT immunostaining, GnRH neuron counting\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with systematic neuroanatomical and endocrine dissection of mechanism, epistasis with glutamatergic vs. kisspeptin pathways\",\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, thereby restricting tumorigenicity and self-renewal of tumor-initiating cells, limiting G-CSF release, and impairing polymorphonuclear myeloid-derived suppressor cell function.\",\n      \"method\": \"Transcriptomic analysis, co-immunoprecipitation of destruction complex components, β-Catenin activity reporter assays, in vivo preclinical models, cytokine measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic co-IP of destruction complex with functional readouts (reporter, G-CSF, in vivo tumor), multiple orthogonal methods\",\n      \"pmids\": [\"37169737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p140Cap promotes increased flux through the mevalonate pathway by positively regulating HMGCR via transcriptional and post-translational mechanisms; this leads to enhanced cholesterol efflux, increased cholesterol in the plasma membrane, reduction of lipid raft-associated Rac1 signaling, impaired membrane fluidity and cell migration in a cholesterol-dependent manner.\",\n      \"method\": \"In vitro and in vivo metabolic flux analysis, HMGCR expression/activity assays, cholesterol localization imaging, lipid raft fractionation, Rac1 activity assay, statin sensitivity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo evidence with mechanistic cholesterol pathway dissection and Rac1 signaling readout\",\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 required for dendritic spine maturation, as Snx17 haploinsufficiency reduces spine maturation and impairs synaptic transmission.\",\n      \"method\": \"GST pulldown, interactome analysis, Snx17 knockout/haploinsufficient mice, spine morphology analysis, electrophysiology\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — GST pulldown identifies interaction, functional consequence shown in vivo by haploinsufficiency but direct mechanistic link requires further validation\",\n      \"pmids\": [\"37704928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BIN1 SH3 domain directly binds p140Cap via two class II proline-rich motifs (KD = 7.7 μM by surface plasmon resonance); alanine-scanning mutagenesis maps the binding residues. BIN1 and p140Cap colocalize and are within molecular distance in cultured cells and mouse brain by confocal microscopy and proximity ligation assay. A rare BIN1 coding variant (rs138047593) significantly reduces p140Cap (and tau) binding.\",\n      \"method\": \"Surface plasmon resonance, alanine-scanning mutagenesis, confocal microscopy, proximity ligation assay, co-immunoprecipitation, GST pulldown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — binding affinity by SPR with mutagenesis mapping, validated by multiple orthogonal methods in cells and mouse brain\",\n      \"pmids\": [\"40889683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"p140Cap and its paralog KIAA1217/SKT are centrosomal proteins; loss of p140Cap or KIAA1217 impairs ciliogenesis (fewer and shorter cilia), and these defects are rescued by inhibiting actin polymerization or Src family kinase activity, indicating p140Cap regulates ciliogenesis through Src-dependent actin remodeling.\",\n      \"method\": \"BioID proximity labeling, ciliogenesis assays, actin polymerization inhibitors, Src inhibitors, domain mapping for centrosomal targeting\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue with pharmacological inhibitors establishes pathway placement; 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 a multidomain adaptor/scaffold protein that acts as a hub inhibiting Src kinase activity through Csk recruitment (via EPLYA/EGLYA tyrosine motifs phosphorylated by Abl kinase), suppressing downstream signaling cascades (Rac1/Tiam1, Ras/Erk, STAT3, β-Catenin destruction complex, and NMDAR/PSD95 assembly in lipid rafts), regulating actin cytoskeleton organization through cortactin, cofilin/RhoA, and the mevalonate/cholesterol pathway, and controlling synaptic function—including GABA release, glutamatergic input to GnRH neurons, and dendritic spine maturation—through interactions with SNAP-25, Citron-N, endophilin A1, SNX17, β-catenin, and GluN2A, collectively establishing p140Cap as a tumor suppressor and synaptic organizer that coordinates Src-dependent signaling, cytoskeletal dynamics, and membrane organization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SRCIN1 (p140Cap) is a multidomain scaffold protein that coordinates Src family kinase inhibition, actin cytoskeleton remodeling, and membrane organization in both epithelial cells and neurons. In cancer cells, p140Cap recruits and activates Csk through Abl-phosphorylated EPLYA/EGLYA tyrosine motifs, thereby inhibiting Src and downstream Ras/Erk, STAT3, and Rac1/Tiam1 signaling; it additionally stabilizes the β-catenin destruction complex and promotes mevalonate pathway flux to modulate cholesterol-dependent membrane dynamics, collectively suppressing tumor growth, invasion, and metastasis [PMID:17525734, PMID:23383002, PMID:37169737, PMID:38123597]. At synapses, p140Cap localizes to both pre- and postsynaptic compartments where it controls dendritic spine maturation through interactions with SNAP-25, cortactin, Citron-N, endophilin A1, and SNX17, organizes GluN2A/PSD-95 complexes into lipid rafts, and restrains GABAergic vesicle release; loss of p140Cap in mice impairs LTP/LTD, object recognition, and female fertility through reduced glutamatergic innervation of GnRH neurons [PMID:24453341, PMID:35953295, PMID:29161354, PMID:35237119].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The initial discovery that p140Cap/SNIP directly binds SNAP-25 via coiled-coil domains and inhibits Ca²⁺-dependent exocytosis established it as a regulator linking exocytic machinery to the cortical actin cytoskeleton, opening the question of its broader signaling roles.\",\n      \"evidence\": \"Yeast two-hybrid, biochemical pulldown, deletion mapping, and Ca²⁺-dependent exocytosis assay in PC12 cells\",\n      \"pmids\": [\"10625663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNAP-25 interaction is relevant in neurons in vivo was untested\", \"Mechanism of actin cytoskeleton linkage undefined\", \"No kinase regulatory function yet identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of p140Cap as a tyrosine-phosphorylated p130Cas-associated protein that delays cell spreading on fibronectin linked it to integrin/growth factor signaling and cytoskeletal regulation, beyond its exocytic role.\",\n      \"evidence\": \"Affinity chromatography, mass spectrometry identification, co-immunoprecipitation, cell spreading assay on fibronectin\",\n      \"pmids\": [\"14657239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for tyrosine phosphorylation unknown\", \"Direct mechanism of spreading inhibition unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstration that p140Cap inhibits Src kinase activity by activating Csk, with silencing increasing and overexpression decreasing Src-dependent migration/invasion and in vivo tumor growth, established the central tumor-suppressive mechanism.\",\n      \"evidence\": \"RNAi and overexpression in multiple breast cancer lines, kinase activity assays, co-IP, in vivo xenograft tumor growth\",\n      \"pmids\": [\"17525734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites mediating Csk recruitment not yet mapped\", \"Src-independent tumor suppressive mechanisms not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localization of p140Cap to pre- and postsynaptic sites in brain and identification of vinexin as a synaptic partner extended the protein's function from cancer biology into neurobiology.\",\n      \"evidence\": \"Subcellular fractionation, electron microscopy, co-IP from rat brain synaptosomes with domain mapping\",\n      \"pmids\": [\"18662323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional synaptic consequence of p140Cap loss not yet tested\", \"Relationship between Src inhibition and synaptic function unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that p140Cap stabilizes E-cadherin at the membrane and independently inhibits both Src-dependent EGFR signaling and Ras/Erk pathway activation revealed dual control over epithelial cell proliferation and scattering.\",\n      \"evidence\": \"Gain/loss of function in breast and colon cancer cells, Ras activity assay, Erk phosphorylation, E-cadherin localization\",\n      \"pmids\": [\"20453886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Src-independent Ras inhibition not fully resolved\", \"Direct versus indirect E-cadherin stabilization unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping the cortactin SH3 domain as the direct binding interface and showing that p140Cap suppresses cortactin Y421 phosphorylation—with rescue by a phosphomimetic mutant—defined the molecular basis for metastasis suppression (80% reduction in lung metastases).\",\n      \"evidence\": \"Orthotopic transplantation in immunodeficient mice, co-IP, domain mapping, EGF-stimulated phosphorylation, phosphomimetic rescue\",\n      \"pmids\": [\"21725361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cortactin inhibition operates through Src or an alternative kinase in vivo not fully distinguished\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of Abl as the kinase phosphorylating the EPLYA/EGLYA motifs and demonstration that these phosphotyrosines are required for Csk binding resolved how p140Cap activates Csk to inhibit Src, completing the upstream regulatory circuit.\",\n      \"evidence\": \"In vivo mass spectrometry phosphosite mapping, site-directed mutagenesis, in vitro kinase assay with Abl, Far Western, co-IP in HEK-293 cells\",\n      \"pmids\": [\"23383002\", \"23841028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Abl phosphorylation of p140Cap is regulated by specific upstream signals in tumors is undefined\", \"Structural basis of p140Cap–Csk interaction unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that postsynaptic SNAP-25 binding to p140Cap is required for dendritic spine morphogenesis established a neuronal function beyond the original exocytosis role.\",\n      \"evidence\": \"shRNA knockdown and overexpression in neurons, spine morphology quantification, co-localization with PSD-95\",\n      \"pmids\": [\"23868368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from SNAP-25–p140Cap to actin in spines not elucidated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"p140Cap knockout mice showed impaired LTP/LTD, reduced mushroom spines, and disrupted object recognition; mechanistically, p140Cap locally inhibits RhoA and cortactin/cofilin through Src inhibition and Citron-N scaffolding, establishing it as a master organizer of synaptic actin dynamics.\",\n      \"evidence\": \"KO mouse model, behavioral testing, electrophysiology, phalloidin staining, co-IP with Citron-N, kinase assays\",\n      \"pmids\": [\"24453341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Src-dependent versus Src-independent pathways in spine regulation not quantified\", \"Role at presynaptic terminals in excitatory synapses not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of endophilin A1 as a direct upstream partner that regulates p140Cap distribution into spines revealed how p140Cap is recruited to postsynaptic sites to control cortactin and F-actin.\",\n      \"evidence\": \"GST pulldown, co-IP, shRNA knockdown with spine morphology and synaptic function readouts\",\n      \"pmids\": [\"25771685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of endophilin A1–p140Cap binding not resolved\", \"Whether endophilin A1 also modulates p140Cap in non-neuronal cells unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three parallel advances—(i) p140Cap dampening ERBB2/Rac1 signaling to suppress EMT and metastasis in vivo, (ii) presynaptic β-catenin requiring p140Cap to enhance excitatory transmission, and (iii) a synaptic interactome of 351 proteins—broadened p140Cap's role to Rac GTPase control in cancer and trans-synaptic signaling in brain.\",\n      \"evidence\": \"NeuT mouse model with Rac1 assays; conditional β-catenin expression with electrophysiology; co-IP/MS from synaptosomes\",\n      \"pmids\": [\"28300085\", \"28641114\", \"28713243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking presynaptic β-catenin–p140Cap to vesicle release probability not defined\", \"Which of the 351 synaptic interactors are functionally required is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extension of the Src/STAT3 inhibitory mechanism to neuroblastoma, with demonstration that p140Cap increases chemosensitivity, generalized the tumor-suppressive activity beyond breast cancer and identified STAT3 as an additional downstream effector.\",\n      \"evidence\": \"SRCIN1 overexpression/silencing in neuroblastoma cells, xenograft models, Src/STAT3 activity assays, drug sensitivity assays\",\n      \"pmids\": [\"31285546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p140Cap-mediated chemosensitization is solely through Src/STAT3 or involves additional pathways not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional knockout showed p140Cap is present in presynaptic GABAergic terminals and restrains inhibitory synaptogenesis and vesicle release, with loss causing increased seizure susceptibility, revealing a previously unknown role in inhibitory circuit homeostasis.\",\n      \"evidence\": \"Global and interneuron-specific conditional KO mice, patch-clamp electrophysiology, vesicle pool assays, seizure models, immunohistochemistry\",\n      \"pmids\": [\"29161354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target through which p140Cap restricts GABA vesicle release probability not identified\", \"Whether Src inhibition mediates the presynaptic GABAergic phenotype untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the N-terminal domain (1–287) as sufficient to bind Tiam1 and directly inhibit its GEF activity toward Rac1 provided a Src-independent mechanism for p140Cap's suppression of Rac1 signaling and E-cadherin stabilization.\",\n      \"evidence\": \"Domain truncation analysis, co-IP, Tiam1 GEF activity assay, E-cadherin immunofluorescence\",\n      \"pmids\": [\"33415001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the Tiam1-binding and Csk-binding functions are coordinately regulated is unknown\", \"No structural data for the N-terminal domain\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that p140Cap directly binds GluN2A and is required for GluN2A/PSD-95 assembly in synaptic lipid rafts, with rescue in KO neurons, established a postsynaptic scaffolding function for NMDAR organization that explains the LTP/LTD deficits.\",\n      \"evidence\": \"Co-IP, synaptosome and lipid raft fractionation, gated-STED super-resolution microscopy, KO rescue, electrophysiology\",\n      \"pmids\": [\"35953295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How p140Cap promotes lipid raft recruitment of GluN2A/PSD-95 mechanistically is unclear\", \"Relationship between cholesterol regulation (mevalonate pathway) and raft organization in neurons not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"KO female mice showed severe hypofertility with reduced GnRH neurons and diminished glutamatergic synapses onto GnRH neurons, extending p140Cap's synaptic function to neuroendocrine reproductive control.\",\n      \"evidence\": \"KO mouse, immunohistochemistry for GnRH/VGLUT, hormone measurements, kisspeptin challenge\",\n      \"pmids\": [\"35237119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p140Cap acts cell-autonomously in GnRH neurons or in their presynaptic partners is unresolved\", \"Mechanism of GnRH neuron loss not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two new tumor-suppressive mechanisms were defined: p140Cap stabilizes the β-catenin destruction complex to restrict tumor-initiating cell self-renewal and immunosuppressive G-CSF release, and it promotes mevalonate pathway flux to increase membrane cholesterol, reducing lipid raft Rac1 signaling and migration.\",\n      \"evidence\": \"Co-IP of destruction complex, β-catenin reporter, in vivo models, HMGCR activity/expression assays, cholesterol imaging, lipid raft fractionation, Rac1 assay\",\n      \"pmids\": [\"37169737\", \"38123597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether β-catenin destruction complex stabilization and mevalonate regulation are mechanistically linked is unknown\", \"Transcriptional versus post-translational contribution to HMGCR regulation not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of SNX17 as a p140Cap interactor required for dendritic spine maturation added an endosomal trafficking component to the synaptic scaffold network.\",\n      \"evidence\": \"GST pulldown, interactome analysis, Snx17 haploinsufficient mice, spine morphology, electrophysiology\",\n      \"pmids\": [\"37704928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanistic link between SNX17–p140Cap and spine actin remodeling not established\", \"Whether SNX17 regulates p140Cap trafficking or vice versa is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Quantitative biophysical mapping of the BIN1 SH3 domain–p140Cap interaction (KD 7.7 µM) and demonstration that a rare BIN1 coding variant disrupts this binding connected p140Cap to Alzheimer's disease-associated BIN1 biology.\",\n      \"evidence\": \"Surface plasmon resonance, alanine-scanning mutagenesis, proximity ligation assay in mouse brain, co-IP, confocal microscopy\",\n      \"pmids\": [\"40889683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of BIN1–p140Cap interaction at synapses not yet demonstrated\", \"Whether the rare BIN1 variant affects synaptic p140Cap function in vivo is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of p140Cap's multivalent scaffold function, whether its cholesterol/mevalonate regulation in cancer cells operates in neurons to control lipid raft NMDAR assembly, and whether Src-dependent actin remodeling underlies its putative role in ciliogenesis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure for any p140Cap domain or complex\", \"Integration of mevalonate/cholesterol regulation with synaptic lipid raft function untested\", \"Ciliogenesis role reported only in a preprint and not independently validated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7, 8, 14, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6, 9, 10, 11, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6, 17]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 5, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 7, 12, 14, 16, 19, 20]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 6, 9, 11, 15, 17]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 16, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"β-catenin destruction complex\"\n    ],\n    \"partners\": [\n      \"SNAP25\",\n      \"CSK\",\n      \"CTTN\",\n      \"CIT\",\n      \"TIAM1\",\n      \"GRIN2A\",\n      \"CTNNB1\",\n      \"BIN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}