{"gene":"BCAR1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1995,"finding":"p130Cas (BCAR1) interacts directly with FAK via its SH3 domain binding to the proline-rich region of FAK (APPKPSR, residues 711-717), as demonstrated by yeast two-hybrid screen and confirmed by co-immunoprecipitation in mouse fibroblasts.","method":"Yeast two-hybrid screen, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and two-hybrid, replicated across multiple subsequent studies","pmids":["7479864"],"is_preprint":false},{"year":1995,"finding":"p130Cas becomes tyrosine-phosphorylated during integrin-mediated cell adhesion to extracellular matrix substrata, dependent on integrin ligation and actin cytoskeleton integrity (blocked by cytochalasin D), but independent of cell adhesion in v-src-transformed cells.","method":"Western blot, immunoprecipitation, cytochalasin D inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditions tested, replicated across subsequent studies","pmids":["7545676"],"is_preprint":false},{"year":1996,"finding":"The C-terminal region of p130Cas directly binds both SH2 and SH3 domains of Src kinase; the SH3-binding site maps to RPLPSPP near the C-terminus, and both this site and Tyr762 are required for Src association, while the substrate domain mediates binding to v-Crk via its SH2 domain.","method":"GST fusion protein pulldown, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with mutagenesis, single lab but multiple domain-mapping experiments","pmids":["8621540"],"is_preprint":false},{"year":1996,"finding":"Individual domains of p130Cas associate with distinct binding partners: FAK, v-Src, and v-Crk binding sites are mapped to distinct regions of p130Cas, and many interactions are dependent on the tyrosine-phosphorylation state of p130Cas.","method":"In vitro domain-binding assays, domain mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, in vitro binding, no mutagenesis confirmation","pmids":["8649789"],"is_preprint":false},{"year":1997,"finding":"FAK phosphorylates p130Cas in vitro and in cells upon fibronectin stimulation (via a FAK/Src 1-298 complex), and FAK-induced phosphorylation of p130Cas promotes SH2-domain-dependent binding of the Nck adaptor protein to p130Cas.","method":"In vitro kinase assay, co-immunoprecipitation, fibronectin stimulation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay plus cell-based co-IP, single lab with multiple orthogonal methods","pmids":["9032297"],"is_preprint":false},{"year":1997,"finding":"During bacterial uptake, p130Cas and FAK are phosphorylated and recruited to peripheral focal complexes in HeLa cells; Yersinia YopH (active PTPase) dephosphorylates p130Cas and FAK and disrupts these complexes, blocking uptake. Inactive YopH co-localizes with and binds the tyrosine-phosphorylated forms of FAK and p130Cas.","method":"Co-localization, immunoprecipitation, PTPase activity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — active vs inactive YopH comparison, co-localization and co-IP, single lab with orthogonal methods","pmids":["9171345"],"is_preprint":false},{"year":1997,"finding":"RAFTK (Pyk2) directly phosphorylates the substrate domain of p130Cas in vitro; full phosphorylation of p130Cas requires cooperation between RAFTK and Src kinases, with the C-terminal domain of p130Cas requiring RAFTK autophosphorylation site Tyr402 (which mediates Src binding).","method":"In vitro kinase assay with purified domains, mutagenesis of Tyr402","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with domain mutants, single lab","pmids":["9242628"],"is_preprint":false},{"year":1998,"finding":"p130Cas (BCAR1) is a mediator of FAK-promoted cell migration; FAK mutant P712/715A (which reduces p130Cas association) fails to promote migration, while co-expression of p130Cas enhances migration and the p130Cas SH3 domain alone acts as a dominant negative inhibitor of migration.","method":"FAK mutant expression, migration assay, co-immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant negative and overexpression rescue with defined mutants, replicated across labs","pmids":["9425168"],"is_preprint":false},{"year":1998,"finding":"Mice lacking p130Cas (Crkas/BCAR1) die in utero with cardiovascular defects, disorganized myofibrils, and impaired actin stress fiber formation in fibroblasts; activated Src in Cas-deficient fibroblasts fails to induce full transformation due to insufficient actin accumulation in podosomes.","method":"Knockout mouse generation, histology, electron microscopy, primary fibroblast analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline knockout with multiple phenotypic readouts, replicated in subsequent rescue experiments","pmids":["9697697"],"is_preprint":false},{"year":1998,"finding":"Angiotensin II induces tyrosine phosphorylation of p130Cas in vascular smooth muscle cells via a pathway requiring c-Src family kinase activity, intracellular Ca2+, and protein kinase C; phosphorylated p130Cas then associates with protein kinase C-alpha and pp120, with c-Src constitutively associated.","method":"Immunoprecipitation, kinase inhibitors, chelators, Western blot","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple inhibitors but no reconstitution or mutagenesis","pmids":["9648724"],"is_preprint":false},{"year":1998,"finding":"Growth hormone stimulates formation of a multiprotein signaling complex centered on p130Cas and CrkII, including c-Src, c-Fyn, tensin, paxillin, IRS-1, p85/PI3K, C3G, SHC, Grb-2, Sos-1, c-Cbl, and Nck; this complex formation correlates with JNK/SAPK activation.","method":"Co-immunoprecipitation, kinase activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP-based complex identification without mutagenesis","pmids":["9837978"],"is_preprint":false},{"year":1999,"finding":"PTEN dephosphorylates FAK and decreases tyrosine phosphorylation of both FAK and p130Cas; p130Cas overexpression reverses PTEN inhibition of cell invasion and migration without affecting PTEN-dependent growth suppression, and p130Cas cannot be directly dephosphorylated by PTEN in vitro or shown to interact with PTEN in cells.","method":"Overexpression, in vitro phosphatase assay, co-immunoprecipitation, invasion assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase assay (negative result confirmed) plus functional rescue experiments, single lab with multiple methods","pmids":["9927060"],"is_preprint":false},{"year":1999,"finding":"p130Cas-deficient fibroblasts exhibit significant defects in cell movement, migration toward fibronectin, and cell spreading; re-expression of p130Cas rescues these defects, establishing a direct role for p130Cas in promoting cell motility.","method":"Knockout fibroblast re-expression rescue, wound healing assay, transwell migration assay, cell spreading assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout/rescue with multiple orthogonal motility assays, single lab","pmids":["10448062"],"is_preprint":false},{"year":1999,"finding":"MCSP (melanoma chondroitin sulphate proteoglycan) stimulation recruits tyrosine-phosphorylated p130Cas and activates Cdc42; MCSP-induced cell spreading is dependent on active Cdc42, the Cdc42-associated kinase Ack-1, and tyrosine phosphorylation of p130Cas; Ack-1 and Cdc42 inhibition abrogates MCSP-induced p130Cas phosphorylation.","method":"Co-immunoprecipitation, dominant negative constructs, cell spreading assay","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, dominant negative constructs with functional readouts, no direct kinase assay","pmids":["10587647"],"is_preprint":false},{"year":1999,"finding":"The transmembrane PTPase LAR dephosphorylates p130Cas in vitro and in vivo, reducing its protein stability and eliminating it from focal adhesions, leading to apoptosis; restoring p130Cas levels alleviates LAR-induced apoptosis, identifying p130Cas as an in vivo substrate of LAR.","method":"In vitro phosphatase assay, substrate-trapping mutants, rescue by p130Cas overexpression, immunofluorescence","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase assay with substrate-trapping, dominant negative, and rescue experiments in single lab","pmids":["10320483"],"is_preprint":false},{"year":2000,"finding":"p130Cas associates with the p85 subunit of PI 3-kinase through its RPLPSPP proline-rich domain (SH3 domain of p85 binding), and this interaction is required for adenovirus internalization mediated by alpha-v integrins; inhibition of p130Cas phosphorylation or deletion of its substrate domain blocks adenovirus cell entry.","method":"Co-immunoprecipitation, dominant negative constructs, adenovirus internalization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping with deletion mutants plus functional internalization assay, single lab","pmids":["10799562"],"is_preprint":false},{"year":2000,"finding":"p130Cas regulates AND-34 (BCAR3) GEF activity: overexpression of p130Cas (but not an AND-34-binding mutant) inhibits AND-34's Ral GEF activity on RalA, Rap1A, and R-Ras; efficient p130Cas-AND-34 binding requires both the Src-binding domain and a flanking C-terminal region of p130Cas.","method":"GEF activity assay in cells, co-immunoprecipitation, mutant binding analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, cell-based GEF assay with defined mutants but no in vitro reconstitution","pmids":["10896938"],"is_preprint":false},{"year":2000,"finding":"BCAR1 (p130Cas) overexpression confers antiestrogen resistance on ZR-75-1 breast cancer cells, identified as the gene responsible for the BCAR1 locus; the gene encodes a 870 amino acid protein homologous to rat p130Cas, located at chromosome 16q23.1.","method":"Retroviral mutagenesis, cell fusion, cDNA transfection, functional growth assay","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional rescue by cDNA transfection with defined phenotypic readout, single lab","pmids":["10639512"],"is_preprint":false},{"year":2000,"finding":"Caspase-3 cleaves p130Cas at two consensus sites DVPD(416)G and DSPD(748)G during etoposide-induced apoptosis; cleavage correlates with loss of FAK from focal adhesions and attenuation of Cas-paxillin interactions, contributing to focal adhesion complex disassembly.","method":"In vitro caspase cleavage assay, site-directed mutagenesis, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay with point mutagenesis confirming cleavage sites, single lab","pmids":["10712510"],"is_preprint":false},{"year":2001,"finding":"Integrin-mediated adhesion induces assembly of a macromolecular complex at the cell membrane containing p130Cas, c-Src, and the EGF receptor; both c-Src and p130Cas are required for integrin-dependent phosphorylation of EGF receptor at specific tyrosines (Y845, Y1068, Y1086, Y1173).","method":"Co-immunoprecipitation, dominant negative constructs, phospho-specific antibodies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP plus functional knockout/dominant negative, no reconstitution","pmids":["11756413"],"is_preprint":false},{"year":2001,"finding":"SHIP2 associates with p130Cas primarily through the SHIP2 SH2 domain; an SH2 domain mutant (R47G) abolishes this interaction and increased SHIP2 expression promotes adhesion, while a catalytic domain deletion mutant inhibits cell spreading.","method":"Co-immunoprecipitation, SH2 domain mutant, cell adhesion and spreading assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP with domain mutants and functional readouts","pmids":["11158326"],"is_preprint":false},{"year":2001,"finding":"FAK and p130Cas localize to sarcomeric Z-lines in cardiac myocytes; expression of the p130Cas-binding proline-rich region 1 of FAK disrupts Cas-FAK association and impairs sarcomere structural stability; Cas alone or with Src modulates atrial natriuretic peptide (ANP) gene promoter activity as a marker of cardiac hypertrophy.","method":"Immunofluorescence localization, dominant negative expression, luciferase reporter assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, dominant negative/localization studies with functional gene expression readout","pmids":["11514617"],"is_preprint":false},{"year":2001,"finding":"SAP-1 phosphatase dephosphorylates p130Cas in intact cells and preferentially in vitro; a substrate-trapping SAP-1 mutant induces hyperphosphorylation of p130Cas (dominant negative effect); SAP-1 overexpression inhibits cell spreading on fibronectin and colony formation.","method":"Substrate-trapping mutagenesis, in vitro phosphatase assay, immunoprecipitation, spreading assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase assay with substrate-trapping and dominant negative mutants, single lab","pmids":["11278335"],"is_preprint":false},{"year":2001,"finding":"p130Cas localizes to focal adhesions in podocytes and colocalizes with F-actin at stress fiber ends, distinct from CD2AP which colocalizes with dynamic F-actin at lamellipodia.","method":"Immunofluorescence, immunoelectron microscopy","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, localization only without functional consequence directly tested","pmids":["11553524"],"is_preprint":false},{"year":2002,"finding":"EphrinA1-induced cytoskeletal reorganization and cell spreading in NIH3T3 cells requires both FAK and p130Cas; MEFs from FAK-/- and p130Cas-/- mice have severe defects in ephrinA1-induced spreading, reversed by re-expression of FAK or p130Cas respectively; EphA2, FAK, and p130Cas are the major ephrin-dependent phosphotyrosyl proteins.","method":"Knockout MEFs, re-expression rescue, phosphotyrosine analysis, cell spreading assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout and rescue with defined readouts, two orthogonal null models (FAK-/- and p130Cas-/-), single lab","pmids":["12134157"],"is_preprint":false},{"year":2003,"finding":"The p130CAS-CrkII complex functions as a molecular switch in cell motility; KAI1/CD82 expression decreases p130CAS protein levels, reduces p130CAS-CrkII complex formation, and inhibits migration; overexpression of p130CAS in KAI1/CD82-expressing cells restores complex formation and largely reverses migration inhibition.","method":"Co-immunoprecipitation, overexpression rescue, migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP and rescue experiments","pmids":["12738793"],"is_preprint":false},{"year":2003,"finding":"Bmx/Etk kinase interacts with p130Cas at membrane ruffles, phosphorylates p130Cas, and promotes Cas-Crk complex formation; a Bmx mutant failing to interact with Cas also fails to induce cell migration; dominant-negative Cas (unable to bind Crk) inhibits Bmx-induced membrane ruffling and migration.","method":"Co-immunoprecipitation, dominant negative constructs, membrane ruffling and migration assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP with functional mutant analysis","pmids":["12832404"],"is_preprint":false},{"year":2003,"finding":"p140Cap (Cas-associated protein) directly interacts with p130Cas through the p140Cap carboxy-terminal region; the two proteins co-immunoprecipitate and colocalize in lamellipodia; p140Cap overexpression delays cell spreading on fibronectin.","method":"Affinity chromatography, mass spectrometry, co-immunoprecipitation, immunofluorescence, cell spreading assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, biochemical pulldown with domain localization and functional spreading assay","pmids":["14657239"],"is_preprint":false},{"year":2004,"finding":"p130Cas rapidly associates with estrogen receptor alpha (ERα) in a multi-molecular complex containing c-Src and p85/PI3K within 3 minutes of estrogen treatment; this association is c-Src-dependent; p130Cas overexpression enhances estrogen-dependent Src kinase and ERK1/2 activities, while siRNA silencing of p130Cas inhibits estrogen-dependent ERK1/2 activity and cyclin D1 induction.","method":"Co-immunoprecipitation, siRNA knockdown, kinase activity assays, reporter assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus gain/loss-of-function with defined pathway readouts, single lab","pmids":["15020686"],"is_preprint":false},{"year":2005,"finding":"Ajuba (LIM protein) associates with the focal adhesion-targeting domain of p130Cas and acts upstream of p130Cas to localize it to nascent adhesive sites; Ajuba-null cells have reduced p130Cas, Crk, Dock180, and FAK at nascent focal complexes and blunted Rac activation in response to migratory cues.","method":"Co-immunoprecipitation, knockout mouse fibroblasts, FRET analysis of Rac activation, rescue experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout fibroblasts with rescue, FRET, and co-IP, single lab","pmids":["15728191"],"is_preprint":false},{"year":2005,"finding":"p130Cas overexpression in mammary gland (MMTV-p130Cas mice) leads to mammary epithelial hyperplasia associated with activation of Src, ERK1/2, and Akt; crossing with MMTV-HER2-Neu mice accelerates multifocal mammary tumor development with increased Src and Akt activation; p130Cas siRNA increases apoptosis in HER2-Neu-expressing cells.","method":"Transgenic mouse models, signaling pathway analysis, siRNA knockdown, tumor latency measurement","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with double-transgenic, siRNA, and signaling readouts, single lab","pmids":["16651418"],"is_preprint":false},{"year":2005,"finding":"NPM-ALK (anaplastic lymphoma kinase fusion) binds p130Cas and induces its phosphorylation in a manner dependent on ALK kinase activity and the adaptor Grb2; p130Cas-/- fibroblasts expressing NPM-ALK show impaired actin depolymerization and are no longer transformed, establishing p130Cas as essential for ALK-mediated transformation.","method":"Mass spectrometry identification, co-immunoprecipitation, kinase-dead mutant, Grb2 dominant negative, Cas-/- fibroblast reconstitution","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus co-IP, kinase-dead mutant, and knockout rescue, single lab","pmids":["16105984"],"is_preprint":false},{"year":2006,"finding":"Fibronectin matrix rigidity response requires Fyn (but not endogenous c-Src) recruitment to early adhesions; p130Cas is also required for the rigidity response and is phosphorylated at the leading edge in a Fyn-dependent manner, suggesting force-dependent Fyn phosphorylation of p130Cas.","method":"Live cell imaging, dominant negative mutants, phosphorylation site analysis, leading edge localization","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, dominant negative/localization with functional rigidity readout","pmids":["16597701"],"is_preprint":false},{"year":2006,"finding":"Ack1 mediates Cdc42-dependent cell migration through p130Cas: Ack1 forms a signaling complex with Cdc42, p130Cas, and Crk via SH3 domain interactions; Ack1 phosphorylates the substrate domain of p130Cas; siRNA knockdown of either p130Cas or Ack1 blocks Cdc42-induced migration.","method":"Co-immunoprecipitation, siRNA knockdown, migration assay, phosphorylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP of complex, domain mapping, siRNA knockdown with functional migration readout, single lab","pmids":["17038317"],"is_preprint":false},{"year":2007,"finding":"p130CAS is required for netrin-1 signaling: netrin-1 induces p130CAS tyrosine phosphorylation downstream of Src family kinases and upstream of Rac1/Cdc42; inhibiting p130CAS signaling blocks netrin-1-promoted neurite outgrowth and axon attraction; p130CAS RNAi causes defects in commissural axon projection in vivo.","method":"Biochemical epistasis, RNAi knockdown, in vivo commissural axon projection analysis","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis analysis plus in vivo RNAi with defined axon guidance phenotype, single lab","pmids":["17251438"],"is_preprint":false},{"year":2008,"finding":"Tyrosine phosphorylation of p130Cas is sufficient to activate Rac1 and induce membrane ruffling/lamellipodium formation in SYF cells; the kinase activity of Src (not FAK) is essential for phosphorylating p130Cas within the Src-FAK-p130Cas trimolecular complex at focal adhesions.","method":"Functional Interaction Trap (FIT) method for selective substrate phosphorylation, Rac1 activation assay, dominant negative FAK","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — novel selective phosphorylation method plus Rac activation assay, single lab with two orthogonal approaches","pmids":["18793427"],"is_preprint":false},{"year":2008,"finding":"Once tyrosine-phosphorylated via integrin signaling, p130Cas binds to Smad3 and reduces Smad3 phosphorylation, inhibiting TGF-β-mediated growth arrest; loss of p130Cas abrogates integrin-mediated suppression of TGF-β/Smad3 signaling.","method":"Co-immunoprecipitation, loss/gain of function, Smad3 phosphorylation assay, cell cycle analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP of p130Cas-Smad3 interaction with loss/gain function and phosphorylation readouts, single lab","pmids":["18321991"],"is_preprint":false},{"year":2009,"finding":"Estrogen-dependent formation of ERα-BCAR1 complexes (within ~5 min) is increased by RANKL co-treatment; BCAR1 associates with the RANKL signaling intermediate Traf6 in this complex; BCAR1 siRNA knockdown abolishes estradiol inhibition of osteoclast differentiation, demonstrating BCAR1 is required for estrogen's non-genomic inhibition of NF-κB-mediated osteoclastogenesis.","method":"Co-immunoprecipitation, siRNA knockdown, osteoclast differentiation assay, NF-κB localization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP plus siRNA knockdown with functional osteoclast differentiation readout","pmids":["19331827"],"is_preprint":false},{"year":2010,"finding":"Both the N-terminal SH3 domain and the C-terminal Cas-family homology (CCH) domain of p130Cas are required for its localization to focal adhesions (FA targeting requires FAK for the SH3 domain function); deletion of either domain impairs FA localization and tyrosine phosphorylation; both domains are necessary for p130Cas to promote cell migration.","method":"Live cell microscopy, FRAP, deletion mutants, FA targeting analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live imaging with FRAP plus multiple deletion mutants and functional migration assay, single lab","pmids":["20430882"],"is_preprint":false},{"year":2010,"finding":"p130Cas substrate domain (SD) phosphorylation is the sole p130Cas signaling function for promoting leading-edge actin flux and FA assembly/disassembly rates, while the Src-binding domain (SBD) has a distinct function in sustained FA disassembly and cell migration that is independent of its known role in promoting SD phosphorylation.","method":"Cas-/- MEF rescue with domain mutants, quantitative live cell imaging of FA dynamics and actin flux","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout rescue with structure-function mutants and quantitative live imaging, single lab","pmids":["20976150"],"is_preprint":false},{"year":2010,"finding":"p130Cas is an essential transducer in ErbB2 transformation: p130Cas forms a functional complex with ErbB2, c-Src, and FAK in transformed cells; p130Cas silencing impairs foci formation, anchorage-independent growth, and in vivo tumor growth; p130Cas overexpression with ErbB2 activates Rac1 and MMP9 secretion, conferring invasive properties.","method":"siRNA knockdown, in vivo tumor growth, co-immunoprecipitation, Rac1 activation assay, invasion assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in vivo and in vitro with signaling mechanism, single lab","pmids":["20505116"],"is_preprint":false},{"year":2011,"finding":"BCAR1/p130Cas and NEDD9 signal through SRC to promote E-cadherin removal from the cell membrane and lysosomal degradation, negatively regulating E-cadherin expression in human mammary cells without affecting E-cadherin transcription.","method":"siRNA knockdown, inhibitor studies, pulse-chase/degradation assay, in vivo mammary tumor analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, mechanism inferred from inhibitor and knockdown studies without direct reconstitution","pmids":["21765937"],"is_preprint":false},{"year":2011,"finding":"NRP1 (neuropilin-1) co-immunoprecipitates with PDGFRα and selectively mediates PDGF-induced tyrosine phosphorylation of p130Cas; NRP1 siRNA and NRP1 mutants lacking the intracellular domain inhibit PDGF-induced p130Cas phosphorylation and VSMC migration; p130Cas knockdown also inhibits HCASMC migration.","method":"Co-immunoprecipitation, siRNA knockdown, adenoviral overexpression of NRP1 mutants, migration assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP plus siRNA/mutant with functional migration readout","pmids":["21306301"],"is_preprint":false},{"year":2012,"finding":"PTPN14 directly dephosphorylates p130Cas specifically at tyrosine residue Y128; homozygous Y128F knock-in CRC cells show reduced migration, colony formation, and slower xenograft tumor growth with decreased AKT phosphorylation; SRC phosphorylates p130Cas Y128.","method":"Phospho-proteomic screen, knock-in mutagenesis, in vitro phosphatase/kinase assay, xenograft tumor growth","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro direct phosphatase activity, knock-in mutagenesis, in vivo xenograft, single lab with multiple methods","pmids":["22710723"],"is_preprint":false},{"year":2012,"finding":"p130Cas-dependent actin remodeling regulates myogenic differentiation: p130Cas phosphorylation (mediated by integrin β3) promotes F-actin formation, nuclear localization of MAL/SRF co-activator, and myotube formation; phosphorylation-defective p130Cas mutant fails to rescue these processes; p130Cas phosphorylation prevents cofilin activation.","method":"siRNA knockdown, phosphorylation-defective mutant re-expression, F-actin staining, nuclear MAL localization assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss of function, phosphorylation-defective mutant rescue, and mechanistic analysis with defined downstream readouts, single lab","pmids":["22587391"],"is_preprint":false},{"year":2013,"finding":"In osteoclasts, p130Cas is required for actin ring formation and bone resorption; p130Cas conditional knockout osteoclasts show reduced Rac1 activity, disrupted Rac1 distribution, and failure of Dock5 (a Rac GEF) to associate with Src or Pyk2, while initial β3-integrin and Src phosphorylation events are intact.","method":"Osteoclast-specific conditional knockout, actin ring assay, pit formation assay, co-immunoprecipitation of Dock5","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout with molecular mechanism (Dock5 association) defined, single lab","pmids":["23526406"],"is_preprint":false},{"year":2014,"finding":"BCAR1 and BCAR3 bind tightly through their C-terminal domains; structure-based interaction-disrupting mutants show that BCAR3-induced antiestrogen resistance critically depends on binding to BCAR1; BCAR3-BCAR1 interaction increases phosphorylated BCAR1 levels and ERK1/2 activity, which mediates resistance.","method":"Structure-based mutagenesis of interaction interface, co-immunoprecipitation, antiestrogen resistance functional assay, ERK inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — structure-guided mutants with functional rescue and defined signaling pathway, single lab","pmids":["24584939"],"is_preprint":false},{"year":2019,"finding":"p130Cas (BCAR1) is recruited to filopodia tips via its C-terminal Cas family homology domain (CCHD) and acts as a mechanosensitive regulator of filopodia stability, as demonstrated by structured-illumination microscopy mapping and live imaging.","method":"SIM-based protein localization screen, live imaging, domain deletion analysis (CCHD)","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic SIM screen with domain mutant and live imaging, single lab with multiple orthogonal methods","pmids":["30639111"],"is_preprint":false},{"year":2019,"finding":"p130Cas (Cas) translocates to the nucleus in osteocytes in response to fluid shear stress and alleviates NF-κB activity; osteocyte-specific Cas deficiency increases NF-κB-mediated RANKL expression and osteoclastic bone resorption, leading to osteopenia; shear stress-dependent nuclear Cas translocation was directly observed.","method":"Osteocyte-specific conditional knockout, nuclear fractionation, live-cell imaging of Cas translocation, NF-κB reporter assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout plus direct imaging of nuclear translocation with NF-κB pathway readout, single lab","pmids":["31579816"],"is_preprint":false},{"year":2021,"finding":"SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-β-catenin-dependent mechanism; BCAR1 siRNA sensitizes pancreatic cancer cells to ERK inhibition, identifying BCAR1 as a synthetic lethal interactor with mutant KRAS.","method":"siRNA/CRISPR genome-scale screen, pathway inhibitors, MYC reporter, DOCK1/RAC1/β-catenin epistasis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-scale CRISPR screen plus mechanistic epistasis analysis with multiple inhibitors and siRNA, single lab","pmids":["34192548"],"is_preprint":false},{"year":2006,"finding":"Salmonella typhimurium invasion of host cells requires p130Cas; Cas-/- cells are impaired in bacterial internalization, and reconstitution requires the central Cas YXXP repeat domain; FAK overexpression suppresses the invasion defect in Cas-/- cells, suggesting a functional FAK-Cas link in Salmonella invasion.","method":"Knockout MEFs, reconstitution with domain mutants, genetic suppressor analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout and domain-specific rescue with genetic epistasis, single lab","pmids":["16914515"],"is_preprint":false},{"year":2011,"finding":"Cyclic stretch induces cell reorientation in a Src family kinase- and p130Cas-dependent manner; knockout or knockdown of p130Cas reduces reorientation upon cyclic stretch, and mutation of stretch-sensitive tyrosines of p130Cas produces identical impairment.","method":"SYF knockout MEFs, siRNA knockdown, p130Cas tyrosine mutants, cyclic stretch device","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout and site-directed tyrosine mutants with defined mechanical stimulus, single lab","pmids":["22178114"],"is_preprint":false},{"year":2004,"finding":"p130Cas cleavage occurs during anoikis; overexpression of the p130Cas cleavage product induces apoptosis; caspases and calpain are both involved in cleavage, though additional unidentified proteases may also cleave p130Cas at the early stage of anoikis.","method":"Cell detachment-induced anoikis assay, cleavage fragment overexpression, caspase/calpain inhibitors","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, cleavage product overexpression with apoptosis readout","pmids":["14743392"],"is_preprint":false}],"current_model":"BCAR1/p130Cas is a multidomain scaffold/adaptor protein that localizes to focal adhesions (via SH3 and CCH domains), filopodia tips (via CCHD), and the nucleus, where it integrates signals from integrins, receptor tyrosine kinases, Src family kinases, and GPCRs: FAK binds the p130Cas SH3 domain at APPKPSR; Src phosphorylates the substrate domain YXXP motifs to create Crk-SH2 binding sites, activating Rac1-dependent membrane ruffling and cell migration; it acts as a mechanosensor (stretch-dependent tyrosine phosphorylation promotes cytoskeletal remodeling and cell reorientation); it interacts with estrogen receptor α to transduce non-genomic estrogen signaling; phospho-p130Cas binds Smad3 to suppress TGF-β-mediated growth arrest; it is directly dephosphorylated by LAR, SAP-1, and PTPN14 phosphatases; caspase-3 cleaves it at DVPD416 and DSPD748 during apoptosis; and in the nucleus it alleviates NF-κB activity to support bone homeostasis."},"narrative":{"mechanistic_narrative":"BCAR1/p130Cas is a multidomain scaffold protein that converts integrin and growth-factor engagement into actin-based cell motility by nucleating a tyrosine-phosphorylation-dependent signaling complex at focal adhesions [PMID:7479864, PMID:7545676, PMID:20430882]. Its N-terminal SH3 domain binds the proline-rich region of FAK (APPKPSR, 711-717), while a C-terminal RPLPSPP motif and Tyr762 engage the SH3/SH2 domains of Src; both the SH3 and C-terminal Cas-family-homology (CCH) domains are required for focal-adhesion targeting and for promoting migration [PMID:7479864, PMID:8621540, PMID:20430882]. Within the Src–FAK–p130Cas complex, Src kinase activity phosphorylates the central substrate-domain YXXP repeats, creating docking sites for the Crk family and other SH2 adaptors, which is sufficient to activate Rac1 and drive membrane ruffling, lamellipodium formation, and leading-edge actin flux [PMID:8621540, PMID:17038317, PMID:18793427, PMID:20976150]. Genetic ablation establishes these functions as physiological: p130Cas-null mice die in utero with cardiovascular defects and disorganized myofibrils, and null fibroblasts have impaired stress-fiber formation and severe defects in spreading and migration that are rescued by re-expression [PMID:9697697, PMID:10448062]. p130Cas operates as a mechanosensor, undergoing stretch- and rigidity-dependent tyrosine phosphorylation that drives cell reorientation and, via filopodia-tip recruitment through its CCHD, regulates filopodia stability [PMID:16597701, PMID:30639111, PMID:22178114]. The same scaffold transduces signals from diverse upstream inputs—it is phosphorylated downstream of Pyk2/RAFTK, Ack1, Bmx, NPM-ALK, EphA2, and netrin-1, and forms estrogen-induced ERα–c-Src–PI3K complexes that drive ERK1/2 activation and cyclin D1 induction [PMID:9242628, PMID:12832404, PMID:15020686, PMID:16105984, PMID:17038317, PMID:17251438]. Its phosphorylation state is set by phosphatases LAR, SAP-1, and PTPN14 (the latter acting specifically at Tyr128), and the protein is cleaved by caspase-3 at DVPD416 and DSPD748 during apoptosis, dismantling focal adhesions [PMID:10320483, PMID:11278335, PMID:22710723, PMID:10712510]. p130Cas is oncogenic in breast and HER2/ErbB2-driven contexts, mediates antiestrogen resistance through binding partner BCAR3, and is a synthetic-lethal dependency in mutant-KRAS pancreatic cancer [PMID:10639512, PMID:16651418, PMID:20505116, PMID:24584939, PMID:34192548]. Beyond migration and transformation, nuclear p130Cas alleviates NF-κB activity in osteocytes to restrain RANKL-driven bone resorption [PMID:31579816].","teleology":[{"year":1995,"claim":"Established the founding physical link between p130Cas and the focal-adhesion machinery, defining how the scaffold is recruited and how adhesion controls its activation state.","evidence":"Yeast two-hybrid and co-IP mapping the SH3-FAK interaction; integrin-adhesion-dependent tyrosine phosphorylation blocked by cytochalasin D","pmids":["7479864","7545676"],"confidence":"High","gaps":["Did not identify the kinase responsible for adhesion-induced phosphorylation","Did not define downstream effectors of phosphorylated p130Cas"]},{"year":1996,"claim":"Resolved the modular architecture of the scaffold by mapping FAK, Src, and Crk binding to distinct phosphorylation-state-dependent sites, explaining how one protein integrates multiple partners.","evidence":"GST pulldowns and mutagenesis mapping RPLPSPP/Tyr762 (Src) and substrate-domain (Crk) sites","pmids":["8621540","8649789"],"confidence":"High","gaps":["In vitro binding without cellular validation of all sites","Did not establish functional consequence of each interaction"]},{"year":1997,"claim":"Identified the kinases that phosphorylate p130Cas, showing FAK, Src, and Pyk2/RAFTK cooperate to fully phosphorylate the substrate domain and recruit downstream adaptors.","evidence":"In vitro kinase assays with purified domains, Tyr402 mutagenesis, fibronectin stimulation, and Nck recruitment co-IP","pmids":["9032297","9242628"],"confidence":"High","gaps":["Relative in-cell contribution of each kinase not quantified","Did not link phosphorylation to a motility phenotype"]},{"year":1997,"claim":"Demonstrated that pathogen-driven phosphatase activity (Yersinia YopH) dephosphorylates and disassembles the FAK–p130Cas focal complex, establishing the complex as a target for host-pathogen manipulation.","evidence":"Active vs inactive YopH comparison, co-localization, and PTPase assays in HeLa cells","pmids":["9171345"],"confidence":"High","gaps":["Did not identify endogenous mammalian phosphatases","Mechanism of uptake downstream of complex not detailed"]},{"year":1998,"claim":"Proved p130Cas is functionally required for FAK-promoted migration and for organismal development, moving the scaffold from a binding partner to a causal motility/cytoskeletal effector.","evidence":"FAK P712/715A mutant migration assays, SH3 dominant-negative, and germline knockout mouse with cardiovascular/cytoskeletal phenotypes","pmids":["9425168","9697697"],"confidence":"High","gaps":["Embryonic lethality limited tissue-specific dissection","Did not isolate which downstream effector drives migration"]},{"year":1998,"claim":"Showed p130Cas is a convergence node for GPCR and cytokine receptor inputs, nucleating large multiprotein signaling complexes coupled to JNK activation.","evidence":"Co-IP and inhibitor studies in angiotensin-II-stimulated VSMC and growth-hormone-stimulated cells","pmids":["9648724","9837978"],"confidence":"Medium","gaps":["Co-IP-based complexes lack mutagenesis confirmation","Direct versus indirect associations not distinguished"]},{"year":1999,"claim":"Confirmed p130Cas is a bona fide phosphatase substrate (LAR) controlling its stability and adhesion localization, and dissociated its motility role from PTEN-dependent growth suppression.","evidence":"Substrate-trapping LAR mutants with rescue; in vitro PTEN phosphatase assay (negative) plus invasion rescue","pmids":["10320483","9927060"],"confidence":"High","gaps":["How dephosphorylation triggers degradation not defined","PTEN effect shown to be indirect, leaving the relevant phosphatase open"]},{"year":1999,"claim":"Provided definitive knockout/rescue evidence that p130Cas drives cell spreading and motility, and linked it to Cdc42 activation downstream of MCSP.","evidence":"Knockout fibroblast re-expression with wound-healing/transwell assays; MCSP-Ack1-Cdc42 dominant-negative spreading assays","pmids":["10448062","10587647"],"confidence":"High","gaps":["Did not resolve which adaptor links p130Cas to the GTPase","Cdc42 link based on dominant negatives without direct kinase assay"]},{"year":2000,"claim":"Expanded the partner repertoire (PI3K-p85, AND-34/BCAR3) and identified BCAR1 as the human gene conferring antiestrogen resistance, anchoring its cancer relevance.","evidence":"Domain-mapped co-IP for p85; GEF assays for AND-34; retroviral mutagenesis/cDNA rescue identifying the BCAR1 locus","pmids":["10799562","10896938","10639512"],"confidence":"High","gaps":["Mechanism coupling p130Cas to antiestrogen resistance not yet defined","GEF regulation shown only in cells without reconstitution"]},{"year":2000,"claim":"Defined how p130Cas is dismantled during apoptosis, identifying caspase-3 cleavage sites that drive focal-adhesion disassembly.","evidence":"In vitro caspase cleavage with DVPD416/DSPD748 point mutagenesis and immunofluorescence","pmids":["10712510"],"confidence":"High","gaps":["Functional consequence of cleavage fragments not fully established here","Did not test other proteases"]},{"year":2001,"claim":"Positioned p130Cas as a hub linking integrins to RTK transactivation and to additional phosphatase/adaptor regulators in adhesion and cardiac contexts.","evidence":"Co-IP of integrin-induced p130Cas-Src-EGFR complex; SAP-1 substrate-trapping; SHIP2 SH2-mutant studies; FAK/Cas Z-line localization","pmids":["11756413","11278335","11158326","11514617"],"confidence":"Medium","gaps":["Several interactions rest on single-lab co-IP","SAP-1 is High-confidence but in-vivo substrate specificity not broadly tested"]},{"year":2003,"claim":"Solidified the p130Cas-CrkII complex as a migration switch and added kinases (Bmx) and regulators (p140Cap, KAI1/CD82) that tune complex formation and protein level.","evidence":"Co-IP, dominant negatives, and overexpression rescue in migration/ruffling assays; affinity-MS identification of p140Cap","pmids":["12738793","12832404","14657239"],"confidence":"Medium","gaps":["Mechanisms largely correlative co-IP without reconstitution","Direct vs indirect kinase action on p130Cas not fully resolved"]},{"year":2004,"claim":"Established p130Cas as a transducer of non-genomic estrogen signaling and characterized its proteolytic processing during anoikis.","evidence":"Rapid ERα-Src-p85 co-IP with siRNA/kinase readouts; anoikis cleavage-fragment overexpression with caspase/calpain inhibitors","pmids":["15020686","14743392"],"confidence":"High","gaps":["Direct ERα-p130Cas contact versus Src-bridged not resolved","Anoikis proteases incompletely identified (Medium-confidence)"]},{"year":2005,"claim":"Identified upstream localization machinery (Ajuba) and demonstrated p130Cas oncogenicity in vivo, showing overexpression drives mammary hyperplasia and accelerates HER2-Neu tumors.","evidence":"Ajuba-null fibroblasts with FRET Rac readouts; MMTV-p130Cas and double-transgenic mouse tumor models with siRNA","pmids":["15728191","16651418"],"confidence":"High","gaps":["How Ajuba targets p130Cas to nascent adhesions not molecularly defined","Whether mammary phenotype is cell-autonomous to p130Cas signaling not isolated"]},{"year":2006,"claim":"Established p130Cas as essential for oncogenic-kinase transformation (NPM-ALK), mechanotransduction (rigidity sensing via Fyn), and pathogen invasion via its YXXP substrate domain.","evidence":"Cas-/- reconstitution for NPM-ALK transformation and Salmonella invasion; Fyn-dependent leading-edge phosphorylation in rigidity assays; Ack1-Cdc42-Crk complex with siRNA migration readout","pmids":["16105984","16914515","16597701","17038317"],"confidence":"High","gaps":["Force-dependent Fyn phosphorylation inferred rather than directly measured","Substrate-domain requirement defined but specific YXXP residues not all mapped"]},{"year":2007,"claim":"Extended p130Cas function to neuronal guidance, placing it downstream of Src kinases and upstream of Rac1/Cdc42 in netrin-1-driven axon attraction in vivo.","evidence":"Biochemical epistasis and in vivo RNAi of commissural axon projection","pmids":["17251438"],"confidence":"High","gaps":["Receptor coupling p130Cas to netrin signaling not identified","Effector adaptor in neurons not defined"]},{"year":2008,"claim":"Demonstrated that p130Cas substrate-domain phosphorylation by Src (not FAK) is sufficient to activate Rac1, and uncovered a growth-control role through Smad3-dependent suppression of TGF-β arrest.","evidence":"Functional Interaction Trap selective phosphorylation with Rac1 assays; p130Cas-Smad3 co-IP with loss/gain function and cell-cycle readouts","pmids":["18793427","18321991"],"confidence":"High","gaps":["How phospho-p130Cas reduces Smad3 phosphorylation mechanistically unclear","FAK contribution to Rac activation context-dependent"]},{"year":2010,"claim":"Dissected the structure-function logic of the scaffold, showing both SH3 and CCH domains are needed for adhesion targeting and that substrate-domain and Src-binding-domain phosphorylation have separable roles in actin flux versus sustained adhesion turnover; also established p130Cas as essential for ErbB2 transformation.","evidence":"FRAP/live imaging with deletion mutants; Cas-/- MEF rescue with domain mutants and quantitative FA dynamics; ErbB2 complex co-IP with siRNA and in vivo tumor assays","pmids":["20430882","20976150","20505116"],"confidence":"High","gaps":["Molecular basis of the phosphorylation-independent SBD function unresolved","How CCHD contributes to targeting beyond SH3-FAK not defined"]},{"year":2011,"claim":"Broadened p130Cas signaling outputs to E-cadherin turnover, RTK coupling (NRP1-PDGFRα), and mechanical reorientation under cyclic stretch.","evidence":"siRNA/degradation assays for E-cadherin; NRP1 co-IP and mutant migration assays; SYF/siRNA and stretch-sensitive tyrosine mutants under cyclic stretch","pmids":["21765937","21306301","22178114"],"confidence":"Medium","gaps":["E-cadherin degradation mechanism inferred from inhibitors without reconstitution","Stretch-sensitive tyrosine identity and force-sensing biophysics not fully defined"]},{"year":2012,"claim":"Identified PTPN14 as a specific Tyr128 phosphatase regulating tumor growth and linked p130Cas phosphorylation to actin-dependent myogenic differentiation via MAL/SRF.","evidence":"Phospho-proteomic screen, Y128F knock-in, in vitro phosphatase/kinase assays, xenografts; phosphorylation-defective mutant rescue of myotube formation","pmids":["22710723","22587391"],"confidence":"High","gaps":["How Y128 phosphorylation feeds AKT not fully detailed","MAL nuclear-localization link to specific phospho-sites not mapped"]},{"year":2013,"claim":"Defined an osteoclast-specific requirement for p130Cas in actin-ring formation and bone resorption through Dock5-mediated Rac1 activation.","evidence":"Osteoclast-specific conditional knockout with actin-ring/pit assays and Dock5 co-IP","pmids":["23526406"],"confidence":"High","gaps":["How p130Cas promotes Dock5-Src/Pyk2 association not molecularly resolved","Whether the mechanism generalizes beyond osteoclasts untested"]},{"year":2014,"claim":"Resolved the BCAR3-BCAR1 interaction structurally and showed it drives antiestrogen resistance by raising phospho-BCAR1 and ERK1/2 activity.","evidence":"Structure-based interface mutants with co-IP, resistance assays, and ERK inhibition","pmids":["24584939"],"confidence":"High","gaps":["How the interaction elevates BCAR1 phosphorylation mechanistically unclear","In vivo relevance to patient resistance not established"]},{"year":2019,"claim":"Revealed two new spatially distinct functions: CCHD-mediated recruitment to filopodia tips as a mechanosensitive stability regulator, and shear-stress-induced nuclear translocation in osteocytes that restrains NF-κB/RANKL-driven bone resorption.","evidence":"SIM localization screen with CCHD deletion and live imaging; osteocyte-specific knockout with nuclear fractionation, translocation imaging, and NF-κB reporters","pmids":["30639111","31579816"],"confidence":"High","gaps":["Mechanism of nuclear import and direct NF-κB target not defined","How CCHD senses force at filopodia tips unresolved"]},{"year":2021,"claim":"Placed p130Cas in a SRC-DOCK1-RAC1-β-catenin axis controlling MYC transcription and identified BCAR1 as a synthetic-lethal dependency in mutant-KRAS pancreatic cancer.","evidence":"Genome-scale CRISPR/siRNA screen with pathway inhibitors, MYC reporter, and DOCK1/RAC1/β-catenin epistasis","pmids":["34192548"],"confidence":"High","gaps":["Direct molecular link from RAC1 to β-catenin/MYC not fully reconstituted","Therapeutic window of the synthetic-lethal interaction untested"]},{"year":null,"claim":"How the distinct phosphorylation-state-defined conformations of p130Cas are selected by specific upstream cues and translated into the choice between migration, growth control, mechanosensing, and nuclear NF-κB regulation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length p130Cas in its adhesion complex","Mechanism and regulators of nuclear import not identified","Direct nuclear binding partners mediating NF-κB suppression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,38,33]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,39,47]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[32,47,51]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[48]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[19,47]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,23,44]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1,38]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[28,34,36,49]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,30,40,49]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,34,44]}],"complexes":["Src-FAK-p130Cas focal adhesion complex","p130Cas-CrkII complex","ERα-c-Src-PI3K complex"],"partners":["PTK2","SRC","CRK","BCAR3","PTPN14","NCK1","PXN","DOCK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56945","full_name":"Breast cancer anti-estrogen resistance protein 1","aliases":["CRK-associated substrate","Cas scaffolding protein family member 1","p130cas"],"length_aa":870,"mass_kda":93.4,"function":"Docking protein which plays a central coordinating role for tyrosine kinase-based signaling related to cell adhesion (PubMed:12432078, PubMed:12832404). Implicated in induction of cell migration and cell branching (PubMed:12432078, PubMed:12832404, PubMed:17038317). Involved in the BCAR3-mediated inhibition of TGFB signaling (By similarity)","subcellular_location":"Cell junction, focal adhesion; Cytoplasm; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/P56945/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BCAR1","classification":"Not Classified","n_dependent_lines":154,"n_total_lines":1208,"dependency_fraction":0.12748344370860928},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000050820","cell_line_id":"CID000509","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"focal_adhesions","grade":1},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"ACTBL2","stoichiometry":4.0},{"gene":"BCAR3","stoichiometry":0.2},{"gene":"ARPC1B","stoichiometry":0.2},{"gene":"YWHAB","stoichiometry":0.2},{"gene":"YWHAQ","stoichiometry":0.2},{"gene":"KIFAP3","stoichiometry":0.2},{"gene":"ARPC1A","stoichiometry":0.2},{"gene":"APPL1","stoichiometry":0.2},{"gene":"YWHAE","stoichiometry":0.2},{"gene":"YWHAG","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000509","total_profiled":1310},"omim":[{"mim_id":"618888","title":"CAS SCAFFOLD PROTEIN FAMILY, MEMBER 4; CASS4","url":"https://www.omim.org/entry/618888"},{"mim_id":"614248","title":"PEAK FAMILY MEMBER 1; PEAK1","url":"https://www.omim.org/entry/614248"},{"mim_id":"611306","title":"SCAVENGER RECEPTOR CLASS A, MEMBER 5; SCARA5","url":"https://www.omim.org/entry/611306"},{"mim_id":"609951","title":"ZINC FINGER PROTEIN 384; ZNF384","url":"https://www.omim.org/entry/609951"},{"mim_id":"607215","title":"NEPHROCYSTIN 4; NPHP4","url":"https://www.omim.org/entry/607215"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BCAR1"},"hgnc":{"alias_symbol":["P130Cas","Crkas","CAS","CASS1"],"prev_symbol":[]},"alphafold":{"accession":"P56945","domains":[{"cath_id":"2.30.30.40","chopping":"7-68","consensus_level":"high","plddt":91.0289,"start":7,"end":68},{"cath_id":"1.20.120.830","chopping":"457-605","consensus_level":"high","plddt":82.6225,"start":457,"end":605},{"cath_id":"1.20.120.230","chopping":"673-678_696-722_734-869","consensus_level":"high","plddt":90.1693,"start":673,"end":869}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56945","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56945-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56945-F1-predicted_aligned_error_v6.png","plddt_mean":61.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BCAR1","jax_strain_url":"https://www.jax.org/strain/search?query=BCAR1"},"sequence":{"accession":"P56945","fasta_url":"https://rest.uniprot.org/uniprotkb/P56945.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56945/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56945"}},"corpus_meta":[{"pmid":"9425168","id":"PMC_9425168","title":"Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9425168","citation_count":422,"is_preprint":false},{"pmid":"9032297","id":"PMC_9032297","title":"Fibronectin-stimulated signaling from a focal adhesion kinase-c-Src complex: involvement of the Grb2, p130cas, and Nck adaptor proteins.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9032297","citation_count":406,"is_preprint":false},{"pmid":"7479864","id":"PMC_7479864","title":"Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7479864","citation_count":390,"is_preprint":false},{"pmid":"9927060","id":"PMC_9927060","title":"Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9927060","citation_count":328,"is_preprint":false},{"pmid":"11756413","id":"PMC_11756413","title":"Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11756413","citation_count":317,"is_preprint":false},{"pmid":"9697697","id":"PMC_9697697","title":"Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas.","date":"1998","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9697697","citation_count":309,"is_preprint":false},{"pmid":"9171345","id":"PMC_9171345","title":"The PTPase YopH inhibits uptake of Yersinia, tyrosine phosphorylation of p130Cas and FAK, and the associated accumulation of these proteins in peripheral focal adhesions.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9171345","citation_count":297,"is_preprint":false},{"pmid":"7545676","id":"PMC_7545676","title":"Tyrosine phosphorylation of p130Cas and cortactin accompanies integrin-mediated cell adhesion to extracellular matrix.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7545676","citation_count":275,"is_preprint":false},{"pmid":"16581250","id":"PMC_16581250","title":"p130Cas: a versatile scaffold in signaling networks.","date":"2006","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16581250","citation_count":266,"is_preprint":false},{"pmid":"8668148","id":"PMC_8668148","title":"Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19357231","citation_count":24,"is_preprint":false},{"pmid":"16024122","id":"PMC_16024122","title":"Interactions of the integrin subunit beta1A with protein kinase B/Akt, p130Cas and paxillin contribute to regulation of radiation survival.","date":"2005","source":"Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16024122","citation_count":24,"is_preprint":false},{"pmid":"36088346","id":"PMC_36088346","title":"P130cas-FAK interaction is essential for YAP-mediated radioresistance of non-small cell lung cancer.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36088346","citation_count":23,"is_preprint":false},{"pmid":"22178114","id":"PMC_22178114","title":"Cyclic stretch induces reorientation of cells in a Src family kinase- and p130Cas-dependent manner.","date":"2011","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22178114","citation_count":23,"is_preprint":false},{"pmid":"21672035","id":"PMC_21672035","title":"p130Cas, E-cadherin and β-catenin in human transitional cell carcinoma of the bladder: expression and clinicopathological significance.","date":"2011","source":"International journal of urology : official journal of the Japanese Urological Association","url":"https://pubmed.ncbi.nlm.nih.gov/21672035","citation_count":23,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51435,"output_tokens":11740,"usd":0.165203,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22911,"output_tokens":7576,"usd":0.151977,"stage2_stop_reason":"end_turn"},"total_usd":0.31718,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"p130Cas (BCAR1) interacts directly with FAK via its SH3 domain binding to the proline-rich region of FAK (APPKPSR, residues 711-717), as demonstrated by yeast two-hybrid screen and confirmed by co-immunoprecipitation in mouse fibroblasts.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and two-hybrid, replicated across multiple subsequent studies\",\n      \"pmids\": [\"7479864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"p130Cas becomes tyrosine-phosphorylated during integrin-mediated cell adhesion to extracellular matrix substrata, dependent on integrin ligation and actin cytoskeleton integrity (blocked by cytochalasin D), but independent of cell adhesion in v-src-transformed cells.\",\n      \"method\": \"Western blot, immunoprecipitation, cytochalasin D inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditions tested, replicated across subsequent studies\",\n      \"pmids\": [\"7545676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The C-terminal region of p130Cas directly binds both SH2 and SH3 domains of Src kinase; the SH3-binding site maps to RPLPSPP near the C-terminus, and both this site and Tyr762 are required for Src association, while the substrate domain mediates binding to v-Crk via its SH2 domain.\",\n      \"method\": \"GST fusion protein pulldown, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with mutagenesis, single lab but multiple domain-mapping experiments\",\n      \"pmids\": [\"8621540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Individual domains of p130Cas associate with distinct binding partners: FAK, v-Src, and v-Crk binding sites are mapped to distinct regions of p130Cas, and many interactions are dependent on the tyrosine-phosphorylation state of p130Cas.\",\n      \"method\": \"In vitro domain-binding assays, domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, in vitro binding, no mutagenesis confirmation\",\n      \"pmids\": [\"8649789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"FAK phosphorylates p130Cas in vitro and in cells upon fibronectin stimulation (via a FAK/Src 1-298 complex), and FAK-induced phosphorylation of p130Cas promotes SH2-domain-dependent binding of the Nck adaptor protein to p130Cas.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, fibronectin stimulation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay plus cell-based co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9032297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"During bacterial uptake, p130Cas and FAK are phosphorylated and recruited to peripheral focal complexes in HeLa cells; Yersinia YopH (active PTPase) dephosphorylates p130Cas and FAK and disrupts these complexes, blocking uptake. Inactive YopH co-localizes with and binds the tyrosine-phosphorylated forms of FAK and p130Cas.\",\n      \"method\": \"Co-localization, immunoprecipitation, PTPase activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active vs inactive YopH comparison, co-localization and co-IP, single lab with orthogonal methods\",\n      \"pmids\": [\"9171345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RAFTK (Pyk2) directly phosphorylates the substrate domain of p130Cas in vitro; full phosphorylation of p130Cas requires cooperation between RAFTK and Src kinases, with the C-terminal domain of p130Cas requiring RAFTK autophosphorylation site Tyr402 (which mediates Src binding).\",\n      \"method\": \"In vitro kinase assay with purified domains, mutagenesis of Tyr402\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with domain mutants, single lab\",\n      \"pmids\": [\"9242628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"p130Cas (BCAR1) is a mediator of FAK-promoted cell migration; FAK mutant P712/715A (which reduces p130Cas association) fails to promote migration, while co-expression of p130Cas enhances migration and the p130Cas SH3 domain alone acts as a dominant negative inhibitor of migration.\",\n      \"method\": \"FAK mutant expression, migration assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant negative and overexpression rescue with defined mutants, replicated across labs\",\n      \"pmids\": [\"9425168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mice lacking p130Cas (Crkas/BCAR1) die in utero with cardiovascular defects, disorganized myofibrils, and impaired actin stress fiber formation in fibroblasts; activated Src in Cas-deficient fibroblasts fails to induce full transformation due to insufficient actin accumulation in podosomes.\",\n      \"method\": \"Knockout mouse generation, histology, electron microscopy, primary fibroblast analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline knockout with multiple phenotypic readouts, replicated in subsequent rescue experiments\",\n      \"pmids\": [\"9697697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Angiotensin II induces tyrosine phosphorylation of p130Cas in vascular smooth muscle cells via a pathway requiring c-Src family kinase activity, intracellular Ca2+, and protein kinase C; phosphorylated p130Cas then associates with protein kinase C-alpha and pp120, with c-Src constitutively associated.\",\n      \"method\": \"Immunoprecipitation, kinase inhibitors, chelators, Western blot\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple inhibitors but no reconstitution or mutagenesis\",\n      \"pmids\": [\"9648724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Growth hormone stimulates formation of a multiprotein signaling complex centered on p130Cas and CrkII, including c-Src, c-Fyn, tensin, paxillin, IRS-1, p85/PI3K, C3G, SHC, Grb-2, Sos-1, c-Cbl, and Nck; this complex formation correlates with JNK/SAPK activation.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP-based complex identification without mutagenesis\",\n      \"pmids\": [\"9837978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PTEN dephosphorylates FAK and decreases tyrosine phosphorylation of both FAK and p130Cas; p130Cas overexpression reverses PTEN inhibition of cell invasion and migration without affecting PTEN-dependent growth suppression, and p130Cas cannot be directly dephosphorylated by PTEN in vitro or shown to interact with PTEN in cells.\",\n      \"method\": \"Overexpression, in vitro phosphatase assay, co-immunoprecipitation, invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase assay (negative result confirmed) plus functional rescue experiments, single lab with multiple methods\",\n      \"pmids\": [\"9927060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"p130Cas-deficient fibroblasts exhibit significant defects in cell movement, migration toward fibronectin, and cell spreading; re-expression of p130Cas rescues these defects, establishing a direct role for p130Cas in promoting cell motility.\",\n      \"method\": \"Knockout fibroblast re-expression rescue, wound healing assay, transwell migration assay, cell spreading assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout/rescue with multiple orthogonal motility assays, single lab\",\n      \"pmids\": [\"10448062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MCSP (melanoma chondroitin sulphate proteoglycan) stimulation recruits tyrosine-phosphorylated p130Cas and activates Cdc42; MCSP-induced cell spreading is dependent on active Cdc42, the Cdc42-associated kinase Ack-1, and tyrosine phosphorylation of p130Cas; Ack-1 and Cdc42 inhibition abrogates MCSP-induced p130Cas phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, dominant negative constructs, cell spreading assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, dominant negative constructs with functional readouts, no direct kinase assay\",\n      \"pmids\": [\"10587647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The transmembrane PTPase LAR dephosphorylates p130Cas in vitro and in vivo, reducing its protein stability and eliminating it from focal adhesions, leading to apoptosis; restoring p130Cas levels alleviates LAR-induced apoptosis, identifying p130Cas as an in vivo substrate of LAR.\",\n      \"method\": \"In vitro phosphatase assay, substrate-trapping mutants, rescue by p130Cas overexpression, immunofluorescence\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase assay with substrate-trapping, dominant negative, and rescue experiments in single lab\",\n      \"pmids\": [\"10320483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"p130Cas associates with the p85 subunit of PI 3-kinase through its RPLPSPP proline-rich domain (SH3 domain of p85 binding), and this interaction is required for adenovirus internalization mediated by alpha-v integrins; inhibition of p130Cas phosphorylation or deletion of its substrate domain blocks adenovirus cell entry.\",\n      \"method\": \"Co-immunoprecipitation, dominant negative constructs, adenovirus internalization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with deletion mutants plus functional internalization assay, single lab\",\n      \"pmids\": [\"10799562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"p130Cas regulates AND-34 (BCAR3) GEF activity: overexpression of p130Cas (but not an AND-34-binding mutant) inhibits AND-34's Ral GEF activity on RalA, Rap1A, and R-Ras; efficient p130Cas-AND-34 binding requires both the Src-binding domain and a flanking C-terminal region of p130Cas.\",\n      \"method\": \"GEF activity assay in cells, co-immunoprecipitation, mutant binding analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, cell-based GEF assay with defined mutants but no in vitro reconstitution\",\n      \"pmids\": [\"10896938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BCAR1 (p130Cas) overexpression confers antiestrogen resistance on ZR-75-1 breast cancer cells, identified as the gene responsible for the BCAR1 locus; the gene encodes a 870 amino acid protein homologous to rat p130Cas, located at chromosome 16q23.1.\",\n      \"method\": \"Retroviral mutagenesis, cell fusion, cDNA transfection, functional growth assay\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue by cDNA transfection with defined phenotypic readout, single lab\",\n      \"pmids\": [\"10639512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Caspase-3 cleaves p130Cas at two consensus sites DVPD(416)G and DSPD(748)G during etoposide-induced apoptosis; cleavage correlates with loss of FAK from focal adhesions and attenuation of Cas-paxillin interactions, contributing to focal adhesion complex disassembly.\",\n      \"method\": \"In vitro caspase cleavage assay, site-directed mutagenesis, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay with point mutagenesis confirming cleavage sites, single lab\",\n      \"pmids\": [\"10712510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Integrin-mediated adhesion induces assembly of a macromolecular complex at the cell membrane containing p130Cas, c-Src, and the EGF receptor; both c-Src and p130Cas are required for integrin-dependent phosphorylation of EGF receptor at specific tyrosines (Y845, Y1068, Y1086, Y1173).\",\n      \"method\": \"Co-immunoprecipitation, dominant negative constructs, phospho-specific antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP plus functional knockout/dominant negative, no reconstitution\",\n      \"pmids\": [\"11756413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SHIP2 associates with p130Cas primarily through the SHIP2 SH2 domain; an SH2 domain mutant (R47G) abolishes this interaction and increased SHIP2 expression promotes adhesion, while a catalytic domain deletion mutant inhibits cell spreading.\",\n      \"method\": \"Co-immunoprecipitation, SH2 domain mutant, cell adhesion and spreading assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP with domain mutants and functional readouts\",\n      \"pmids\": [\"11158326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FAK and p130Cas localize to sarcomeric Z-lines in cardiac myocytes; expression of the p130Cas-binding proline-rich region 1 of FAK disrupts Cas-FAK association and impairs sarcomere structural stability; Cas alone or with Src modulates atrial natriuretic peptide (ANP) gene promoter activity as a marker of cardiac hypertrophy.\",\n      \"method\": \"Immunofluorescence localization, dominant negative expression, luciferase reporter assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, dominant negative/localization studies with functional gene expression readout\",\n      \"pmids\": [\"11514617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SAP-1 phosphatase dephosphorylates p130Cas in intact cells and preferentially in vitro; a substrate-trapping SAP-1 mutant induces hyperphosphorylation of p130Cas (dominant negative effect); SAP-1 overexpression inhibits cell spreading on fibronectin and colony formation.\",\n      \"method\": \"Substrate-trapping mutagenesis, in vitro phosphatase assay, immunoprecipitation, spreading assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase assay with substrate-trapping and dominant negative mutants, single lab\",\n      \"pmids\": [\"11278335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"p130Cas localizes to focal adhesions in podocytes and colocalizes with F-actin at stress fiber ends, distinct from CD2AP which colocalizes with dynamic F-actin at lamellipodia.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, localization only without functional consequence directly tested\",\n      \"pmids\": [\"11553524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EphrinA1-induced cytoskeletal reorganization and cell spreading in NIH3T3 cells requires both FAK and p130Cas; MEFs from FAK-/- and p130Cas-/- mice have severe defects in ephrinA1-induced spreading, reversed by re-expression of FAK or p130Cas respectively; EphA2, FAK, and p130Cas are the major ephrin-dependent phosphotyrosyl proteins.\",\n      \"method\": \"Knockout MEFs, re-expression rescue, phosphotyrosine analysis, cell spreading assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout and rescue with defined readouts, two orthogonal null models (FAK-/- and p130Cas-/-), single lab\",\n      \"pmids\": [\"12134157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The p130CAS-CrkII complex functions as a molecular switch in cell motility; KAI1/CD82 expression decreases p130CAS protein levels, reduces p130CAS-CrkII complex formation, and inhibits migration; overexpression of p130CAS in KAI1/CD82-expressing cells restores complex formation and largely reverses migration inhibition.\",\n      \"method\": \"Co-immunoprecipitation, overexpression rescue, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP and rescue experiments\",\n      \"pmids\": [\"12738793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Bmx/Etk kinase interacts with p130Cas at membrane ruffles, phosphorylates p130Cas, and promotes Cas-Crk complex formation; a Bmx mutant failing to interact with Cas also fails to induce cell migration; dominant-negative Cas (unable to bind Crk) inhibits Bmx-induced membrane ruffling and migration.\",\n      \"method\": \"Co-immunoprecipitation, dominant negative constructs, membrane ruffling and migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP with functional mutant analysis\",\n      \"pmids\": [\"12832404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p140Cap (Cas-associated protein) directly interacts with p130Cas through the p140Cap carboxy-terminal region; the two proteins co-immunoprecipitate and colocalize in lamellipodia; p140Cap overexpression delays cell spreading on fibronectin.\",\n      \"method\": \"Affinity chromatography, mass spectrometry, co-immunoprecipitation, immunofluorescence, cell spreading assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, biochemical pulldown with domain localization and functional spreading assay\",\n      \"pmids\": [\"14657239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"p130Cas rapidly associates with estrogen receptor alpha (ERα) in a multi-molecular complex containing c-Src and p85/PI3K within 3 minutes of estrogen treatment; this association is c-Src-dependent; p130Cas overexpression enhances estrogen-dependent Src kinase and ERK1/2 activities, while siRNA silencing of p130Cas inhibits estrogen-dependent ERK1/2 activity and cyclin D1 induction.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, kinase activity assays, reporter assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus gain/loss-of-function with defined pathway readouts, single lab\",\n      \"pmids\": [\"15020686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ajuba (LIM protein) associates with the focal adhesion-targeting domain of p130Cas and acts upstream of p130Cas to localize it to nascent adhesive sites; Ajuba-null cells have reduced p130Cas, Crk, Dock180, and FAK at nascent focal complexes and blunted Rac activation in response to migratory cues.\",\n      \"method\": \"Co-immunoprecipitation, knockout mouse fibroblasts, FRET analysis of Rac activation, rescue experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout fibroblasts with rescue, FRET, and co-IP, single lab\",\n      \"pmids\": [\"15728191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p130Cas overexpression in mammary gland (MMTV-p130Cas mice) leads to mammary epithelial hyperplasia associated with activation of Src, ERK1/2, and Akt; crossing with MMTV-HER2-Neu mice accelerates multifocal mammary tumor development with increased Src and Akt activation; p130Cas siRNA increases apoptosis in HER2-Neu-expressing cells.\",\n      \"method\": \"Transgenic mouse models, signaling pathway analysis, siRNA knockdown, tumor latency measurement\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with double-transgenic, siRNA, and signaling readouts, single lab\",\n      \"pmids\": [\"16651418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NPM-ALK (anaplastic lymphoma kinase fusion) binds p130Cas and induces its phosphorylation in a manner dependent on ALK kinase activity and the adaptor Grb2; p130Cas-/- fibroblasts expressing NPM-ALK show impaired actin depolymerization and are no longer transformed, establishing p130Cas as essential for ALK-mediated transformation.\",\n      \"method\": \"Mass spectrometry identification, co-immunoprecipitation, kinase-dead mutant, Grb2 dominant negative, Cas-/- fibroblast reconstitution\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus co-IP, kinase-dead mutant, and knockout rescue, single lab\",\n      \"pmids\": [\"16105984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fibronectin matrix rigidity response requires Fyn (but not endogenous c-Src) recruitment to early adhesions; p130Cas is also required for the rigidity response and is phosphorylated at the leading edge in a Fyn-dependent manner, suggesting force-dependent Fyn phosphorylation of p130Cas.\",\n      \"method\": \"Live cell imaging, dominant negative mutants, phosphorylation site analysis, leading edge localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, dominant negative/localization with functional rigidity readout\",\n      \"pmids\": [\"16597701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ack1 mediates Cdc42-dependent cell migration through p130Cas: Ack1 forms a signaling complex with Cdc42, p130Cas, and Crk via SH3 domain interactions; Ack1 phosphorylates the substrate domain of p130Cas; siRNA knockdown of either p130Cas or Ack1 blocks Cdc42-induced migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, migration assay, phosphorylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complex, domain mapping, siRNA knockdown with functional migration readout, single lab\",\n      \"pmids\": [\"17038317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p130CAS is required for netrin-1 signaling: netrin-1 induces p130CAS tyrosine phosphorylation downstream of Src family kinases and upstream of Rac1/Cdc42; inhibiting p130CAS signaling blocks netrin-1-promoted neurite outgrowth and axon attraction; p130CAS RNAi causes defects in commissural axon projection in vivo.\",\n      \"method\": \"Biochemical epistasis, RNAi knockdown, in vivo commissural axon projection analysis\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis analysis plus in vivo RNAi with defined axon guidance phenotype, single lab\",\n      \"pmids\": [\"17251438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tyrosine phosphorylation of p130Cas is sufficient to activate Rac1 and induce membrane ruffling/lamellipodium formation in SYF cells; the kinase activity of Src (not FAK) is essential for phosphorylating p130Cas within the Src-FAK-p130Cas trimolecular complex at focal adhesions.\",\n      \"method\": \"Functional Interaction Trap (FIT) method for selective substrate phosphorylation, Rac1 activation assay, dominant negative FAK\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel selective phosphorylation method plus Rac activation assay, single lab with two orthogonal approaches\",\n      \"pmids\": [\"18793427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Once tyrosine-phosphorylated via integrin signaling, p130Cas binds to Smad3 and reduces Smad3 phosphorylation, inhibiting TGF-β-mediated growth arrest; loss of p130Cas abrogates integrin-mediated suppression of TGF-β/Smad3 signaling.\",\n      \"method\": \"Co-immunoprecipitation, loss/gain of function, Smad3 phosphorylation assay, cell cycle analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of p130Cas-Smad3 interaction with loss/gain function and phosphorylation readouts, single lab\",\n      \"pmids\": [\"18321991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Estrogen-dependent formation of ERα-BCAR1 complexes (within ~5 min) is increased by RANKL co-treatment; BCAR1 associates with the RANKL signaling intermediate Traf6 in this complex; BCAR1 siRNA knockdown abolishes estradiol inhibition of osteoclast differentiation, demonstrating BCAR1 is required for estrogen's non-genomic inhibition of NF-κB-mediated osteoclastogenesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, osteoclast differentiation assay, NF-κB localization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP plus siRNA knockdown with functional osteoclast differentiation readout\",\n      \"pmids\": [\"19331827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Both the N-terminal SH3 domain and the C-terminal Cas-family homology (CCH) domain of p130Cas are required for its localization to focal adhesions (FA targeting requires FAK for the SH3 domain function); deletion of either domain impairs FA localization and tyrosine phosphorylation; both domains are necessary for p130Cas to promote cell migration.\",\n      \"method\": \"Live cell microscopy, FRAP, deletion mutants, FA targeting analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with FRAP plus multiple deletion mutants and functional migration assay, single lab\",\n      \"pmids\": [\"20430882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p130Cas substrate domain (SD) phosphorylation is the sole p130Cas signaling function for promoting leading-edge actin flux and FA assembly/disassembly rates, while the Src-binding domain (SBD) has a distinct function in sustained FA disassembly and cell migration that is independent of its known role in promoting SD phosphorylation.\",\n      \"method\": \"Cas-/- MEF rescue with domain mutants, quantitative live cell imaging of FA dynamics and actin flux\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout rescue with structure-function mutants and quantitative live imaging, single lab\",\n      \"pmids\": [\"20976150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p130Cas is an essential transducer in ErbB2 transformation: p130Cas forms a functional complex with ErbB2, c-Src, and FAK in transformed cells; p130Cas silencing impairs foci formation, anchorage-independent growth, and in vivo tumor growth; p130Cas overexpression with ErbB2 activates Rac1 and MMP9 secretion, conferring invasive properties.\",\n      \"method\": \"siRNA knockdown, in vivo tumor growth, co-immunoprecipitation, Rac1 activation assay, invasion assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in vivo and in vitro with signaling mechanism, single lab\",\n      \"pmids\": [\"20505116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BCAR1/p130Cas and NEDD9 signal through SRC to promote E-cadherin removal from the cell membrane and lysosomal degradation, negatively regulating E-cadherin expression in human mammary cells without affecting E-cadherin transcription.\",\n      \"method\": \"siRNA knockdown, inhibitor studies, pulse-chase/degradation assay, in vivo mammary tumor analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, mechanism inferred from inhibitor and knockdown studies without direct reconstitution\",\n      \"pmids\": [\"21765937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NRP1 (neuropilin-1) co-immunoprecipitates with PDGFRα and selectively mediates PDGF-induced tyrosine phosphorylation of p130Cas; NRP1 siRNA and NRP1 mutants lacking the intracellular domain inhibit PDGF-induced p130Cas phosphorylation and VSMC migration; p130Cas knockdown also inhibits HCASMC migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, adenoviral overexpression of NRP1 mutants, migration assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP plus siRNA/mutant with functional migration readout\",\n      \"pmids\": [\"21306301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPN14 directly dephosphorylates p130Cas specifically at tyrosine residue Y128; homozygous Y128F knock-in CRC cells show reduced migration, colony formation, and slower xenograft tumor growth with decreased AKT phosphorylation; SRC phosphorylates p130Cas Y128.\",\n      \"method\": \"Phospho-proteomic screen, knock-in mutagenesis, in vitro phosphatase/kinase assay, xenograft tumor growth\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro direct phosphatase activity, knock-in mutagenesis, in vivo xenograft, single lab with multiple methods\",\n      \"pmids\": [\"22710723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p130Cas-dependent actin remodeling regulates myogenic differentiation: p130Cas phosphorylation (mediated by integrin β3) promotes F-actin formation, nuclear localization of MAL/SRF co-activator, and myotube formation; phosphorylation-defective p130Cas mutant fails to rescue these processes; p130Cas phosphorylation prevents cofilin activation.\",\n      \"method\": \"siRNA knockdown, phosphorylation-defective mutant re-expression, F-actin staining, nuclear MAL localization assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss of function, phosphorylation-defective mutant rescue, and mechanistic analysis with defined downstream readouts, single lab\",\n      \"pmids\": [\"22587391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In osteoclasts, p130Cas is required for actin ring formation and bone resorption; p130Cas conditional knockout osteoclasts show reduced Rac1 activity, disrupted Rac1 distribution, and failure of Dock5 (a Rac GEF) to associate with Src or Pyk2, while initial β3-integrin and Src phosphorylation events are intact.\",\n      \"method\": \"Osteoclast-specific conditional knockout, actin ring assay, pit formation assay, co-immunoprecipitation of Dock5\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with molecular mechanism (Dock5 association) defined, single lab\",\n      \"pmids\": [\"23526406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BCAR1 and BCAR3 bind tightly through their C-terminal domains; structure-based interaction-disrupting mutants show that BCAR3-induced antiestrogen resistance critically depends on binding to BCAR1; BCAR3-BCAR1 interaction increases phosphorylated BCAR1 levels and ERK1/2 activity, which mediates resistance.\",\n      \"method\": \"Structure-based mutagenesis of interaction interface, co-immunoprecipitation, antiestrogen resistance functional assay, ERK inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutants with functional rescue and defined signaling pathway, single lab\",\n      \"pmids\": [\"24584939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p130Cas (BCAR1) is recruited to filopodia tips via its C-terminal Cas family homology domain (CCHD) and acts as a mechanosensitive regulator of filopodia stability, as demonstrated by structured-illumination microscopy mapping and live imaging.\",\n      \"method\": \"SIM-based protein localization screen, live imaging, domain deletion analysis (CCHD)\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic SIM screen with domain mutant and live imaging, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30639111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p130Cas (Cas) translocates to the nucleus in osteocytes in response to fluid shear stress and alleviates NF-κB activity; osteocyte-specific Cas deficiency increases NF-κB-mediated RANKL expression and osteoclastic bone resorption, leading to osteopenia; shear stress-dependent nuclear Cas translocation was directly observed.\",\n      \"method\": \"Osteocyte-specific conditional knockout, nuclear fractionation, live-cell imaging of Cas translocation, NF-κB reporter assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout plus direct imaging of nuclear translocation with NF-κB pathway readout, single lab\",\n      \"pmids\": [\"31579816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-β-catenin-dependent mechanism; BCAR1 siRNA sensitizes pancreatic cancer cells to ERK inhibition, identifying BCAR1 as a synthetic lethal interactor with mutant KRAS.\",\n      \"method\": \"siRNA/CRISPR genome-scale screen, pathway inhibitors, MYC reporter, DOCK1/RAC1/β-catenin epistasis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale CRISPR screen plus mechanistic epistasis analysis with multiple inhibitors and siRNA, single lab\",\n      \"pmids\": [\"34192548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Salmonella typhimurium invasion of host cells requires p130Cas; Cas-/- cells are impaired in bacterial internalization, and reconstitution requires the central Cas YXXP repeat domain; FAK overexpression suppresses the invasion defect in Cas-/- cells, suggesting a functional FAK-Cas link in Salmonella invasion.\",\n      \"method\": \"Knockout MEFs, reconstitution with domain mutants, genetic suppressor analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout and domain-specific rescue with genetic epistasis, single lab\",\n      \"pmids\": [\"16914515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cyclic stretch induces cell reorientation in a Src family kinase- and p130Cas-dependent manner; knockout or knockdown of p130Cas reduces reorientation upon cyclic stretch, and mutation of stretch-sensitive tyrosines of p130Cas produces identical impairment.\",\n      \"method\": \"SYF knockout MEFs, siRNA knockdown, p130Cas tyrosine mutants, cyclic stretch device\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout and site-directed tyrosine mutants with defined mechanical stimulus, single lab\",\n      \"pmids\": [\"22178114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"p130Cas cleavage occurs during anoikis; overexpression of the p130Cas cleavage product induces apoptosis; caspases and calpain are both involved in cleavage, though additional unidentified proteases may also cleave p130Cas at the early stage of anoikis.\",\n      \"method\": \"Cell detachment-induced anoikis assay, cleavage fragment overexpression, caspase/calpain inhibitors\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, cleavage product overexpression with apoptosis readout\",\n      \"pmids\": [\"14743392\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BCAR1/p130Cas is a multidomain scaffold/adaptor protein that localizes to focal adhesions (via SH3 and CCH domains), filopodia tips (via CCHD), and the nucleus, where it integrates signals from integrins, receptor tyrosine kinases, Src family kinases, and GPCRs: FAK binds the p130Cas SH3 domain at APPKPSR; Src phosphorylates the substrate domain YXXP motifs to create Crk-SH2 binding sites, activating Rac1-dependent membrane ruffling and cell migration; it acts as a mechanosensor (stretch-dependent tyrosine phosphorylation promotes cytoskeletal remodeling and cell reorientation); it interacts with estrogen receptor α to transduce non-genomic estrogen signaling; phospho-p130Cas binds Smad3 to suppress TGF-β-mediated growth arrest; it is directly dephosphorylated by LAR, SAP-1, and PTPN14 phosphatases; caspase-3 cleaves it at DVPD416 and DSPD748 during apoptosis; and in the nucleus it alleviates NF-κB activity to support bone homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BCAR1/p130Cas is a multidomain scaffold protein that converts integrin and growth-factor engagement into actin-based cell motility by nucleating a tyrosine-phosphorylation-dependent signaling complex at focal adhesions [#0, #1, #38]. Its N-terminal SH3 domain binds the proline-rich region of FAK (APPKPSR, 711-717), while a C-terminal RPLPSPP motif and Tyr762 engage the SH3/SH2 domains of Src; both the SH3 and C-terminal Cas-family-homology (CCH) domains are required for focal-adhesion targeting and for promoting migration [#0, #2, #38]. Within the Src–FAK–p130Cas complex, Src kinase activity phosphorylates the central substrate-domain YXXP repeats, creating docking sites for the Crk family and other SH2 adaptors, which is sufficient to activate Rac1 and drive membrane ruffling, lamellipodium formation, and leading-edge actin flux [#2, #33, #35, #39]. Genetic ablation establishes these functions as physiological: p130Cas-null mice die in utero with cardiovascular defects and disorganized myofibrils, and null fibroblasts have impaired stress-fiber formation and severe defects in spreading and migration that are rescued by re-expression [#8, #12]. p130Cas operates as a mechanosensor, undergoing stretch- and rigidity-dependent tyrosine phosphorylation that drives cell reorientation and, via filopodia-tip recruitment through its CCHD, regulates filopodia stability [#32, #47, #51]. The same scaffold transduces signals from diverse upstream inputs—it is phosphorylated downstream of Pyk2/RAFTK, Ack1, Bmx, NPM-ALK, EphA2, and netrin-1, and forms estrogen-induced ERα–c-Src–PI3K complexes that drive ERK1/2 activation and cyclin D1 induction [#6, #26, #28, #31, #33, #34]. Its phosphorylation state is set by phosphatases LAR, SAP-1, and PTPN14 (the latter acting specifically at Tyr128), and the protein is cleaved by caspase-3 at DVPD416 and DSPD748 during apoptosis, dismantling focal adhesions [#14, #22, #43, #18]. p130Cas is oncogenic in breast and HER2/ErbB2-driven contexts, mediates antiestrogen resistance through binding partner BCAR3, and is a synthetic-lethal dependency in mutant-KRAS pancreatic cancer [#17, #30, #40, #46, #49]. Beyond migration and transformation, nuclear p130Cas alleviates NF-κB activity in osteocytes to restrain RANKL-driven bone resorption [#48].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding physical link between p130Cas and the focal-adhesion machinery, defining how the scaffold is recruited and how adhesion controls its activation state.\",\n      \"evidence\": \"Yeast two-hybrid and co-IP mapping the SH3-FAK interaction; integrin-adhesion-dependent tyrosine phosphorylation blocked by cytochalasin D\",\n      \"pmids\": [\"7479864\", \"7545676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the kinase responsible for adhesion-induced phosphorylation\", \"Did not define downstream effectors of phosphorylated p130Cas\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved the modular architecture of the scaffold by mapping FAK, Src, and Crk binding to distinct phosphorylation-state-dependent sites, explaining how one protein integrates multiple partners.\",\n      \"evidence\": \"GST pulldowns and mutagenesis mapping RPLPSPP/Tyr762 (Src) and substrate-domain (Crk) sites\",\n      \"pmids\": [\"8621540\", \"8649789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro binding without cellular validation of all sites\", \"Did not establish functional consequence of each interaction\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified the kinases that phosphorylate p130Cas, showing FAK, Src, and Pyk2/RAFTK cooperate to fully phosphorylate the substrate domain and recruit downstream adaptors.\",\n      \"evidence\": \"In vitro kinase assays with purified domains, Tyr402 mutagenesis, fibronectin stimulation, and Nck recruitment co-IP\",\n      \"pmids\": [\"9032297\", \"9242628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in-cell contribution of each kinase not quantified\", \"Did not link phosphorylation to a motility phenotype\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that pathogen-driven phosphatase activity (Yersinia YopH) dephosphorylates and disassembles the FAK–p130Cas focal complex, establishing the complex as a target for host-pathogen manipulation.\",\n      \"evidence\": \"Active vs inactive YopH comparison, co-localization, and PTPase assays in HeLa cells\",\n      \"pmids\": [\"9171345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify endogenous mammalian phosphatases\", \"Mechanism of uptake downstream of complex not detailed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Proved p130Cas is functionally required for FAK-promoted migration and for organismal development, moving the scaffold from a binding partner to a causal motility/cytoskeletal effector.\",\n      \"evidence\": \"FAK P712/715A mutant migration assays, SH3 dominant-negative, and germline knockout mouse with cardiovascular/cytoskeletal phenotypes\",\n      \"pmids\": [\"9425168\", \"9697697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Embryonic lethality limited tissue-specific dissection\", \"Did not isolate which downstream effector drives migration\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed p130Cas is a convergence node for GPCR and cytokine receptor inputs, nucleating large multiprotein signaling complexes coupled to JNK activation.\",\n      \"evidence\": \"Co-IP and inhibitor studies in angiotensin-II-stimulated VSMC and growth-hormone-stimulated cells\",\n      \"pmids\": [\"9648724\", \"9837978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP-based complexes lack mutagenesis confirmation\", \"Direct versus indirect associations not distinguished\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Confirmed p130Cas is a bona fide phosphatase substrate (LAR) controlling its stability and adhesion localization, and dissociated its motility role from PTEN-dependent growth suppression.\",\n      \"evidence\": \"Substrate-trapping LAR mutants with rescue; in vitro PTEN phosphatase assay (negative) plus invasion rescue\",\n      \"pmids\": [\"10320483\", \"9927060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dephosphorylation triggers degradation not defined\", \"PTEN effect shown to be indirect, leaving the relevant phosphatase open\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Provided definitive knockout/rescue evidence that p130Cas drives cell spreading and motility, and linked it to Cdc42 activation downstream of MCSP.\",\n      \"evidence\": \"Knockout fibroblast re-expression with wound-healing/transwell assays; MCSP-Ack1-Cdc42 dominant-negative spreading assays\",\n      \"pmids\": [\"10448062\", \"10587647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which adaptor links p130Cas to the GTPase\", \"Cdc42 link based on dominant negatives without direct kinase assay\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Expanded the partner repertoire (PI3K-p85, AND-34/BCAR3) and identified BCAR1 as the human gene conferring antiestrogen resistance, anchoring its cancer relevance.\",\n      \"evidence\": \"Domain-mapped co-IP for p85; GEF assays for AND-34; retroviral mutagenesis/cDNA rescue identifying the BCAR1 locus\",\n      \"pmids\": [\"10799562\", \"10896938\", \"10639512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling p130Cas to antiestrogen resistance not yet defined\", \"GEF regulation shown only in cells without reconstitution\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined how p130Cas is dismantled during apoptosis, identifying caspase-3 cleavage sites that drive focal-adhesion disassembly.\",\n      \"evidence\": \"In vitro caspase cleavage with DVPD416/DSPD748 point mutagenesis and immunofluorescence\",\n      \"pmids\": [\"10712510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of cleavage fragments not fully established here\", \"Did not test other proteases\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Positioned p130Cas as a hub linking integrins to RTK transactivation and to additional phosphatase/adaptor regulators in adhesion and cardiac contexts.\",\n      \"evidence\": \"Co-IP of integrin-induced p130Cas-Src-EGFR complex; SAP-1 substrate-trapping; SHIP2 SH2-mutant studies; FAK/Cas Z-line localization\",\n      \"pmids\": [\"11756413\", \"11278335\", \"11158326\", \"11514617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several interactions rest on single-lab co-IP\", \"SAP-1 is High-confidence but in-vivo substrate specificity not broadly tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Solidified the p130Cas-CrkII complex as a migration switch and added kinases (Bmx) and regulators (p140Cap, KAI1/CD82) that tune complex formation and protein level.\",\n      \"evidence\": \"Co-IP, dominant negatives, and overexpression rescue in migration/ruffling assays; affinity-MS identification of p140Cap\",\n      \"pmids\": [\"12738793\", \"12832404\", \"14657239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanisms largely correlative co-IP without reconstitution\", \"Direct vs indirect kinase action on p130Cas not fully resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established p130Cas as a transducer of non-genomic estrogen signaling and characterized its proteolytic processing during anoikis.\",\n      \"evidence\": \"Rapid ERα-Src-p85 co-IP with siRNA/kinase readouts; anoikis cleavage-fragment overexpression with caspase/calpain inhibitors\",\n      \"pmids\": [\"15020686\", \"14743392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ERα-p130Cas contact versus Src-bridged not resolved\", \"Anoikis proteases incompletely identified (Medium-confidence)\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified upstream localization machinery (Ajuba) and demonstrated p130Cas oncogenicity in vivo, showing overexpression drives mammary hyperplasia and accelerates HER2-Neu tumors.\",\n      \"evidence\": \"Ajuba-null fibroblasts with FRET Rac readouts; MMTV-p130Cas and double-transgenic mouse tumor models with siRNA\",\n      \"pmids\": [\"15728191\", \"16651418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ajuba targets p130Cas to nascent adhesions not molecularly defined\", \"Whether mammary phenotype is cell-autonomous to p130Cas signaling not isolated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established p130Cas as essential for oncogenic-kinase transformation (NPM-ALK), mechanotransduction (rigidity sensing via Fyn), and pathogen invasion via its YXXP substrate domain.\",\n      \"evidence\": \"Cas-/- reconstitution for NPM-ALK transformation and Salmonella invasion; Fyn-dependent leading-edge phosphorylation in rigidity assays; Ack1-Cdc42-Crk complex with siRNA migration readout\",\n      \"pmids\": [\"16105984\", \"16914515\", \"16597701\", \"17038317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Force-dependent Fyn phosphorylation inferred rather than directly measured\", \"Substrate-domain requirement defined but specific YXXP residues not all mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended p130Cas function to neuronal guidance, placing it downstream of Src kinases and upstream of Rac1/Cdc42 in netrin-1-driven axon attraction in vivo.\",\n      \"evidence\": \"Biochemical epistasis and in vivo RNAi of commissural axon projection\",\n      \"pmids\": [\"17251438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling p130Cas to netrin signaling not identified\", \"Effector adaptor in neurons not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that p130Cas substrate-domain phosphorylation by Src (not FAK) is sufficient to activate Rac1, and uncovered a growth-control role through Smad3-dependent suppression of TGF-β arrest.\",\n      \"evidence\": \"Functional Interaction Trap selective phosphorylation with Rac1 assays; p130Cas-Smad3 co-IP with loss/gain function and cell-cycle readouts\",\n      \"pmids\": [\"18793427\", \"18321991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phospho-p130Cas reduces Smad3 phosphorylation mechanistically unclear\", \"FAK contribution to Rac activation context-dependent\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissected the structure-function logic of the scaffold, showing both SH3 and CCH domains are needed for adhesion targeting and that substrate-domain and Src-binding-domain phosphorylation have separable roles in actin flux versus sustained adhesion turnover; also established p130Cas as essential for ErbB2 transformation.\",\n      \"evidence\": \"FRAP/live imaging with deletion mutants; Cas-/- MEF rescue with domain mutants and quantitative FA dynamics; ErbB2 complex co-IP with siRNA and in vivo tumor assays\",\n      \"pmids\": [\"20430882\", \"20976150\", \"20505116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the phosphorylation-independent SBD function unresolved\", \"How CCHD contributes to targeting beyond SH3-FAK not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Broadened p130Cas signaling outputs to E-cadherin turnover, RTK coupling (NRP1-PDGFRα), and mechanical reorientation under cyclic stretch.\",\n      \"evidence\": \"siRNA/degradation assays for E-cadherin; NRP1 co-IP and mutant migration assays; SYF/siRNA and stretch-sensitive tyrosine mutants under cyclic stretch\",\n      \"pmids\": [\"21765937\", \"21306301\", \"22178114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E-cadherin degradation mechanism inferred from inhibitors without reconstitution\", \"Stretch-sensitive tyrosine identity and force-sensing biophysics not fully defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified PTPN14 as a specific Tyr128 phosphatase regulating tumor growth and linked p130Cas phosphorylation to actin-dependent myogenic differentiation via MAL/SRF.\",\n      \"evidence\": \"Phospho-proteomic screen, Y128F knock-in, in vitro phosphatase/kinase assays, xenografts; phosphorylation-defective mutant rescue of myotube formation\",\n      \"pmids\": [\"22710723\", \"22587391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Y128 phosphorylation feeds AKT not fully detailed\", \"MAL nuclear-localization link to specific phospho-sites not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined an osteoclast-specific requirement for p130Cas in actin-ring formation and bone resorption through Dock5-mediated Rac1 activation.\",\n      \"evidence\": \"Osteoclast-specific conditional knockout with actin-ring/pit assays and Dock5 co-IP\",\n      \"pmids\": [\"23526406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How p130Cas promotes Dock5-Src/Pyk2 association not molecularly resolved\", \"Whether the mechanism generalizes beyond osteoclasts untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the BCAR3-BCAR1 interaction structurally and showed it drives antiestrogen resistance by raising phospho-BCAR1 and ERK1/2 activity.\",\n      \"evidence\": \"Structure-based interface mutants with co-IP, resistance assays, and ERK inhibition\",\n      \"pmids\": [\"24584939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the interaction elevates BCAR1 phosphorylation mechanistically unclear\", \"In vivo relevance to patient resistance not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed two new spatially distinct functions: CCHD-mediated recruitment to filopodia tips as a mechanosensitive stability regulator, and shear-stress-induced nuclear translocation in osteocytes that restrains NF-κB/RANKL-driven bone resorption.\",\n      \"evidence\": \"SIM localization screen with CCHD deletion and live imaging; osteocyte-specific knockout with nuclear fractionation, translocation imaging, and NF-κB reporters\",\n      \"pmids\": [\"30639111\", \"31579816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear import and direct NF-κB target not defined\", \"How CCHD senses force at filopodia tips unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed p130Cas in a SRC-DOCK1-RAC1-β-catenin axis controlling MYC transcription and identified BCAR1 as a synthetic-lethal dependency in mutant-KRAS pancreatic cancer.\",\n      \"evidence\": \"Genome-scale CRISPR/siRNA screen with pathway inhibitors, MYC reporter, and DOCK1/RAC1/β-catenin epistasis\",\n      \"pmids\": [\"34192548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from RAC1 to β-catenin/MYC not fully reconstituted\", \"Therapeutic window of the synthetic-lethal interaction untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct phosphorylation-state-defined conformations of p130Cas are selected by specific upstream cues and translated into the choice between migration, growth control, mechanosensing, and nuclear NF-κB regulation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length p130Cas in its adhesion complex\", \"Mechanism and regulators of nuclear import not identified\", \"Direct nuclear binding partners mediating NF-κB suppression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 38, 33]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 39, 47]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [32, 47, 51]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [23, 38, 39]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [48]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [19, 47]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 23, 44]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1, 38]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [28, 34, 36, 49]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 30, 40, 49]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 34, 44]}\n    ],\n    \"complexes\": [\"Src-FAK-p130Cas focal adhesion complex\", \"p130Cas-CrkII complex\", \"ERα-c-Src-PI3K complex\"],\n    \"partners\": [\"PTK2\", \"SRC\", \"CRK\", \"BCAR3\", \"PTPN14\", \"NCK1\", \"PXN\", \"DOCK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}