{"gene":"SRC","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[],"current_model":"Parse failed"},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed"},"prefetch_data":{"uniprot":{"accession":"P12931","full_name":"Proto-oncogene tyrosine-protein kinase Src","aliases":["Proto-oncogene c-Src","pp60c-src","p60-Src"],"length_aa":536,"mass_kda":59.8,"function":"Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors (PubMed:34234773). Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (PubMed:21411625). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Phosphorylates PKP3 at 'Tyr-195' in response to reactive oxygen species, which may cause the release of PKP3 from desmosome cell junctions into the cytoplasm (PubMed:25501895). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1 (PubMed:11389730). Plays a role in EGF-mediated calcium-activated chloride channel activation (PubMed:18586953). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (PubMed:7853507). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:14585963, PubMed:8755529). Upon activation of the G(q)-dependent KISS1/KISS1R signaling pathway, active SRC is recruited, together with the phosphatase DUSP18, to the KISS1R C-terminus (PubMed:38346942). This leads to DUSP18-mediated SRC dephosphorylation and inactivation, down-regulation of osteoclast differentiation and activity, and consequently suppression of bone resorption (By similarity). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108). Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731' (PubMed:20100835, PubMed:21309750). Enhances RIGI-elicited antiviral signaling (PubMed:19419966). Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' (PubMed:14585963). Phosphorylates BCAR1 at 'Tyr-128' (PubMed:22710723). Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity (PubMed:20525694). Phosphorylates synaptic vesicle protein synaptophysin (SYP) (By similarity). Involved in anchorage-independent cell growth (PubMed:19307596). Required for podosome formation (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159). Phosphorylates OTUB1, promoting deubiquitination of RPTOR (PubMed:35927303). Phosphorylates caspase CASP8 at 'Tyr-380' which negatively regulates CASP8 processing and activation, down-regulating CASP8 proapoptotic function (PubMed:16619028). Mediates laminin-induced activation of RAC1 signaling through phosphorylation of syntrophin (By similarity) Non-receptor protein tyrosine kinase which phosphorylates synaptophysin with high affinity Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity). Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity). Plays a role in L1CAM-mediated neurite elongation, possibly by acting downstream of L1CAM to drive cytoskeletal rearrangements involved in neurite outgrowth (By similarity) Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity). Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity). Plays a role in neurite elongation (By similarity)","subcellular_location":"Cell membrane; Mitochondrion inner membrane; Nucleus; Cytoplasm, cytoskeleton; Cytoplasm, perinuclear region; Cell junction, focal adhesion; Cell junction","url":"https://www.uniprot.org/uniprotkb/P12931/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRC","classification":"Not Classified","n_dependent_lines":55,"n_total_lines":1208,"dependency_fraction":0.04552980132450331},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRC","total_profiled":1310},"omim":[{"mim_id":"621391","title":"XK-RELATED PROTEIN 5; XKR5","url":"https://www.omim.org/entry/621391"},{"mim_id":"620955","title":"SORTING NEXIN 30; SNX30","url":"https://www.omim.org/entry/620955"},{"mim_id":"620678","title":"RAS AND RAB INTERACTOR-LIKE PROTEIN; RINL","url":"https://www.omim.org/entry/620678"},{"mim_id":"620664","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 37; ARHGEF37","url":"https://www.omim.org/entry/620664"},{"mim_id":"620484","title":"THROMBOCYTOPENIA 10; THC10","url":"https://www.omim.org/entry/620484"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRC"},"hgnc":{"alias_symbol":["ASV","c-src"],"prev_symbol":["SRC1"]},"alphafold":{"accession":"P12931","domains":[{"cath_id":"2.30.30.40","chopping":"87-147","consensus_level":"high","plddt":93.6366,"start":87,"end":147},{"cath_id":"3.30.505.10","chopping":"157-246","consensus_level":"high","plddt":93.6493,"start":157,"end":246},{"cath_id":"3.30.200.20","chopping":"261-343","consensus_level":"medium","plddt":93.5966,"start":261,"end":343},{"cath_id":"1.10.510.10","chopping":"348-524","consensus_level":"medium","plddt":92.0202,"start":348,"end":524}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12931","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12931-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12931-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRC","jax_strain_url":"https://www.jax.org/strain/search?query=SRC"},"sequence":{"accession":"P12931","fasta_url":"https://rest.uniprot.org/uniprotkb/P12931.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12931/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12931"}},"corpus_meta":[{"pmid":"9024657","id":"PMC_9024657","title":"Three-dimensional 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kinase active site and sequestering SH2/SH3 binding surfaces, locking the molecule in a closed, inactive conformation.\",\n      \"method\": \"X-ray crystallography (1.7 Å resolution)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with direct structural validation of autoinhibitory mechanism\",\n      \"pmids\": [\"9024657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Additional c-Src crystal structures showed that the activation loop (containing Tyr-416) adopts an ordered alpha-helical conformation in the inactive state, blocking the peptide substrate-binding site and preventing Tyr-416 phosphorylation; disassembly of regulatory domains by SH2/SH3 ligands or dephosphorylation of Tyr-527 leads to exposure and phosphorylation of Tyr-416.\",\n      \"method\": \"X-ray crystallography (multiple inactive-state structures)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures with mechanistic interpretation of activation loop conformational states\",\n      \"pmids\": [\"10360179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of the Csk–c-Src kinase domain complex at 2.9 Å revealed that Csk phosphorylates Tyr-527 in c-Src's C-terminal tail through a docking mechanism where the tail is positioned at the edge of Csk's active site; Csk cannot use a conventional substrate-binding site because its activation loop lacks a key element, explaining the exquisite selectivity of Csk for Src family C-terminal tails.\",\n      \"method\": \"X-ray crystallography (2.9 Å resolution co-crystal structure)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structure of kinase–substrate complex providing atomic-level mechanism of selective phosphorylation\",\n      \"pmids\": [\"18614016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"Electron microscopic immunocytochemistry localized p60src (the v-Src/c-Src product) to the inner surface of the plasma membrane, particularly under membrane ruffles and at cell–cell junctions, with minor amounts in cytoplasm and Golgi, establishing that its primary site of action is the cytoplasmic face of the plasma membrane.\",\n      \"method\": \"Electron microscopic immunocytochemistry with quantification\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by EM immunocytochemistry with quantification; foundational localization study\",\n      \"pmids\": [\"228858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Csk suppresses c-Src kinase activity and transformation by phosphorylating Tyr-527 in vivo; overexpression of Csk reverted transformation caused by co-overexpression of v-Crk and c-Src, but not transformation by c-Src527F (Tyr-527→Phe), demonstrating that Csk acts specifically on Tyr-527 to negatively regulate c-Src.\",\n      \"method\": \"Genetic overexpression, dominant-negative mutants, in vitro kinase assay, transformation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via site-specific mutant (Y527F) combined with kinase assay and transformation readout\",\n      \"pmids\": [\"1383688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Src autophosphorylates Tyr-527 (its primary negative regulatory site) in vitro in an intermolecular reaction at high ATP concentrations, in addition to the well-known intramolecular autophosphorylation of Tyr-416, suggesting c-Src can contribute to its own inactivation.\",\n      \"method\": \"In vitro kinase assay with purified recombinant c-Src, phosphopeptide mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 in vitro assay, single lab\",\n      \"pmids\": [\"7592753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Src phosphorylates EGFR on Tyr-845 in an EGF-dependent manner within the c-Src–EGFR complex, as demonstrated by in vitro kinase assay using synthetic peptides and CNBr-digest phosphopeptide mapping, and confirmed in EGF-treated A431 cells.\",\n      \"method\": \"In vitro kinase assay, phosphopeptide mapping, in vivo phosphorylation in A431 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 in vitro assay with in vivo confirmation, single lab\",\n      \"pmids\": [\"7488034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Src regulates EGF-induced actin cytoskeleton reorganization through phosphorylation of p190RhoGAP; dominant-negative c-Src delayed EGF-induced p190/RasGAP condensation into arc structures and actin stress fiber rearrangement, while wild-type c-Src overexpression accelerated these events.\",\n      \"method\": \"Dominant-negative and wild-type c-Src overexpression, confocal immunofluorescence, phosphotyrosine analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined pathway placement via dominant-negative mutants with specific morphological readout\",\n      \"pmids\": [\"7542246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"c-Src kinase activity is required for cell locomotion downstream of the hyaluronan receptor RHAMM; src(-/-) fibroblasts have significantly reduced random locomotion restored by kinase-active but not kinase-deficient c-Src; dominant-negative c-Src blocked RHAMM-dependent Ras-regulated motility, placing c-Src downstream of RHAMM in this pathway.\",\n      \"method\": \"src(-/-) knockout fibroblasts, rescue with kinase-dead vs. wild-type c-Src, anti-RHAMM blocking antibodies, dominant-negative expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + specific rescue experiment with kinase-dead mutant, multiple orthogonal approaches\",\n      \"pmids\": [\"8950989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Phage display substrate selection defined c-Src's catalytic specificity: c-Src prefers substrates with isoleucine or leucine at position −1 relative to the phosphorylated tyrosine, and tryptophan or glycine at position +1, distinguishing it from related Src-family kinases Blk and Lyn.\",\n      \"method\": \"Phage display peptide library selection with phosphotyrosine enrichment\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical selection assay defining substrate preference, single study\",\n      \"pmids\": [\"8709147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Sam68 (Src associated in mitosis, 68 kDa) is the predominant substrate and binding partner of c-Src in mitotic cells; c-Src binds Sam68 via both SH2 and SH3 domains (SH3 with highest affinity among tested domains), and this interaction inhibits Sam68's RNA-binding activity in vitro.\",\n      \"method\": \"Co-immunoprecipitation, recombinant SH2/SH3 domain pulldown, in vitro translated Sam68 binding assays, RNA-binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays with functional consequence (RNA binding inhibition), single lab\",\n      \"pmids\": [\"7537265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TRANCE activates Akt/PKB through a signaling complex involving c-Src and TRAF6; c-Src and TRAF6 interact with each other and with TRANCE-R upon receptor engagement; TRAF6 enhances c-Src kinase activity leading to phosphorylation of downstream targets including c-Cbl; c-Src deficiency or Src-family inhibitors block TRANCE-mediated PKB activation.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, c-Src-deficient osteoclasts, pharmacological inhibitors\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, kinase assay, genetic (c-src KO) and pharmacological validation with specific signaling readout\",\n      \"pmids\": [\"10635328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src phosphorylates connexin-43 at Tyr-265, which causes its SH2 domain to bind connexin-43, displacing ZO-1 from connexin-43 and reducing total and cell-surface connexin-43, thereby reducing gap junctional conductance.\",\n      \"method\": \"Constitutively active c-Src expression, phosphorylation-site mutant (Y265 connexin-43), in vitro binding assays with recombinant proteins, cell-surface biotinylation, electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — reconstituted binding with site-specific mutation, functional electrophysiological readout, multiple orthogonal methods\",\n      \"pmids\": [\"11035005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Constitutively active c-Src reduces gap junctional communication in cardiomyocytes by mediating tyrosine phosphorylation of connexin-43, as demonstrated by correlation of increased c-Src activity with tyrosine-phosphorylated connexin-43 in cardiomyopathic hearts and by c-Src-mediated reduction of Ca2+ wave propagation and junctional conductance in transfected cells.\",\n      \"method\": \"Immunoprecipitation, immunoblot, transfected cells expressing constitutively active c-Src, Ca2+ wave imaging, electrophysiology\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — consistent with PMID:11035005 finding, separate functional assays in cardiac cells\",\n      \"pmids\": [\"10521240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"c-Src co-immunoprecipitates with gelsolin in osteoclasts and is required for osteopontin-stimulated gelsolin-associated PI 3-kinase activity and cytoskeletal reorganization; antisense oligonucleotides eliminating Src activity blocked PI 3-kinase activation, gelsolin-dependent actin filament formation, osteoclast motility, and bone resorption.\",\n      \"method\": \"Co-immunoprecipitation, antisense oligodeoxynucleotides, PI 3-kinase activity assay, actin filament and bone resorption assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional loss-of-function via antisense, multiple cellular readouts\",\n      \"pmids\": [\"9565618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"c-Src localizes to mitochondria in osteoclasts where it phosphorylates cytochrome c oxidase (Cox); c-src gene deletion reduces Cox activity, restored by exogenous c-Src; Src kinase activity modulates Cox activity and is required for normal osteoclast function and ATP production.\",\n      \"method\": \"c-src knockout cells, exogenous c-Src rescue, Cox activity assay, kinase inhibitors, calcitonin inhibition experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + rescue, direct enzymatic assay, replicated by related work (PMID:16633924, PMID:22823520)\",\n      \"pmids\": [\"12615910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mitochondrial c-Src phosphorylates NDUFV2 (complex I) at Tyr-193 and SDHA (complex II) at Tyr-215; NDUFV2 phosphorylation is required for NADH dehydrogenase activity affecting respiration and ATP content; SDHA phosphorylation perturbs electron transfer, inducing ROS; loss of these phosphorylation events reduces cell viability.\",\n      \"method\": \"Kinase-dead c-Src with mitochondrial targeting sequence, phosphorylation-defective mutants, respiration assay, ATP measurement, ROS assay, cell viability assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific mutants with functional consequences in respiration and cell viability, single lab\",\n      \"pmids\": [\"22823520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Syk, c-Src, and the αvβ3 integrin form a signaling complex only when αvβ3 is activated; activated c-Src phosphorylates Syk; the ITAM proteins Dap12 and FcRγ mediate αvβ3-induced Syk phosphorylation and its association with c-Src; this complex is essential for osteoclast cytoskeletal organization and bone resorption.\",\n      \"method\": \"Syk(-/-) osteoclasts, Co-IP, kinase assays, in vivo skeletal phenotype analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, reciprocal Co-IP, in vivo and in vitro validation with specific phenotypic readout\",\n      \"pmids\": [\"17353363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The lipid raft-anchored adaptor Cbp/PAG controls c-Src oncogenicity by binding phosphorylated c-Src and sequestering it in lipid rafts, suppressing c-Src function independently of Csk; Cbp expression is downregulated by c-Src activation and re-expression suppresses c-Src-mediated transformation and tumorigenesis.\",\n      \"method\": \"Csk-deficient cell transformation assay, Cbp-deficient cells, co-IP, lipid raft fractionation, tumor xenograft experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic approaches (KO, overexpression, knockdown) with transformation and in vivo tumor readouts\",\n      \"pmids\": [\"18498747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Intracellular acidosis activates c-Src within 30 seconds; maneuvers that decrease intracellular pH without changing extracellular pH (sodium propionate, NH4Cl prepulse, nigericin) all activate c-Src; a protein tyrosine phosphatase inhibitor blocks c-Src activation by acid, suggesting activation occurs through inhibition of a phosphatase acting on c-Src.\",\n      \"method\": \"Immune complex kinase assay, intracellular pH manipulation, pharmacological inhibitors\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological approaches establishing pH-sensing mechanism, single lab\",\n      \"pmids\": [\"9124524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"c-Src pre-mRNA undergoes neuron-specific alternative splicing, inserting an 18 nt (NI) and/or a 33 nt (NII) exon between exons 3 and 4, producing neuronal c-Src isoforms with 6 or 17 additional amino acids; splicing of NI and NII together changes an arginine to serine, creating a potential novel phosphorylation site; expression of these splice variants is developmentally regulated in human brain.\",\n      \"method\": \"cDNA cloning, sequencing, RNA analysis from adult and fetal human brain\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — molecular cloning and sequence analysis establishing distinct neuronal isoform; developmental regulation confirmed\",\n      \"pmids\": [\"1691439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Ca2+-induced keratinocyte differentiation results in rapid elevation of c-Src tyrosine kinase activity accompanied by dephosphorylation of c-Src (consistent with reduced Tyr-527 phosphorylation), redistribution of phosphotyrosine to the nucleus, nuclear translocation of a fraction of c-Src, and binding of activated c-Src to three cellular proteins (120, 65, and 34 kDa).\",\n      \"method\": \"In vitro kinase assay, immunoprecipitation, subcellular fractionation, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase assay with fractionation and binding data, single lab\",\n      \"pmids\": [\"1381508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The Unique domain and SH3 domain of c-Src bind lipids; these domains interact intramolecularly; calmodulin binds the Unique domain and allosterically modulates SH3–lipid interactions; phosphorylation of conserved Unique domain sites reduces lipid binding; mutations abolishing lipid binding by the Unique domain produce a distinct in vivo phenotype in Xenopus oocytes, establishing a functional regulatory role for this domain.\",\n      \"method\": \"NMR spectroscopy, lipid-binding assays, intramolecular interaction studies, Xenopus oocyte injection with mutants\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — NMR plus in vivo functional assay with mutants; single lab\",\n      \"pmids\": [\"23416516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The PDZ domain of AF-6 binds the C-terminal Leu of c-Src, recruiting c-Src to cell–cell contact sites; this interaction interferes with Csk-mediated phosphorylation of Tyr-527 and reduces autophosphorylation at Tyr-416, producing a moderately activated c-Src; AF-6 knockdown expands c-Src substrate repertoire.\",\n      \"method\": \"Co-IP, PDZ binding assays, AF-6 knockdown (siRNA), phosphorylation analysis, site-directed mutagenesis of C-terminal Leu\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding assay with mutagenesis and knockdown, specific phosphorylation readout\",\n      \"pmids\": [\"17491594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"X-ray crystallography demonstrates that small molecules can induce the DFG-out (inactive) conformation in c-Src, contradicting the prevailing hypothesis that c-Src cannot adopt this conformation with high affinity, and revealing the structural basis for differential imatinib selectivity between c-Src and Abl.\",\n      \"method\": \"X-ray crystallography, structure-activity relationship analysis\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with SAR validation, single study\",\n      \"pmids\": [\"18940662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src activity is regulated by the chloride channel protein CLIC-5b in osteoclasts; c-Src suppression causes failure of co-localization of proton pump and CLIC-5b (without affecting CLIC-5b steady-state levels), blocking chloride conductance and reducing vesicular acidification required for bone resorption; CLIC-5b has affinity for both Src SH2 and SH3 domains.\",\n      \"method\": \"Antisense suppression of c-Src or CLIC-5b, vesicular acidification assay, valinomycin rescue, SH2/SH3 pulldown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific mechanistic and functional readouts; domain binding assay\",\n      \"pmids\": [\"16831863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"c-Src is required for acid-induced activation of NHE3 (sodium-hydrogen exchanger 3) in renal epithelial cells; dominant-negative c-Src (K295M) prevented acid-induced NHE3 activation; acidosis activates both c-Src and MEK/ERK/c-fos through independent pathways, both required for NHE3 activation.\",\n      \"method\": \"Dominant-negative c-Src transfection, immune complex kinase assay, NHE3 activity measurement (pHi recovery), MEK inhibitor\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative genetic approach with functional transporter assay and pathway epistasis\",\n      \"pmids\": [\"12081562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Src associates with ErbB2 through an interaction between their catalytic domains (not requiring Src SH2/SH3 domains or receptor phosphorylation), mediated by a conserved motif surrounding ErbB2 Tyr-877; this interaction confers enhanced transformation, partially dependent on Stat3 activation.\",\n      \"method\": \"Chimeric EGFR/ErbB2 constructs, Co-IP, transformation assays in vitro and in vivo, site-directed mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chimeric receptor approach with mutagenesis and functional transformation readout\",\n      \"pmids\": [\"19704002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endosomal NADPH oxidases (Nox1/Nox2), activated downstream of Rac1-mediated endocytosis following hypoxia/reoxygenation, generate ROS that activate c-Src within endosomes; endosomal c-Src then tyrosine-phosphorylates IκBα to activate NF-κB; Rac1 siRNA prevents c-Src recruitment to endosomes without affecting its activation per se.\",\n      \"method\": \"siRNA knockdown of Rac1, Nox1/Nox2; endocytosis inhibition; intraluminal ROS quenching; co-localization and kinase assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple siRNA knockdowns with compartment-specific functional readout\",\n      \"pmids\": [\"18397177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src signaling through the SH3-binding adapters Sin and Cas is mediated exclusively by the Crk–Rap1 GTPase pathway (not Ras), whereas oncogenic SrcY527 signals through both Ras and Rap1, demonstrating mechanistic divergence between wild-type and transforming c-Src alleles.\",\n      \"method\": \"Dominant-negative and constitutively active constructs, transcriptional reporter assays, epistasis analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple constructs, single lab\",\n      \"pmids\": [\"10982853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Constitutively active c-Src promotes invadopodium formation (containing phospho-cortactin), while kinase-inactive c-Src promotes microtentacle (McTN) formation; pharmacological c-Src inhibition blocks invadopodia including ECM degradation but enhances McTN formation, demonstrating that c-Src differentially and oppositely regulates these two protrusion types.\",\n      \"method\": \"Constitutively active and dominant-negative c-Src expression, pharmacological inhibition (SU6656), Tks5 siRNA, ECM degradation assay, in vivo capillary retention\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches with distinct structural and functional readouts\",\n      \"pmids\": [\"20956943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Src phosphorylates PFKFB3 at Tyr-194, activating this key glycolytic enzyme that produces fructose-2,6-bisphosphate to boost glycolysis; PFKFB3-Y194F knockin mice show impaired glycolysis and attenuated spontaneous colon cancer formation in APCmin/+ mice; PFKFB3-Y194 phosphorylation correlates with c-Src activity in clinical tumor samples.\",\n      \"method\": \"In vitro kinase assay, site-specific knockin mice (Y194F), tumor xenografts, metabolic flux analysis, clinical sample correlation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assay with site-specific knockin mice, multiple functional readouts including in vivo tumor model\",\n      \"pmids\": [\"32209481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"c-Src phosphorylates glucose-6-phosphate dehydrogenase (G6PD) at Tyr-112, dramatically decreasing its Km and increasing its Kcat for glucose-6-phosphate, thereby activating the pentose phosphate pathway for NADPH and ribose-5-phosphate production to support cancer cell biosynthesis and ROS detoxification.\",\n      \"method\": \"In vitro kinase assay, co-IP, phospho-deficient mutant (Y112F), PPP flux analysis, tumor xenograft, clinical sample correlation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with site-specific mutant and kinetic parameters, confirmed in vivo\",\n      \"pmids\": [\"33686238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATP-competitive Src inhibitors induce a conformational change in c-Src that promotes its association with FAK; upon inhibitor washout, c-Src dissociates from the complex and phosphorylates FAK, initiating FAK–Grb2–Erk signaling; a drug-resistant c-Src mutation converts Src inhibitors into facilitators of cell proliferation by enhancing FAK and Erk phosphorylation.\",\n      \"method\": \"Co-IP, phosphorylation analysis, drug-resistant mutant cells, Erk/FAK signaling readouts, cell proliferation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with conformational change data and drug-resistant mutant validation, single lab\",\n      \"pmids\": [\"33761359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tissue transglutaminase (TG2) promotes integrin-mediated adhesion to fibronectin, physically recruits c-Src, which in turn phosphorylates β-catenin at Tyr-654, releasing it from E-cadherin and enabling its transcriptional activity (cyclin D1, c-Myc induction).\",\n      \"method\": \"Co-IP, site-specific phosphorylation analysis, knockdown/overexpression, transcriptional reporter assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with specific phosphorylation site and transcriptional readout, single lab\",\n      \"pmids\": [\"23640056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MPP2 (a MAGUK/PDZ protein) interacts with c-Src in epithelial cells; c-Src kinase activity promotes the MPP2–c-Src interaction; MPP2 negatively regulates c-Src kinase activity and suppresses c-Src-dependent disorganization of the cortical actin cytoskeleton.\",\n      \"method\": \"PDZ domain array screen, co-IP, kinase activity assay, actin cytoskeleton imaging\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pulldown screen confirmed by co-IP with functional kinase and actin readout, single lab\",\n      \"pmids\": [\"19665017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"N-acetyl-l-cysteine (NAC) reduces c-Src cysteine oxidation, reducing Tyr-419 phosphorylation (activation) and causing a massive redistribution of c-Src from the plasma membrane to endolysosomal compartments, demonstrating that cysteine oxidation state controls both c-Src activity and its subcellular localization.\",\n      \"method\": \"Thiol-specific labeling of c-Src cysteines, phosphorylation analysis, subcellular fractionation/imaging, kinetic enzyme assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinetic assay combined with subcellular localization and phosphorylation readouts, single lab\",\n      \"pmids\": [\"18845245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Src controls the secretion of collagenolytic cysteine proteases (cathepsin K and L) by osteoclasts through a PI 3-kinase- and actin cytoskeleton-dependent pathway; PP1 (c-Src inhibitor) suppressed secretion without affecting synthesis, and also suppressed F-actin ring formation and bone resorption.\",\n      \"method\": \"Pharmacological inhibitors of c-Src (PP1), PI 3-kinase (wortmannin), actin (cytochalasin B); protease synthesis and secretion assays; bone resorption assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological inhibitors with synthesis/secretion distinction, specific functional readout\",\n      \"pmids\": [\"10872813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In ErbB2-driven breast cancer, c-Src stimulates mitochondrial ATP production, suppressing AMPK/energy stress and maintaining mTORC1 activation, which increases translation of EZH2 and Suz12 mRNAs (PRC2 subunits), thereby driving epigenetic reprogramming and mammary tumorigenesis.\",\n      \"method\": \"Genetic models (c-Src inhibition/activation), mTORC1 inhibitors, polysome profiling, in vivo mammary tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches with translational and in vivo readouts, single lab\",\n      \"pmids\": [\"31263101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HER2/heregulin signaling selectively upregulates c-Src phosphorylation at Tyr-215 within the SH2 domain and increases c-Src kinase activity, which in turn selectively upregulates FAK phosphorylation at Tyr-861.\",\n      \"method\": \"Phospho-specific antibodies, kinase activity assay, receptor overexpression, IHC on human tumor samples\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — phospho-specific antibody readouts without direct mechanistic reconstitution, single lab\",\n      \"pmids\": [\"12753909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PRL stimulates c-Src kinase activity independently of Jak2; cells expressing a Box 1-mutated PRLR that cannot bind or activate Jak2 still exhibit normal c-Src activation upon PRL treatment, demonstrating that PRL activates c-Src through a Jak2-independent pathway.\",\n      \"method\": \"Dominant-negative Jak2 and Box 1 mutant PRLR expression, kinase activity assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with specific mutants distinguishing Jak2-dependent and -independent pathways\",\n      \"pmids\": [\"10600634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"c-Src phosphorylates HDAC3 at Tyr-328 and Tyr-331, increasing HDAC3 deacetylase activity; EGF stimulation recruits HDAC3 to the plasma membrane in an EGFR/c-Src-dependent manner; c-Src inhibition reduces HDAC3 phosphorylation, enzymatic activity, and breast cancer cell invasiveness.\",\n      \"method\": \"Phospho-specific HDAC3 antibody, site-specific mutants (Y328/331A), c-Src inhibitor (PP2), TIRF imaging, invasion assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific mutagenesis with enzymatic activity assay and functional invasion readout, single lab\",\n      \"pmids\": [\"31430896\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"c-Src is a non-receptor tyrosine kinase maintained in a closed, inactive conformation by intramolecular interactions in which phospho-Tyr-527 (installed by Csk, whose substrate selectivity is dictated by a docking mechanism revealed by co-crystal structure) engages the SH2 domain and the SH3 domain engages the linker, while the activation loop forms an inhibitory helix; relief of these restraints—by SH2/SH3 ligands, Tyr-527 dephosphorylation, or interaction with scaffolds such as Cbp/PDZ proteins—allows Tyr-416 autophosphorylation that locks the active conformation, enabling c-Src to phosphorylate a broad array of substrates (EGFR-Tyr845, connexin-43-Tyr265, Sam68, p190RhoGAP, PFKFB3-Tyr194, G6PD-Tyr112, HDAC3-Tyr328/331, Cox, NDUFV2-Tyr193) at the plasma membrane, in mitochondria, and in endosomes, thereby coordinating actin cytoskeleton remodeling, gap junction regulation, metabolic reprogramming, and mitogenic signaling downstream of growth factor receptors, integrins, and GPCRs.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers only.\n\n**Classification notes:**\n- Papers [4], [5], [6], [26], [49], [50], [53], [74], [83], [84], [88], [97] — these describe SRC-1 (steroid receptor coactivator-1, gene NCOA1), not the tyrosine kinase c-Src (gene SRC). These are ALIAS COLLISION → EXCLUDE\n- Papers from additional corpus: [8] (NGF review, no SRC mechanism), [10] (TRIF/TLR), [14] (JAK/STAT/gp130), [15] (tau protein) — not about SRC → EXCLUDE\n- All remaining papers describe the canonical c-Src tyrosine kinase → KEEP\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1979,\n      \"finding\": \"The src gene product (p60src) of avian sarcoma virus is localized to the inner surface of the plasma membrane, particularly concentrated under ruffles and near cell-cell junctions, as determined by electron microscopic immunocytochemistry. This plasma membrane localization indicates that p60src exerts its effects on cell growth, shape, and membrane structure by acting initially at the cell membrane.\",\n      \"method\": \"Electron microscopic immunocytochemistry with quantitative localization\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by EM immunocytochemistry with quantification, foundational study\",\n      \"pmids\": [\"228858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"Overexpression of c-src alone does not transform NIH 3T3 cells, whereas v-src does, demonstrating that v-src transformation requires mutations distinguishing viral from cellular protein, not merely overexpression. A c-src/v-src recombinant combining the 5' c-src with 3' v-src sequences induced focus formation, mapping transforming determinants to the 3' end of v-src.\",\n      \"method\": \"Transfection, focus formation assay, soft agar colony assay, in vitro kinase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts (focus formation, soft agar growth, kinase assay) with domain-swap genetics\",\n      \"pmids\": [\"6594680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Two src-related loci were isolated from the human genome: c-src1(human) on chromosome 20 encodes the canonical pp60c-src (highly related to chicken c-src), while c-src2(human) on chromosome 1 is slightly more divergent and not detectably expressed in human cell lines.\",\n      \"method\": \"Recombinant DNA library screening, partial nucleotide sequencing, chromosomal mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic cloning and chromosomal mapping, single study\",\n      \"pmids\": [\"2581127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"pp60c-src is expressed specifically in neurons (not flat fibroblastic cells) of chick dorsal root ganglia, with immunoreactivity distributed over cell body, processes, and growth cones, establishing c-Src as a product of sensory neurons.\",\n      \"method\": \"Western immunoblotting, immunoperoxidase staining, double immunofluorescence with neurofilament antibodies\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by multiple immunological methods, single lab\",\n      \"pmids\": [\"2427734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Human C-SRC undergoes neuron-specific alternative splicing that inserts an 18-nucleotide exon (NI exon) between exons 3 and 4, producing a brain-specific mRNA isoform; C-YES and FYN do not show analogous splicing at this region.\",\n      \"method\": \"cDNA cloning, sequencing, tissue RNA analysis\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct sequence analysis of cDNA clones from multiple tissues, single lab\",\n      \"pmids\": [\"2681803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"A second neuronal exon (NII exon, 33 nucleotides, encoding 11 amino acids) of C-SRC is present between exons 3 and 4 in human brain, primarily used in conjunction with the NI exon, and its expression is developmentally regulated (similar levels in adult and fetal brain for the NI+NII form, but NI-only and nonneuronal forms are higher in fetal brain).\",\n      \"method\": \"cDNA isolation from adult and fetal brain, nucleotide sequencing, RNA analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct sequencing and developmental expression analysis, single lab\",\n      \"pmids\": [\"1691439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Ca2+-induced keratinocyte differentiation causes rapid elevation of c-Src tyrosine kinase activity accompanied by tyrosine dephosphorylation (suggesting activation via Tyr527 dephosphorylation), redistribution of intracellular phosphotyrosine to the nucleus, and association of activated c-Src with three cellular proteins (120 kDa, 65 kDa, 34 kDa). c-Src was found in the nucleus after Ca2+ treatment.\",\n      \"method\": \"In vitro kinase assay, subcellular fractionation, co-immunoprecipitation, immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (kinase assay, fractionation, co-IP), single lab\",\n      \"pmids\": [\"1381508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Csk suppresses c-Src kinase activity in vivo by phosphorylating Tyr-527 of c-Src. v-Crk activates c-Src by altering the phosphorylation state of Tyr-527. Overexpression of Csk reverts morphological transformation induced by coexpression of v-Crk and c-Src, but not transformation by v-Src or c-SrcY527F, demonstrating that Csk acts specifically on Tyr-527.\",\n      \"method\": \"Co-transfection, morphological transformation assay, kinase activity measurement, dominant-negative and gain-of-function mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with point mutants plus kinase activity measurements, strong mechanistic evidence\",\n      \"pmids\": [\"1383688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Src regulates EGF-induced actin cytoskeleton reorganization through tyrosine phosphorylation of p190-RhoGAP. p190 is a preferred substrate of c-Src (its phosphotyrosine content correlates with c-Src activity, not with EGF treatment per se). In cells overexpressing active c-Src, EGF-induced condensation of p190 and RasGAP into cytoplasmic arc structures was accelerated, while kinase-dead c-Src delayed it.\",\n      \"method\": \"Immunofluorescence microscopy, confocal microscopy, stable overexpression of wild-type and dominant-negative c-Src\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell lines with gain/loss-of-function c-Src variants, correlated with substrate phosphorylation\",\n      \"pmids\": [\"7542246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Src phosphorylates EGFR at tyrosine 845 in an EGF-dependent manner. A synthetic peptide containing Y845 was phosphorylated by c-Src in vitro; tryptic phosphopeptide mapping of c-Src-associated EGFR confirmed Y845 phosphorylation in EGF-treated A431 cells.\",\n      \"method\": \"In vitro kinase assay with synthetic peptides, cyanogen bromide digestion, tryptic phosphopeptide mapping, in vivo confirmation in EGF-treated cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with peptide substrates plus in vivo validation, peptide mapping to specific residue\",\n      \"pmids\": [\"7488034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Src autophosphorylates Tyr-527 (its primary negative regulatory site) in vitro when sufficiently high ATP concentrations are used. This autophosphorylation can occur both intra- and intermolecularly, with higher enzyme concentrations required for intermolecular Tyr-527 phosphorylation than for Tyr-416 autophosphorylation, suggesting c-Src can negatively regulate itself.\",\n      \"method\": \"In vitro kinase assay with bacterially expressed purified c-Src at varying ATP and enzyme concentrations, phosphorylation-site identification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified protein, mechanistic characterization of auto- vs. intermolecular phosphorylation\",\n      \"pmids\": [\"7592753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Src interacts with the mitotic RNA-binding protein Sam68 through highly specific SH2 and SH3 domain interactions. Mitotic tyrosine-phosphorylated Sam68 binds the c-Src SH2 domain; Sam68 also binds the Src SH3 domain, and this SH3 binding inhibits Sam68's RNA binding activity, suggesting that c-Src-Sam68 interaction modulates RNA binding during mitosis.\",\n      \"method\": \"In vitro binding assays with recombinant SH2/SH3 domains, poly(U) binding assays, SH3 inhibitory peptides, whole-cell homogenate pulldowns\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple reconstituted in vitro binding assays with domain mutants and competing peptides\",\n      \"pmids\": [\"7537265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"c-Src is required for cell locomotion regulated by the hyaluronan receptor RHAMM. Src-/- fibroblasts have significantly slower random locomotion, restored by c-Src with functional kinase domain but not by kinase-deficient or truncated c-Src. c-Src acts downstream of RHAMM in motility regulation, as dominant-negative c-Src inhibits RHAMM-dependent cell locomotion, while v-Src enhances motility in a RHAMM-independent fashion.\",\n      \"method\": \"Src-/- fibroblasts, rescue with wild-type and mutant c-Src constructs, anti-RHAMM blocking antibodies, cell motility assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout cells with domain-specific rescue, epistasis established by multiple genetic approaches\",\n      \"pmids\": [\"8950989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Phage display assessment of substrate specificity shows that c-Src prefers substrates with isoleucine or leucine at position -1 relative to the phosphorylated tyrosine, and tryptophan or glycine at position +1, distinguishing it from related kinases Blk and Lyn (which prefer acidic residues at +1).\",\n      \"method\": \"Phage display peptide library, multiple rounds of phosphorylation and selection, sequence analysis of enriched phosphopeptides\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical selection with library, multiple selection rounds defining substrate consensus\",\n      \"pmids\": [\"8709147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Caveolin directly binds wild-type c-Src (but not mutationally activated v-Src) via caveolin residues 82–101 (the caveolin scaffolding domain), and this interaction negatively regulates c-Src auto-activation. A caveolin peptide (residues 82–101) suppressed purified recombinant c-Src kinase activity in vitro, and co-expression of full-length caveolin with c-Src in 293T cells dramatically suppressed c-Src tyrosine kinase activity.\",\n      \"method\": \"GST fusion pulldown, in vitro kinase assay with caveolin peptide, co-immunoprecipitation, immune complex kinase assay, deletion mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro binding and kinase inhibition with purified proteins plus in vivo validation\",\n      \"pmids\": [\"8910575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The three-dimensional structure of a large c-Src fragment (SH2, SH3, kinase domains, and C-terminal tail) was solved at 1.7 Å resolution in a closed, inactive state. Phosphorylated Tyr-527 in the tail binds the SH2 domain, the SH3 domain contacts the SH2-kinase linker, and these intramolecular interactions simultaneously disrupt the kinase active site and sequester SH2/SH3 binding surfaces, revealing the autoinhibitory mechanism.\",\n      \"method\": \"X-ray crystallography at 1.7 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure revealing complete autoinhibitory mechanism, foundational and highly replicated\",\n      \"pmids\": [\"9024657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Tyrosine-phosphorylated c-Src associates with the cytoskeleton in pressure-overloaded myocardium within 4 hours of right ventricular pressure overload, along with FAK and β3-integrin. Cytoskeletal-bound c-Src shows phosphorylation not at Tyr-527 but presumably at Tyr-416 (active form), suggesting load-induced integrin-mediated signaling activates c-Src association with cytoskeletal structures.\",\n      \"method\": \"Subcellular fractionation, Western blotting with phospho-specific antibodies, co-immunoprecipitation, in vivo pressure overload model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation and phospho-site analysis in vivo, single lab\",\n      \"pmids\": [\"9020175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Intracellular acidosis (decreased intracellular pH) activates c-Src within 30 seconds. Multiple maneuvers that decrease intracellular pH without changing extracellular pH (sodium propionate, NH4Cl prepulse, nigericin) all activate c-Src. Sodium orthovanadate (a phosphatase inhibitor) prevented c-Src activation by acidosis, indicating that a phosphatase is required for acid-induced c-Src activation.\",\n      \"method\": \"c-Src immune complex kinase assay, intracellular pH manipulation with multiple agents, phosphatase inhibitor studies\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal pH-manipulating approaches all yielding consistent kinase activation results\",\n      \"pmids\": [\"9124524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"c-Src activates both STAT1 and STAT3 in PDGF-stimulated NIH3T3 cells. Overexpression of c-Src increases tyrosine phosphorylation and DNA-binding activity of both STATs, while dominant-negative c-Src reduces them. STAT1 co-immunoprecipitates with c-Src, suggesting direct interaction mediates STAT activation.\",\n      \"method\": \"Overexpression and dominant-negative c-Src, kinase assays, EMSA for DNA binding, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss-of-function with co-IP, single lab\",\n      \"pmids\": [\"9344858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Stat3 activation by Src is required for Src-induced cell transformation. v-Src activates Stat3 transcriptional activity through a Stat3-specific binding element; dominant-negative Stat3β blocks Src-induced gene expression and focus formation in NIH 3T3 cells but has a much less pronounced effect on Ras-induced transformation, demonstrating pathway specificity.\",\n      \"method\": \"Luciferase reporter assays, focus formation assays, stable cell line generation, dominant-negative Stat3β overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with dominant-negative, multiple independent clones, pathway-specific controls, replicated\",\n      \"pmids\": [\"9566874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"c-Src is required for osteopontin/integrin αvβ3-stimulated gelsolin-associated PI 3-kinase activation in osteoclasts. c-Src co-immunoprecipitates with gelsolin, osteopontin stimulates c-Src activity associated with gelsolin, and antisense oligonucleotides blocking Src eliminate gelsolin-associated PI 3-kinase activity, gelsolin-dependent cytoskeletal reorganization, and bone resorption.\",\n      \"method\": \"Co-immunoprecipitation, antisense oligodeoxynucleotides, PI 3-kinase activity assay, F-actin measurement, bone resorption assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional knockdown with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"9565618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Four additional c-Src crystal structures revealed that the activation loop (containing Tyr-416) adopts an ordered inhibitory α-helical conformation in the inactive state, blocking the peptide substrate-binding site and preventing Tyr-416 phosphorylation. This ordered conformation is stabilized by the closed assembly of regulatory domains and disrupted by SH2/SH3 ligands or dephosphorylation of Tyr-527.\",\n      \"method\": \"X-ray crystallography (four crystal structures)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — four independent crystal structures revealing activation loop conformation, mechanistic insight into autoinhibition\",\n      \"pmids\": [\"10360179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TRANCE activates Akt/PKB through a signaling complex involving c-Src and TRAF6. c-Src and TRAF6 interact with each other and with TRANCE-R upon receptor engagement. TRAF6 enhances c-Src kinase activity, leading to tyrosine phosphorylation of c-Cbl. c-Src deficiency or Src family kinase inhibitors block TRANCE-mediated PKB activation in osteoclasts.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, Src-deficient cells, pharmacological inhibitors, in vitro binding\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, genetic (Src-/-) and pharmacological loss-of-function, in vitro kinase activity, multiple methods\",\n      \"pmids\": [\"10635328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Beta-arrestin functions as an adapter protein that recruits c-Src to agonist-occupied β2 adrenergic receptors, forming a receptor-arrestin-c-Src signaling complex. Beta-arrestin 1 mutants impaired in c-Src binding or clathrin-coated pit targeting act as dominant-negative inhibitors of β2AR-mediated Erk1/2 MAP kinase activation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative beta-arrestin mutants, MAP kinase activation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus domain-specific dominant-negative mutants with defined signaling readout, highly cited\",\n      \"pmids\": [\"9924018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Src-mediated phosphorylation of EGFR at Tyr845 and Tyr1101 occurs both in vitro and in vivo following EGF stimulation. Tyr845 (analogous to Tyr416 in c-Src activation loop) phosphorylation by c-Src is associated with regulation of EGFR function; a Y845F EGFR mutant ablated EGF-induced DNA synthesis, demonstrating functional significance.\",\n      \"method\": \"In vitro kinase assay, Edman degradation, tryptic phosphopeptide mapping with synthetic peptide co-migration, Y845F mutant EGFR transfection, DNA synthesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro mapping with Edman degradation, site-specific mutant EGFR with functional readout (DNA synthesis)\",\n      \"pmids\": [\"10075741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Src reduces gap junctional conductance in cardiomyopathic hearts through tyrosine phosphorylation of connexin-43. Increased tyrosine-phosphorylated connexin-43 and increased c-Src activity are correlated in BIO 14.6 hamster hearts with congestive heart failure. Constitutively active c-Src diminished Ca2+ wave propagation and reduced gap junctional conductance between cardiac myocyte pairs.\",\n      \"method\": \"Immunoprecipitation, immunoblotting, transfection of constitutively active c-Src, Ca2+ wave propagation assay, electrophysiology (gap junction conductance measurement)\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo correlation plus functional electrophysiology assay with constitutively active c-Src, single lab\",\n      \"pmids\": [\"10521240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src regulates the interaction between connexin-43 and ZO-1 in cardiac myocytes by phosphorylating connexin-43 at Tyr265. Phosphorylated Tyr265 binds the c-Src SH2 domain, displacing ZO-1. A Tyr265 mutant connexin-43 maintained ZO-1 interaction despite constitutively active c-Src. Both the Tyr265 phosphorylation site and the ZO-1 binding domain regulate gap junctional function.\",\n      \"method\": \"In vitro binding assays with recombinant proteins, cell surface biotinylation, co-immunoprecipitation, mutant connexin-43 constructs, electrophysiological analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro binding, site-specific mutants, electrophysiological functional readout\",\n      \"pmids\": [\"11035005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src is required for acid-induced activation of NHE3 (sodium-hydrogen exchanger 3) in renal proximal tubule cells. Dominant-negative c-SrcK295M prevented acid-induced NHE3 activation. Acidosis activates c-Src and MEK/ERK pathways independently; both pathways are necessary for NHE3 activation.\",\n      \"method\": \"Dominant-negative c-Src transfection, immune complex kinase assays, cytoplasmic pH measurement (BCECF), MEK inhibitor (PD98059), in vivo renal cortical assay\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative plus pharmacological inhibitors with defined functional readout (NHE3 activity), single lab\",\n      \"pmids\": [\"12081562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src is involved in DPV-induced endothelial cell barrier dysfunction. DPV increases c-Src association with cortactin and myosin light chain kinase. Wild-type and constitutively active c-Src potentiated barrier disruption while dominant-negative c-Src attenuated it, providing direct evidence for Src's role in ROS-induced endothelial barrier dysfunction.\",\n      \"method\": \"Src inhibitor PP-2, co-immunoprecipitation (Src with cortactin and MLCK), transient overexpression of wild-type, constitutively active, and dominant-negative Src, transendothelial electrical resistance measurement\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss-of-function plus co-IP with barrier function readout, single lab\",\n      \"pmids\": [\"10956618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src signaling induced by adapters Sin and Cas is mediated by the GTPase Rap1 (not Ras, which mediates oncogenic Src signaling). Sin and Cas bind to and activate c-Src through its SH3 domain, and downstream transcriptional signaling proceeds through Crk and Rap1. In contrast, oncogenic SrcY527F signaling is mediated by both Ras and Rap1.\",\n      \"method\": \"Overexpression of full-length and truncated adapter proteins, reporter gene assays, dominant-negative Rap1 and Ras, Co-IP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using dominant-negative GTPases with transcriptional readout, single lab\",\n      \"pmids\": [\"10982853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Src controls collagenolytic protease (cathepsin K, cathepsin L) secretion in osteoclasts via PI 3-kinase-dependent regulation of the cytoskeleton. PP1 (c-Src inhibitor) suppressed cathepsin K and L secretion and F-actin ring formation without affecting synthesis, and wortmannin (PI 3-kinase inhibitor) and cytochalasin B (actin inhibitor) mimicked this effect.\",\n      \"method\": \"pp60c-Src inhibitor PP1, wortmannin, cytochalasin B, ELISA for protease secretion, hydroxyproline release (bone resorption), F-actin ring staining\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection with multiple inhibitors and multiple readouts, single lab\",\n      \"pmids\": [\"10872813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Prolactin stimulates c-Src independently of Jak2. In cells expressing a Box 1-mutated PRLR unable to interact with Jak2, PRL still activates c-Src equivalently to wild-type receptor. This demonstrates that c-Src can be activated by the prolactin receptor through a Jak2-independent and receptor-phosphorylation-independent mechanism.\",\n      \"method\": \"Mutant PRLR constructs (Box1 mutation), kinase-dead Jak2, kinase assays for c-Src and Jak2, tyrosine phosphorylation analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor mutants and dominant-negative Jak2 establishing pathway independence, single lab\",\n      \"pmids\": [\"10600634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"c-Src is present within mitochondria where it phosphorylates cytochrome c oxidase (Cox), activating Cox activity. Deleting the c-src gene reduces Cox activity; exogenous c-Src restores it. Reducing Src kinase activity downregulates Cox activity while activating Src increases it. Calcitonin inhibits osteoclast function partly by downregulating Cox activity, and increasing Src kinase activity overcomes calcitonin-mediated Cox inhibition.\",\n      \"method\": \"c-src gene deletion, exogenous c-Src re-expression, pharmacological Src activation/inhibition, Cox activity assay, mitochondrial fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout plus rescue plus pharmacological manipulation with biochemical activity readout\",\n      \"pmids\": [\"12615910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Pyk2 co-activates EGFR- and c-Src-mediated Stat3 activation. Pyk2 and c-Src together potently activate Stat3 (phosphorylation at Tyr-705 and Ser-727); dominant-negative Pyk2 impairs c-Src-induced Stat3 activation. EGF treatment recruits c-Src, Pyk2, and Stat3 to EGFR. Pyk2 and c-Src both contribute to EGF-induced Stat3 phosphorylation.\",\n      \"method\": \"Reporter gene assays, co-immunoprecipitation, dominant-negative constructs of Pyk2 and c-Src, phospho-specific Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus dominant-negative epistasis with phospho-specific readout, single lab\",\n      \"pmids\": [\"14963038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Galpha16 stimulates STAT3 through a c-Src/JAK pathway and an ERK-dependent pathway. Selective inhibitors and dominant-negative mutants of c-Src and JAK2/JAK3 suppress Galpha16QL-induced STAT3 activation, while EGFR, RhoA, Cdc42, and PI 3-kinase are not required, delineating specific kinase requirements.\",\n      \"method\": \"Constitutively active Galpha16 mutant, selective kinase inhibitors, dominant-negative kinase mutants, luciferase reporter assay, phospho-specific Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple dominant-negative constructs and inhibitors with defined signaling readout, single lab\",\n      \"pmids\": [\"14551213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Src kinase activity is regulated by phosphorylation at Tyr416 (activating, autophosphorylation), Tyr527 (inhibitory, by Csk), and additional sites. Dephosphorylation of pTyr527 by multiple phosphatases (PTP1B, Shp1, Shp2, CD45, PTPα, PTPε) activates Src; dephosphorylation of pTyr416 by PTP-BL decreases activity. CDK1/cdc2 phosphorylation of Thr34, Thr46, and Ser72 increases Src kinase activity.\",\n      \"method\": \"Review synthesizing biochemical and mutagenesis data from multiple studies; key findings from in vitro kinase assays, phosphatase assays, and mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — synthesis of Tier 1 experiments from multiple labs establishing the phosphorylation regulatory network\",\n      \"pmids\": [\"15845350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Src is involved in regulating endocytosis of PDGFβ receptor-GPCR (S1P1) complexes. PDGF and S1P induce c-Src recruitment to the PDGFβR-S1P1 complex. c-Src is regulated by Gβγ subunits and can interact with β-arrestin. c-Src leads to G protein/c-Src-dependent tyrosine phosphorylation of Gab1 and accumulation of dynamin II at the plasma membrane, required for receptor complex endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, Src inhibitors, dominant-negative constructs (GRK2 C-terminal domain, β-arrestin clathrin-binding domain), endocytosis inhibitors\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus multiple dominant-negative approaches, single lab\",\n      \"pmids\": [\"15494217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Neurotensin stimulates prostate cancer cell mitogenesis through a c-Src/Stat5b pathway involving EGFR transactivation. NT induces c-Src phosphorylation, EGFR Tyr845 phosphorylation (a c-Src-specific site), and Stat5b activation. Mutant EGFR Y845F or mutant Stat5b, or selective inhibition of c-Src or EGFR, all block NT-induced DNA synthesis.\",\n      \"method\": \"Phospho-specific antibodies, mutant EGFR (Y845F) and mutant Stat5b, selective kinase inhibitors, BrdU incorporation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific mutants plus pharmacological inhibition with functional readout, single lab\",\n      \"pmids\": [\"16862179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Src controls chloride channel (CLIC-5b) colocalization with the proton pump in osteoclasts. CLIC-5b has affinity for both Src SH2 and SH3 domains. Suppression of c-Src expression by siRNA reduces vesicular acidification (rescuable by valinomycin, consistent with selective loss of chloride conductance) and disrupts colocalization of proton pump and CLIC-5b, impairing bone resorption.\",\n      \"method\": \"SH2/SH3 domain binding assay, siRNA knockdown of c-Src, vesicular acidification assay, valinomycin rescue, immunolocalization of proton pump and CLIC-5b\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain binding plus siRNA knockdown with mechanistic dissection using valinomycin rescue, single lab\",\n      \"pmids\": [\"16831863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Src and c-Met/HGF receptor colocalize in osteosarcoma cells, and Caveolin-1 overexpression inhibits both c-Src and c-Met tyrosine kinase activity, suppressing anchorage-independent growth, migration, invasion, and abrogating metastatic ability in vivo.\",\n      \"method\": \"Caveolin-1 forced overexpression, co-localization by immunofluorescence, in vitro migration/invasion assays, in vivo metastasis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-localization plus gain-of-function with in vivo readout, single lab\",\n      \"pmids\": [\"17699771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Src is required for breast cancer tumorigenesis. Inducible dominant-negative c-Src (K295M/Y527F) in MCF7 cells causes relocation of c-Src, FAK, and paxillin; inhibits FAK-Tyr925, p130CAS, and paxillin phosphorylation; increases FAK-Tyr397 autophosphorylation; decreases p130CAS and p85-PI3K association with FAK; inhibits cell attachment, spreading, migration, and proliferation; and significantly reduces tumorigenesis in nude mice with tumor regression upon induction.\",\n      \"method\": \"Inducible dominant-negative c-Src (Tet-On), siRNA knockdown, phospho-specific Western blotting, co-immunoprecipitation, cell attachment/spreading/migration assays, nude mouse xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — inducible dominant-negative plus siRNA with comprehensive pathway and in vivo readouts\",\n      \"pmids\": [\"16728403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Src, Syk, and αvβ3 integrin form an essential signaling complex in osteoclasts. Syk is essential for osteoclast cytoskeletal organization and bone resorption in vitro and in vivo. αvβ3 activation triggers complex formation of c-Src with Syk; c-Src phosphorylates Syk. This complex formation and phosphorylation requires ITAM proteins Dap12 and FcRγ.\",\n      \"method\": \"Syk-/- mice and chimeric mice, in vitro bone resorption assay, co-immunoprecipitation, in vitro kinase assay, siRNA for ITAM proteins\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout mice plus reconstitution plus kinase assays, multiple orthogonal approaches\",\n      \"pmids\": [\"17353363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Calreticulin affects fibronectin-based cell-substratum adhesion via regulation of c-Src activity. c-Src activity is inversely related to calreticulin abundance, and c-Src activity depends on releasable Ca2+ from the ER. c-Src inhibition rescues the poorly adhesive phenotype of calreticulin-underexpressing cells, restoring spreading, focal contact formation, and fibronectin matrix deposition.\",\n      \"method\": \"Cells with variable calreticulin expression, c-Src inhibitor (PP2), Ca2+ chelation, immunofluorescence, fibronectin matrix assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with defined phenotypic readout and Ca2+-dependence established, single lab\",\n      \"pmids\": [\"17389592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Src is regulated by binding to the PDZ domain of AF-6 at cell-cell contact sites. The C-terminal Leu of c-Src is essential for AF-6 PDZ domain binding. AF-6 binding restricts c-Src substrate range, reduces Tyr527 phosphorylation by Csk, reduces Tyr416 autophosphorylation (yielding moderately activated c-Src), and recruits c-Src to cell-cell junctions.\",\n      \"method\": \"PDZ domain binding assays, co-immunoprecipitation, AF-6 knockdown, Csk overexpression, kinase assays, phospho-specific Western blotting, immunofluorescence localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding and kinase assays with defined localization outcome, single lab\",\n      \"pmids\": [\"17491594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Csk recognition of c-Src is mediated by a specific docking mechanism: crystal structure of the Csk-c-Src kinase domain complex at 2.9 Å shows that the C-terminal tail of c-Src is positioned at the edge of Csk's active site by inter-kinase interactions. The conventional substrate-binding site of Csk is destabilized by a deletion in its activation loop, explaining why the C-terminal tail of Src family kinases is the only known Csk target.\",\n      \"method\": \"X-ray crystallography at 2.9 Å resolution of Csk-c-Src kinase domain complex\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of the kinase-substrate complex revealing the molecular basis for Csk substrate specificity\",\n      \"pmids\": [\"18614016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The lipid raft-anchored adaptor Cbp/PAG directly controls c-Src oncogenicity independently of Csk. Upon phosphorylation, Cbp specifically binds activated c-Src and sequesters it in lipid rafts, suppressing c-Src function. Cbp expression is downregulated by c-Src activation; re-expression of Cbp suppresses c-Src transformation and tumorigenesis. Cbp-deficient cells are more susceptible to v-Src transformation.\",\n      \"method\": \"Csk-deficient cell system, Cbp re-expression, Cbp-/- cells, co-immunoprecipitation, lipid raft fractionation, transformation assay, in vivo tumorigenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic approaches (knockout, re-expression, deficiency) with biochemical and in vivo functional readouts\",\n      \"pmids\": [\"18498747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Small molecules can bind to c-Src in the DFG-out inactive conformation (the Imatinib-binding conformation), which was previously considered energetically unfavorable for c-Src. Structure-activity relationships and X-ray crystallography confirmed inhibitor binding to the DFG-out state of c-Src.\",\n      \"method\": \"X-ray crystallography of inhibitor-c-Src complexes, structure-activity relationship analysis\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures directly demonstrating DFG-out conformation in c-Src\",\n      \"pmids\": [\"18940662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"c-Src identifies novel substrates including NICE-4, RNA binding motif 10, FUSE-binding protein 1, and TRK-fused gene using SILAC proteomics and peptide microarrays. 34 specific tyrosine phosphorylation sites on 14 substrates were identified using c-Src-specific peptide microarrays. RNA binding motif 10, EWS1, and Bcl-2-associated transcription factor were implicated in PDGF signaling via c-Src.\",\n      \"method\": \"SILAC quantitative proteomics, in vitro kinase assays, co-transfection experiments, custom peptide microarrays with Tyr→Phe mutants, c-Src-specific inhibitor\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SILAC plus in vitro kinase validation plus site-specific peptide arrays, multiple orthogonal methods\",\n      \"pmids\": [\"18698806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endosomal NADPH oxidases (Nox1 and Nox2) activated by Rac1 generate ROS that activate c-Src following hypoxia/reoxygenation. Rac1 is required for c-Src recruitment to the endosomal compartment. ROS from endosomal Noxes activate c-Src, enabling it to tyrosine-phosphorylate IκBα and activate NF-κB. Quenching intra-endosomal ROS inhibits c-Src activation without affecting its recruitment.\",\n      \"method\": \"siRNA knockdown of Rac1 and Nox proteins, endocytosis inhibition, intra-endosomal ROS quenching, c-Src kinase activity assay, phospho-IκBα detection\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown of multiple pathway components plus ROS quenching with mechanistic dissection, single lab\",\n      \"pmids\": [\"18397177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"N-acetyl-l-cysteine (NAC) reduces c-Src kinase activity by reverting oxidation-driven activation at cysteine residues. NAC treatment increases reduced thiols on c-Src cysteines, decreases Tyr419 phosphorylation, and causes a massive shift of c-Src from plasma membranes to endolysosomal compartments in cancer cells, revealing redox regulation as an independent mechanism of c-Src control.\",\n      \"method\": \"Kinetic analysis of NAC on c-Src, thiol labeling, Tyr419 phosphorylation Western blot, subcellular fractionation, immunofluorescence\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical kinetic analysis plus subcellular localization change, single lab\",\n      \"pmids\": [\"18845245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Src associates with ErbB2 through an interaction involving the kinase domain regions; a conserved amino acid motif surrounding tyrosine 877 (EGFR YHAD motif) is sufficient to confer c-Src binding to chimeric EGFR/ErbB2 constructs. This association is independent of c-Src SH2 or SH3 domains and of receptor phosphorylation or kinase activity. EGFRs binding c-Src are transforming in vitro and in vivo, with transformation partially dependent on Stat3.\",\n      \"method\": \"Chimeric EGFR/ErbB2 constructs, domain mutation analysis, co-immunoprecipitation, transformation assays in vitro and in vivo, Stat3 reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chimeric receptor approach with co-IP and functional transformation assays, single lab\",\n      \"pmids\": [\"19704002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MPP2 (a MAGUK PDZ protein) interacts with c-Src in epithelial cells through its PDZ domain. MPP2 colocalizes with c-Src in filamentous structures partially overlapping microtubules. MPP2 negatively regulates c-Src kinase activity and suppresses c-Src-dependent disorganization of the cortical actin cytoskeleton.\",\n      \"method\": \"PDZ domain array screen, co-immunoprecipitation, immunofluorescence colocalization, kinase activity assay, actin cytoskeleton analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain array screen, co-IP, kinase assay with functional actin readout, single lab\",\n      \"pmids\": [\"19665017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Prostaglandin E2 (PGE2) promotes lung cancer cell migration via an EP4-βArrestin1-c-Src signaling complex. EP4 receptor engagement activates c-Src; βArrestin1 knockdown significantly impairs PGE2-induced c-Src activation and cell migration. Selective EP4 knockdown with shRNA confirms EP4 as the mediating receptor.\",\n      \"method\": \"shRNA knockdown of EP4 and βArrestin1, c-Src kinase activity assay, cell migration assay, EP subtype-selective ligands\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — shRNA knockdowns for multiple pathway components with functional cell migration readout, single lab\",\n      \"pmids\": [\"20353998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Src activity is required for invadopodium formation but inhibits microtentacle (McTN) formation. Constitutively active c-Src enhances invadopodia (F-actin cores, phospho-cortactin foci, ECM degradation), while inactive c-Src or direct Src inhibition increases McTN formation. Tks5 knockdown blocks invadopodia without affecting McTNs, distinguishing two cytoskeletal structures with opposite dependence on Src activity.\",\n      \"method\": \"Constitutively active and dominant-negative c-Src expression, Src inhibitor SU6656, Tks5 siRNA, invadopodium and McTN assays, in vivo capillary retention\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological manipulation of c-Src with multiple structural and functional readouts, single lab\",\n      \"pmids\": [\"20956943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mitochondrial c-Src phosphorylates NDUFV2 at Tyr193 (Complex I subunit) and SDHA at Tyr215 (Complex II subunit). NDUFV2 phosphorylation is required for NADH dehydrogenase activity and affects respiration and cellular ATP content. SDHA phosphorylation perturbs electron transfer and induces reactive oxygen species. Loss of phosphorylation at these sites causes loss of cell viability, establishing that mitochondrial c-Src activity is essential for cell survival through respiratory chain regulation.\",\n      \"method\": \"Kinase-dead c-Src with mitochondrial targeting sequence, phosphorylation-site mutant NDUFV2 and SDHA, in vivo phosphorylation assay, NADH dehydrogenase activity assay, ROS measurement, cell viability assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — site-specific phosphorylation mutants with multiple biochemical activity and viability readouts, builds on prior Cox work\",\n      \"pmids\": [\"22823520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The Unique domain and SH3 domain of c-Src bind lipids; these domains also interact with each other intramolecularly. Calmodulin (Ca2+-loaded) binds the Unique domain and allosterically modulates the Unique-SH3 intramolecular interaction. Phosphorylation at conserved sites in the Unique domain reduces lipid binding. Mutations abolishing lipid binding by the Unique domain produce a distinct in vivo phenotype from wild-type c-Src in Xenopus oocytes, confirming the Unique domain's functional role in c-Src regulation.\",\n      \"method\": \"NMR spectroscopy (Unique-SH3 interaction), lipid binding assays, phosphomimetic mutations, calmodulin binding assays, Xenopus oocyte injection with functional readout\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — NMR structural characterization plus functional in vivo Xenopus assay, single lab\",\n      \"pmids\": [\"23416516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tissue transglutaminase (TG2) promotes β-catenin signaling through a c-Src-dependent mechanism. TG2 physically associates with and recruits c-Src upon integrin-mediated cell adhesion to fibronectin; c-Src in turn phosphorylates β-catenin at Tyr654, releasing it from E-cadherin and making it available for transcriptional regulation of cyclin D1 and c-Myc.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific antibody for β-catenin Tyr654, siRNA and pharmacological inhibition of c-Src, reporter assays for β-catenin targets\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus phospho-site specific antibody plus functional reporter assays, single lab\",\n      \"pmids\": [\"23640056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Activation loop phosphorylation at Tyr416 stabilizes the active conformation of c-Src by locking critical structural features for catalysis (hydrophobic regulatory spine, HRD motif, electrostatic switch), as shown by free-energy landscape calculations. Unphosphorylated c-Src has considerable flexibility and can transiently visit the active conformation but does not predominantly adopt it.\",\n      \"method\": \"Molecular dynamics umbrella sampling simulations, Markov state model, free-energy landscape calculation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 4 — computational simulation, mechanistically detailed but no experimental validation in this study\",\n      \"pmids\": [\"24103328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"c-Src drives intestinal stem cell (ISC) proliferation and intestinal tumourigenesis through upregulation of EGFR and activation of Ras/MAPK and Stat3 signaling. Genetic gain and loss of function in both Drosophila and mouse intestine shows Src is necessary and sufficient for ISC proliferation during tissue self-renewal and regeneration. c-Src plays a non-redundant role in the mouse intestine not substituted by Fyn or Yes.\",\n      \"method\": \"Drosophila genetic gain/loss-of-function, mouse intestinal conditional knockout and overexpression, APC-min crosses, signaling pathway analysis (EGFR, MAPK, Stat3)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain and loss-of-function in two model organisms with pathway placement, multiple readouts\",\n      \"pmids\": [\"24788409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-34a targets c-SRC mRNA to suppress TNBC tumor growth. Restoration of miR-34a inhibits proliferation and invasion and SRC depletion phenocopies miR-34a effects, while SRC overexpression rescues miR-34a antitumorigenic effects. A negative feedback exists between miR-34a and c-SRC; miR-34a administration reduces tumor growth in vivo with c-SRC downregulation.\",\n      \"method\": \"miRNA profiling, miR-34a transfection/delivery, c-SRC siRNA knockdown and overexpression, xenograft tumor models, dasatinib sensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — miRNA target validation with knockdown/overexpression rescue and in vivo tumor model, single lab\",\n      \"pmids\": [\"26676753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"gp130 associates with and activates c-Src (and the related kinase Yes) upon cytokine stimulation. Active c-Src/Yes then phosphorylates YAP, inducing its stabilization and nuclear translocation independently of STAT3, stimulating epithelial cell proliferation and barrier maintenance. This gp130-Src-YAP module links inflammation to intestinal epithelial regeneration.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, YAP phospho-specific detection, knockout mice, mucosal injury models, human cell studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus genetic knockouts plus in vivo functional readout, independently corroborated in mice and human cells\",\n      \"pmids\": [\"25731159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transition path theory analysis of MSM simulations reveals that c-Src kinase activation proceeds via a dense set of intermediate microstates through a broad 'transition tube': the activation loop opens first, followed by inward rotation of the αC-helix, with multiple microstates of negligible equilibrium probability carrying large transition flux.\",\n      \"method\": \"Markov state model (MSM) combined with transition path theory (TPT), extensive molecular dynamics simulations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational analysis, no direct experimental validation in this study\",\n      \"pmids\": [\"27482115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tescalcin (TESC) activates STAT3 through a c-Src/IGF1Rβ complex. TESC directly recruits c-Src to the IGF1Rβ complex, leading to mutual activation of c-Src and IGF1R, which activates STAT3 to transcriptionally upregulate ALDH1, enhancing cancer stem cell properties and radioresistance.\",\n      \"method\": \"Co-immunoprecipitation, kinase inhibitors, siRNA knockdown, chromatin immunoprecipitation, luciferase reporter assay, ALDH1 activity assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP showing complex plus ChIP/luciferase for downstream transcriptional target, single lab\",\n      \"pmids\": [\"30013043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"c-Src links ErbB2-driven bioenergetics to PRC2 translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress and permits sustained mTORC1 activation, which increases translation of EZH2 and SUZ12 mRNAs. This c-Src/mTORC1/PRC2 axis is essential for ErbB2-mediated mammary tumourigenesis.\",\n      \"method\": \"ErbB2/Src inhibitors, mTORC1 ","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"c-Src is a non-receptor tyrosine kinase that integrates signals from growth factor receptors, integrins, and GPCRs to control actin cytoskeleton remodeling, cell motility, gap junction communication, metabolic reprogramming, and mitogenic signaling. The kinase is maintained in an autoinhibited conformation by intramolecular engagement of phospho-Tyr-527 with the SH2 domain and the SH3 domain with the linker, while the activation loop forms an inhibitory helix that blocks substrate access; Csk phosphorylates Tyr-527 through a unique docking mechanism to enforce this inactive state [PMID:9024657, PMID:10360179, PMID:18614016, PMID:1383688]. Relief of autoinhibition—by SH2/SH3 ligand displacement, Tyr-527 dephosphorylation, PDZ-scaffold sequestration of the C-terminal tail, or redox-dependent cysteine oxidation—permits Tyr-416 autophosphorylation and enables c-Src to phosphorylate substrates including connexin-43 (Tyr-265), PFKFB3 (Tyr-194), G6PD (Tyr-112), HDAC3 (Tyr-328/331), NDUFV2 (Tyr-193), and cytochrome c oxidase at the plasma membrane, in mitochondria, and within endosomes [PMID:11035005, PMID:32209481, PMID:33686238, PMID:31430896, PMID:22823520, PMID:12615910, PMID:18397177]. Through these diverse substrates, c-Src directly boosts glycolysis and the pentose phosphate pathway, stimulates mitochondrial oxidative phosphorylation, promotes invadopodium-driven extracellular matrix degradation, and regulates osteoclast bone resorption [PMID:32209481, PMID:33686238, PMID:12615910, PMID:20956943, PMID:8950989].\",\n  \"teleology\": [\n    {\n      \"year\": 1979,\n      \"claim\": \"Establishing where c-Src operates: EM immunocytochemistry showed that p60src localizes predominantly to the cytoplasmic face of the plasma membrane, particularly at membrane ruffles and cell–cell junctions, defining its primary site of action.\",\n      \"evidence\": \"Electron microscopic immunocytochemistry with quantification in RSV-transformed cells\",\n      \"pmids\": [\"228858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of membrane targeting not yet defined\", \"Whether localization differs in non-transformed cells was unclear\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Revealing tissue-specific complexity: neuron-specific alternative splicing of c-Src pre-mRNA inserts additional exons encoding 6 or 17 amino acids, establishing that c-Src exists as developmentally regulated isoforms with potentially distinct regulatory properties in the brain.\",\n      \"evidence\": \"cDNA cloning and sequencing from adult and fetal human brain RNA\",\n      \"pmids\": [\"1691439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of neuronal isoforms not determined\", \"Whether neuronal splicing alters kinase activity or substrate selectivity unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Identifying the negative regulatory kinase: Csk was shown to suppress c-Src activity and transformation specifically by phosphorylating Tyr-527, as the Y527F escape mutant was refractory to Csk, establishing Csk as the dedicated upstream negative regulator of c-Src.\",\n      \"evidence\": \"Genetic overexpression of Csk with Y527F mutant epistasis, kinase and transformation assays\",\n      \"pmids\": [\"1383688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Csk–Src interaction unknown at this point\", \"Whether Csk acts on all SFK members equally was untested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defining substrate repertoire and mitotic function: Sam68 was identified as the predominant c-Src substrate and SH3-binding partner in mitotic cells, and c-Src was shown to phosphorylate EGFR-Tyr845 and regulate p190RhoGAP-dependent actin remodeling, revealing the breadth of c-Src signaling.\",\n      \"evidence\": \"Co-IP, SH2/SH3 pulldowns, phosphopeptide mapping, dominant-negative c-Src expression in multiple cell types\",\n      \"pmids\": [\"7537265\", \"7488034\", \"7542246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vivo phosphorylation sites not mapped for all substrates\", \"Relative importance of individual substrates to transformation unclear\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Solving the autoinhibition mechanism: the 1.7 Å crystal structure revealed that c-Src is locked in an inactive conformation by intramolecular SH2–pTyr527 and SH3–linker interactions that simultaneously sequester regulatory surfaces and distort the active site, providing the structural framework for understanding all subsequent activation mechanisms.\",\n      \"evidence\": \"X-ray crystallography at 1.7 Å resolution\",\n      \"pmids\": [\"9024657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How activating signals disrupt the closed conformation in cells was not resolved\", \"Structure of the fully active state not determined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Completing the activation loop picture and extending signaling roles: additional crystal structures showed the activation loop forms an inhibitory helix in the inactive state, and c-Src was placed in a TRANCE/TRAF6 signaling complex essential for Akt activation in osteoclasts, broadening its role beyond receptor tyrosine kinase pathways.\",\n      \"evidence\": \"Multiple inactive-state crystal structures; Co-IP and kinase assays in c-Src-deficient osteoclasts\",\n      \"pmids\": [\"10360179\", \"10635328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of TRAF6-mediated c-Src activation not defined\", \"Whether TRANCE–Src–TRAF6 complex is preformed or signal-assembled was unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing c-Src as a direct regulator of gap junction communication: c-Src phosphorylates connexin-43 at Tyr-265, enabling SH2-mediated binding that displaces ZO-1 and reduces gap junctional conductance, providing the first complete mechanism for c-Src-dependent intercellular communication control.\",\n      \"evidence\": \"Constitutively active c-Src with Y265 connexin-43 mutant, electrophysiology, cell-surface biotinylation\",\n      \"pmids\": [\"11035005\", \"10521240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism operates in all connexin-43-expressing tissues not tested\", \"Reversibility and phosphatase involved unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovering a mitochondrial function: c-Src localizes to mitochondria in osteoclasts and directly phosphorylates cytochrome c oxidase to regulate its activity and ATP production, establishing that c-Src has compartment-specific roles beyond the plasma membrane.\",\n      \"evidence\": \"c-src knockout osteoclasts with rescue, Cox enzymatic activity assay\",\n      \"pmids\": [\"12615910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of c-Src import into mitochondria not defined\", \"Specific Cox subunit and residue targeted not identified at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealing PDZ-mediated spatial regulation: AF-6 recruits c-Src to cell–cell contacts via its PDZ domain binding c-Src's C-terminal leucine, interfering with Csk-mediated Tyr-527 phosphorylation and modulating substrate selectivity, establishing scaffold-dependent tuning of c-Src activity.\",\n      \"evidence\": \"Co-IP, PDZ binding assays, AF-6 siRNA knockdown, phosphorylation analysis\",\n      \"pmids\": [\"17491594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How many PDZ-containing proteins regulate c-Src in this manner is unknown\", \"Structural basis of PDZ–c-Src C-tail interaction not solved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Solving Csk substrate selectivity and revealing multiple regulatory layers: the Csk–c-Src co-crystal structure showed Csk uses a unique docking mechanism to phosphorylate Tyr-527, and parallel work showed the lipid raft adaptor Cbp/PAG sequesters c-Src independently of Csk, and endosomal ROS activate c-Src within endosomes for NF-κB signaling.\",\n      \"evidence\": \"Co-crystal structure at 2.9 Å; Csk-deficient transformation assays with Cbp; siRNA/endocytosis inhibition with compartment-specific readouts\",\n      \"pmids\": [\"18614016\", \"18498747\", \"18397177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cbp regulation is tissue-specific not established\", \"How c-Src is selectively activated by endosomal ROS versus cytoplasmic ROS unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanding mitochondrial substrates: c-Src was shown to phosphorylate NDUFV2 (complex I, Tyr-193) and SDHA (complex II, Tyr-215), with these modifications required for NADH dehydrogenase activity, proper electron transfer, and cell viability, generalizing c-Src's mitochondrial role beyond Cox.\",\n      \"evidence\": \"Mitochondria-targeted kinase-dead c-Src, phospho-deficient mutants, respiration and ATP assays\",\n      \"pmids\": [\"22823520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether c-Src regulates all five respiratory complexes untested\", \"Stoichiometry and dynamics of mitochondrial c-Src phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing c-Src as a metabolic kinase in vivo: c-Src phosphorylates PFKFB3-Tyr194 to boost glycolysis and G6PD-Tyr112 to activate the pentose phosphate pathway; PFKFB3-Y194F knockin mice show impaired glycolysis and attenuated colon tumorigenesis, providing genetic proof that c-Src-driven metabolic reprogramming is tumor-promoting.\",\n      \"evidence\": \"In vitro kinase assays, site-specific knockin mice (Y194F), metabolic flux analysis, APCmin/+ tumor model; G6PD kinetic analysis with Y112F mutant and xenografts\",\n      \"pmids\": [\"32209481\", \"33686238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other glycolytic or PPP enzymes are direct Src substrates unknown\", \"Contribution of c-Src metabolic substrates versus signaling substrates to tumorigenesis not disentangled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealing paradoxical drug effects: ATP-competitive Src inhibitors induce a conformational change promoting c-Src–FAK association; upon washout, reactivated c-Src hyper-phosphorylates FAK and drives Erk signaling, and drug-resistant mutations convert inhibitors into proliferation enhancers.\",\n      \"evidence\": \"Co-IP, drug-resistant mutant cells, FAK/Erk phosphorylation and proliferation assays\",\n      \"pmids\": [\"33761359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of inhibitor-induced c-Src–FAK interaction not solved\", \"Clinical relevance of rebound signaling after Src inhibitor withdrawal uncertain\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the mechanism of c-Src import into mitochondria, the full inventory of compartment-specific substrates, how the Unique domain's lipid-binding and calmodulin-sensing functions integrate with SH2/SH3/kinase domain regulation in vivo, and whether distinct neuronal c-Src isoforms have specialized signaling roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mitochondrial import mechanism undefined\", \"Unique domain regulatory role not tested in mammalian physiology\", \"Neuronal isoform-specific functions uncharacterized\", \"No comprehensive phosphoproteomics defining the compartment-specific substrate landscape\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 6, 7, 10, 12, 15, 16, 31, 32, 41]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [14, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 18, 41]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [28, 36]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 11, 17, 27, 29, 34, 40]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15, 16, 31, 32, 38]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [31, 32, 38]}\n    ],\n    \"complexes\": [\n      \"TRAF6–c-Src–TRANCE-R complex\",\n      \"αvβ3–Syk–c-Src integrin signaling complex\"\n    ],\n    \"partners\": [\n      \"CSK\",\n      \"TRAF6\",\n      \"SYK\",\n      \"FAK\",\n      \"ERBB2\",\n      \"GJA1\",\n      \"KHDRBS1\",\n      \"AFDN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (refusal — no on-target evidence) ---\n"}