{"gene":"YES1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2020,"finding":"The small peptide SMIM30, encoded by lncRNA LINC00998, drives membrane anchoring of YES1 (and SRC) by directly binding to them, thereby promoting YES1 phosphorylation and activating the downstream MAPK signaling pathway in hepatocellular carcinoma cells.","method":"RIP-seq, co-immunoprecipitation/pulldown, functional overexpression/knockdown assays, MAPK pathway readout","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, binding demonstrated by pulldown/co-IP and functional validation by OE/KD with pathway readout, two orthogonal approaches","pmids":["32461121"],"is_preprint":false},{"year":2022,"finding":"YES1 (c-Yes tyrosine kinase), rather than Src, is specifically localized at endothelial cell junctions where it becomes activated in a flow-dependent manner, phosphorylates VE-cadherin to regulate its constitutive turnover and endocytosis, and thereby maintains endothelial junction plasticity and vascular integrity. EC-specific YES1 deletion suppressed VE-cadherin phosphorylation and arrested VE-cadherin at junctions, causing loss of collective migration and exaggerated agonist-induced leakage.","method":"Endothelial cell-specific YES1 knockout mice, live imaging, phosphorylation assays, VE-cadherin internalization assays, comparison with Src-deficient ECs","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype, multiple orthogonal readouts (localization, phosphorylation, endocytosis, migration, leakage), rigorous controls with Src-KO comparison","pmids":["37936984"],"is_preprint":false},{"year":2021,"finding":"YES1 is a substrate and effector of the EphA2 receptor tyrosine kinase: EphA2 activates YES1, which then phosphorylates ANXA2 at Tyr24, leading to ANXA2 activation and increased nuclear distribution of ANXA2 in gastric cancer cells, promoting invasion and migration.","method":"Co-immunoprecipitation, knockdown/overexpression, site-directed mutagenesis (ANXA2 Tyr24F mutant), in vitro invasion/migration assays, mouse xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted pathway with mutagenesis (Tyr24F rescue), reciprocal functional assays, multiple orthogonal methods in single study","pmids":["33941853"],"is_preprint":false},{"year":2022,"finding":"YES1 signaling promotes nuclear accumulation and transcriptional activity of YAP and TAZ in hepatocellular carcinoma cells and liver tumors. YES1 phosphorylates YAP/TAZ, driving their nuclear accumulation, and YAP/TAZ are required effectors of YES1-dependent oncogenic transformation of hepatocytes.","method":"Genetic (transgenic expression of activated YES1 in mouse hepatocytes) and pharmacological interventions, phosphorylation assays, nuclear fractionation, epistasis experiments in cellular and mouse HCC models","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological approaches, in vivo mouse models, epistasis placing YAP/TAZ downstream of YES1, replicated across cellular and animal models","pmids":["35041461"],"is_preprint":false},{"year":2019,"finding":"YES1 drives lung cancer growth and metastasis primarily through mTOR signaling. YES1 genetic depletion (CRISPR/Cas9) significantly reduced tumor growth and metastasis in preclinical models, and YES1 gene amplification confers high sensitivity to the SFK inhibitor dasatinib.","method":"CRISPR/Cas9 knockout, in vivo tumor and metastasis models, patient-derived xenografts, mTOR signaling pathway analysis by immunoblotting","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR/Cas9 loss-of-function, in vivo models including patient-derived xenografts, defined signaling pathway (mTOR), multiple complementary approaches","pmids":["31166114"],"is_preprint":false},{"year":2019,"finding":"YES1 regulates YAP1 transcriptional activity by controlling YAP1 nuclear translocation and serine phosphorylation in YES1-amplified cancer cells, placing YAP1 as a downstream effector of YES1 kinase activity.","method":"shRNA knockdown, YES1-specific kinase inhibitor (CH6953755), nuclear fractionation, phosphorylation assays, transcriptional reporter assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, pharmacological and genetic inhibition, multiple assays (nuclear fractionation, phosphorylation, reporter), but no direct in vitro reconstitution","pmids":["31391186"],"is_preprint":false},{"year":1993,"finding":"c-Yes kinase is inactivated by elevation of intracellular calcium levels through a Ca2+-dependent association with specific cellular proteins, which forms complexes not seen with c-Src, and one of these proteins can inhibit c-Yes kinase activity in vitro. This regulation is distinct from c-Src, which is activated under the same conditions.","method":"In vitro kinase assays, immunoprecipitation, gradient sedimentation, Ca2+-supplemented cell extracts, protein tyrosine phosphatase treatment, EGTA reversal","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of inhibition, EGTA reversal, multiple cell types tested, direct comparison to c-Src","pmids":["8246968"],"is_preprint":false},{"year":2005,"finding":"c-Yes kinase activity is specifically required for West Nile virus particle maturation: RNAi knockdown of c-Yes (but not c-Src) reduces virus yield, and Yes kinase activity is needed for the viral envelope glycoprotein E to transit beyond the endoplasmic reticulum, enabling virion egress through the secretory pathway.","method":"RNA interference knockdown, SFK inhibitor PP2 treatment, endoglycosidase H digestion of viral envelope glycoprotein, electron microscopy, viral titer assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific RNAi knockdown distinguishing YES1 from Src, orthogonal mechanistic assay (EndoH digestion), EM confirmation, multiple complementary approaches","pmids":["16140770"],"is_preprint":false},{"year":2006,"finding":"YES1 (c-Yes) plays a unique and non-redundant role in VEGF-mediated endothelial cell migration: selective knockdown of Yes (but not Src or Fyn) by RNAi significantly decreased VEGF-induced cell migration in human retinal microvascular endothelial cells, while all three kinases were required for VEGF mitogenic signaling.","method":"RNA interference selective knockdown of individual Src family kinases, VEGF-induced migration assay, proliferation assay, tube formation assay","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective RNAi distinguishing YES1 from Src/Fyn, multiple functional readouts, single lab","pmids":["16400523"],"is_preprint":false},{"year":2005,"finding":"c-Yes kinase is specifically activated downstream of the leukotriene B4 high-affinity receptor BLT1 following LTB4 stimulation of neutrophils, and BLT1 endocytosis is required for Yes kinase activation. Yes kinase activation (but not c-Src or other SFKs) is required for LTB4-induced neutrophil degranulation.","method":"Src family kinase inhibitor PP1, dominant-negative dynamin (endocytosis block), selective kinase activity assays for individual SFKs, degranulation enzyme release assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and dominant-negative genetic approach, selective kinase activity assays distinguishing YES1 from other SFKs, single lab","pmids":["15749899"],"is_preprint":false},{"year":2021,"finding":"Mislocalized Scribble (Scrib) scaffolds active YES1 (preferentially in its kinase-active, αC helix-in conformation) in the cytoplasm, enhancing YAP1 phosphorylation at Y357. Scrib HaloPROTAC degradation attenuates YAP1-Y357 phosphorylation, and Snail-induced Scrib mislocalization promotes YAP1 nuclear localization independently of Hippo-regulated YAP-S127 phosphorylation.","method":"HaloTag genome engineering, PROTAC degradation, affinity purification mass spectrometry, phosphorylation assays, confocal imaging","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PROTAC-mediated protein degradation with functional phosphorylation readout, AP-MS identification of YES1-Scrib interaction, single lab, multiple orthogonal methods","pmids":["33730553"],"is_preprint":false},{"year":2013,"finding":"YES1 activation in mouse pachytene spermatocytes in response to heat stress is anti-apoptotic, operating via the ERK/MTA1/p53 cascade. Co-culture with Sertoli cells enhances heat stress-induced YES1 activation through paracrine signaling. Pharmacological inhibition of YES1 with SU6656 dramatically increased heat stress-induced apoptosis.","method":"Primary cell culture, YES1 selective inhibitor SU6656, co-culture with Sertoli cells, apoptosis assays, immunoblotting for ERK/MTA1/p53","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with defined pathway readout (ERK/MTA1/p53), single lab, primary cell system","pmids":["24132961"],"is_preprint":false},{"year":2021,"finding":"YES1 phosphorylates OCT1 (organic cation transporter 1) on tyrosine residues, and YES1 kinase inhibition by dasatinib suppresses OCT1 transporter activity both in cells and in mice, as demonstrated by modulation of the OCT1 biomarker isobutyryl L-carnitine.","method":"Phospho-proteomics screen, genetic and pharmacological inhibition of YES1 (dasatinib), targeted metabolomics for OCT1 biomarker, in vivo mouse studies","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased phospho-proteomics identification plus pharmacological/genetic validation, in vivo confirmation, single lab","pmids":["33790797"],"is_preprint":false},{"year":2019,"finding":"Etv2 (an Ets transcription factor) directly binds to the promoter region of YES1 and functions as a transcriptional regulator of YES1 during embryogenesis. Etv2 induction increases YES1 transcript levels dose-dependently, and YES1 is reduced in Etv2 null embryoid bodies.","method":"ChIP-seq, RNA-seq, doxycycline-inducible Etv2 ES/EB system, luciferase reporter assay, promoter binding assays, single-cell RNA-seq","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus inducible expression and loss-of-function systems, multiple orthogonal methods, single lab","pmids":["31278282"],"is_preprint":false},{"year":2024,"finding":"ACSL3 interacts with YES1 and suppresses its activation (phosphorylation at Tyr419). Decreased active YES1 consequently inhibits YAP1 nuclear colocalization and transcriptional complex formation in breast cancer cells.","method":"Co-immunoprecipitation (ACSL3-YES1 interaction), phosphorylation assays (Tyr419), nuclear fractionation, gain- and loss-of-function assays, in vitro and in vivo experiments","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding plus functional phosphorylation readout with downstream YAP1 nuclear localization, single lab, two orthogonal methods","pmids":["38953696"],"is_preprint":false},{"year":2022,"finding":"YES1 promotes YAP1 nuclear translocation and drives gastric cancer cell proliferation. In the linc01133/miR-145-5p/YES1 axis, YES1 upregulation increases CDK4, CDK6, and cyclin D1 to promote G1-S phase transition via YAP1 nuclear translocation.","method":"ceRNA sponging assays, luciferase reporter assay, YES1 knockdown/overexpression, nuclear fractionation, cell cycle analysis","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, YES1's role in YAP1 nuclear translocation established only indirectly via ceRNA pathway, no direct kinase assay","pmids":["35017464"],"is_preprint":false},{"year":2020,"finding":"YES1 amplification leads to resistance to trastuzumab-emtansine (T-DM1) and cross-resistance to all types of HER2-targeted drugs. YES1 activates multiple proliferation-related signaling pathways including EGFR, PI3K, and MAPK. Inhibiting YES1 with dasatinib sensitizes resistant cells in vitro and in vivo.","method":"Acquired resistance modeling with escalating T-DM1, gene copy number analysis, siRNA knockdown and stable overexpression, western blotting for signaling pathways, xenograft models","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological manipulation, in vivo validation, signaling pathway identification by immunoblotting, single lab","pmids":["32572172"],"is_preprint":false},{"year":2020,"finding":"YES1 amplification confers resistance to neratinib (HER2 TKI) in HER2-amplified breast and lung cancers. YES1 activation leads to downregulation of HER2, AKT, and MAPK signaling upon combined dasatinib treatment. Knockdown of YES1 by siRNA or pharmacological inhibition by dasatinib restored neratinib sensitivity.","method":"Acquisition of drug resistance by escalating drug exposure, copy number analysis, siRNA knockdown, pharmacological inhibition, in vitro and in vivo (xenograft) studies, signaling pathway analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological approaches, in vivo validation, signaling pathway readout, single lab","pmids":["31856375"],"is_preprint":false},{"year":2022,"finding":"YES1 inhibition in SCLC cells causes alterations in the replisome and DNA repair processes, conferring sensitivity to irradiation, in addition to reducing proliferation and inducing apoptosis. YES1 protein is detectable in plasma exosomes from patients and mouse models.","method":"Genetic depletion (CRISPR/shRNA), pharmacological inhibition (CH6953755/dasatinib), organoid models, patient-derived xenografts, transcriptomic analysis of replisome/DNA repair pathways, irradiation sensitivity assays","journal":"Journal of thoracic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological interventions, in vivo models, mechanistic pathway (replisome/DNA repair) identified by transcriptomics, single lab","pmids":["35988891"],"is_preprint":false},{"year":2013,"finding":"miR-210 directly targets the 3'UTR of YES1 mRNA and reduces YES1 protein expression, thereby suppressing hepatocellular carcinoma cell proliferation and cell cycle progression.","method":"Luciferase reporter assay (3'UTR binding), siRNA knockdown of YES1, miR-210 mimic/inhibitor transfection, flow cytometry cell cycle analysis, proliferation assay","journal":"World journal of gastroenterology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase validation of 3'UTR targeting plus downstream functional assay, single lab, indirect mechanism","pmids":["26676187"],"is_preprint":false}],"current_model":"YES1 is a non-receptor Src family tyrosine kinase that promotes cell proliferation, survival, invasion, and drug resistance by phosphorylating downstream substrates including VE-cadherin (regulating endothelial junction turnover), ANXA2 (at Tyr24, downstream of EphA2), OCT1, and the transcriptional coactivators YAP/TAZ (promoting their nuclear accumulation and transcriptional activity); its kinase activity is regulated by Ca2+-dependent association with inhibitory proteins, by membrane anchoring driven by the peptide SMIM30, and by upstream transcriptional control via the Etv2 transcription factor, while the mislocalized scaffold protein Scrib recruits active YES1 to enhance YAP1-Y357 phosphorylation independently of canonical Hippo signaling."},"narrative":{"mechanistic_narrative":"YES1 is a non-receptor Src-family tyrosine kinase that drives cell proliferation, survival, migration, and oncogenic transformation by phosphorylating distinct substrates in a manner that is non-redundant with c-Src [PMID:37936984, PMID:16400523]. A recurrent output of YES1 signaling is control of the transcriptional coactivators YAP/TAZ: YES1 phosphorylates YAP/TAZ and promotes their nuclear accumulation and transcriptional activity, and these effectors are required for YES1-dependent oncogenic transformation of hepatocytes [PMID:35041461, PMID:31391186]. YES1 also phosphorylates ANXA2 at Tyr24 downstream of the EphA2 receptor to promote invasion [PMID:33941853], VE-cadherin to govern endothelial junction turnover, endocytosis, and vascular integrity in a flow-dependent manner [PMID:37936984], and the transporter OCT1 to regulate its activity [PMID:33790797]. Beyond YAP/TAZ, YES1 engages mTOR signaling to drive lung tumor growth and metastasis [PMID:31166114]. Its kinase activity is set by both inhibitory and activating inputs: Ca2+-dependent association with inhibitory proteins suppresses c-Yes activity (distinct from c-Src) [PMID:8246968], ACSL3 binds YES1 and suppresses its Tyr419 activation [PMID:38953696], membrane anchoring by the SMIM30 peptide promotes its phosphorylation [PMID:32461121], and the mislocalized scaffold Scrib recruits the active, αC-helix-in conformer to enhance YAP1-Y357 phosphorylation independently of canonical Hippo signaling [PMID:33730553]; transcriptionally, the Ets factor Etv2 directly binds the YES1 promoter to control its expression during embryogenesis [PMID:31278282]. Clinically, YES1 amplification confers sensitivity to the SFK inhibitor dasatinib and drives resistance to HER2-targeted therapies, which dasatinib can reverse [PMID:31166114, PMID:32572172, PMID:31856375].","teleology":[{"year":1993,"claim":"Established that c-Yes is regulated differently from its closest relative c-Src, answering whether SFK members are functionally interchangeable.","evidence":"in vitro kinase assays, immunoprecipitation, and Ca2+-supplemented extracts with EGTA reversal in mammalian cells","pmids":["8246968"],"confidence":"High","gaps":["The identity of the Ca2+-dependent inhibitory protein(s) was not molecularly defined","Physiological contexts triggering this Ca2+-dependent inhibition were not established"]},{"year":2005,"claim":"Showed YES1 has cellular roles non-redundant with c-Src by defining specific requirements in West Nile virus maturation and in BLT1-driven neutrophil degranulation.","evidence":"RNAi knockdown distinguishing Yes from Src, PP2/PP1 inhibitors, dominant-negative dynamin, EndoH digestion, and selective kinase activity assays","pmids":["16140770","15749899"],"confidence":"High","gaps":["Direct YES1 substrates in viral glycoprotein trafficking and neutrophil degranulation were not identified","How endocytosis couples to selective Yes activation was not resolved"]},{"year":2006,"claim":"Demonstrated a unique YES1 function in VEGF-induced endothelial migration distinct from Src and Fyn, refining the division of labor among SFKs in angiogenesis.","evidence":"selective RNAi of individual SFKs with migration, proliferation, and tube formation assays in retinal microvascular endothelial cells","pmids":["16400523"],"confidence":"Medium","gaps":["No substrate linking YES1 to migration machinery was identified","Single lab; mechanism downstream of VEGF receptor not mapped"]},{"year":2013,"claim":"Extended YES1 function to anti-apoptotic stress signaling in germ cells and introduced a miRNA-based control of YES1 abundance.","evidence":"SU6656 inhibition with ERK/MTA1/p53 readout in spermatocytes, and luciferase 3'UTR validation of miR-210 targeting in HCC cells","pmids":["24132961","26676187"],"confidence":"Low","gaps":["miR-210 link is indirect with no direct kinase assay","Whether YES1 directly phosphorylates ERK-pathway components was not tested"]},{"year":2019,"claim":"Identified YAP1 as a downstream effector of YES1 kinase activity and mTOR as a parallel oncogenic output, defining the core proliferative circuitry exploited in YES1-amplified cancers.","evidence":"CRISPR/shRNA depletion, YES1 inhibitor CH6953755, nuclear fractionation, phosphorylation and reporter assays, and PDX models in lung cancer","pmids":["31166114","31391186"],"confidence":"High","gaps":["Whether YES1 directly versus indirectly phosphorylates YAP1 was not fully resolved at this stage","Relative contributions of YAP1 versus mTOR arms not dissected"]},{"year":2019,"claim":"Placed YES1 under direct transcriptional control of Etv2, establishing how YES1 expression is set during development.","evidence":"ChIP-seq, doxycycline-inducible Etv2 ES/EB system, luciferase reporter, and Etv2-null embryoid bodies","pmids":["31278282"],"confidence":"Medium","gaps":["Functional consequence of Etv2-driven YES1 expression in vivo not established","Other transcriptional regulators of YES1 not surveyed"]},{"year":2020,"claim":"Defined a membrane-anchoring activation mechanism via the SMIM30 micropeptide and clarified YES1 amplification as a driver of resistance to HER2-targeted therapy.","evidence":"RIP-seq, co-IP/pulldown with MAPK readout in HCC; T-DM1 acquired-resistance modeling with copy number analysis, siRNA, and dasatinib rescue in xenografts","pmids":["32461121","32572172"],"confidence":"Medium","gaps":["SMIM30 binding interface and selectivity for YES1 versus SRC not structurally defined","Which downstream pathway (EGFR/PI3K/MAPK) is rate-limiting for resistance not isolated"]},{"year":2021,"claim":"Mapped specific YES1 substrate-effector relationships: ANXA2-Tyr24 downstream of EphA2, OCT1 tyrosine phosphorylation, and Scrib-scaffolded YAP1-Y357 phosphorylation independent of Hippo.","evidence":"co-IP, Tyr24F mutagenesis and invasion assays (ANXA2); phospho-proteomics with dasatinib and in vivo biomarker (OCT1); HaloPROTAC degradation, AP-MS, and conformation-selective binding (Scrib)","pmids":["33941853","33790797","33730553"],"confidence":"High","gaps":["Generality of EphA2-YES1-ANXA2 axis beyond gastric cancer not established","Direct kinase-substrate reconstitution for OCT1 and YAP1-Y357 not performed","How Scrib selects the active YES1 conformer mechanistically unresolved"]},{"year":2022,"claim":"Solidified YES1 as a YAP/TAZ-activating kinase in hepatocytes and endothelial-junction kinase, and revealed a replisome/DNA-repair vulnerability conferring radiosensitivity.","evidence":"transgenic activated-YES1 mouse hepatocytes with epistasis (HCC); EC-specific YES1 knockout mice with live imaging and VE-cadherin internalization; CRISPR/shRNA, CH6953755/dasatinib, organoids and PDX with transcriptomics (SCLC)","pmids":["35041461","37936984","35988891"],"confidence":"High","gaps":["Direct YES1 substrate in the replisome/DNA-repair response not identified","Mechanism linking junctional VE-cadherin phosphorylation to collective migration not fully resolved"]},{"year":2024,"claim":"Identified ACSL3 as a negative regulator of YES1 activation, adding a brake on the YES1-YAP1 axis.","evidence":"co-IP, Tyr419 phosphorylation assays, nuclear fractionation, and gain/loss-of-function in breast cancer cells and in vivo","pmids":["38953696"],"confidence":"Medium","gaps":["Whether ACSL3 directly competes with activating inputs or sequesters YES1 not defined","Single lab; reciprocal validation limited"]},{"year":null,"claim":"Whether the multiple activating and inhibitory inputs (SMIM30, Scrib, EphA2, Ca2+-proteins, ACSL3) converge on a single conformational switch governing YES1 substrate selection across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of YES1 activation states","Substrate-selection rules distinguishing YAP/TAZ versus VE-cadherin versus ANXA2 contexts not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,10,12]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,3,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,16,17,18]}],"complexes":[],"partners":["SMIM30","ANXA2","YAP1","TAZ","VE-CADHERIN","SCRIB","ACSL3","EPHA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07947","full_name":"Tyrosine-protein kinase Yes","aliases":["Proto-oncogene c-Yes","p61-Yes"],"length_aa":543,"mass_kda":60.8,"function":"Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGFR, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin-dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis. Catalyzes phosphorylation of organic cation transporter OCT2 which induces its transport activity (PubMed:26979622)","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytosol; Cell junction","url":"https://www.uniprot.org/uniprotkb/P07947/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YES1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000176105","cell_line_id":"CID001307","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"RCBTB2","stoichiometry":0.2},{"gene":"STX4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001307","total_profiled":1310},"omim":[{"mim_id":"619258","title":"SPERMATOGENIC FAILURE 53; SPGF53","url":"https://www.omim.org/entry/619258"},{"mim_id":"619251","title":"ACTIN-LIKE 9; 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/31011480","citation_count":15,"is_preprint":false},{"pmid":"34616865","id":"PMC_34616865","title":"Yes, MAM!","date":"2021","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34616865","citation_count":14,"is_preprint":false},{"pmid":"38770136","id":"PMC_38770136","title":"The role of yes activated protein (YAP) in melanoma metastasis.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38770136","citation_count":14,"is_preprint":false},{"pmid":"38338729","id":"PMC_38338729","title":"Emerging Roles of YES1 in Cancer: The Putative Target in Drug Resistance.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38338729","citation_count":14,"is_preprint":false},{"pmid":"37100374","id":"PMC_37100374","title":"Yes-associated protein nuclear translocation promotes anabolic activity in human articular chondrocytes.","date":"2023","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/37100374","citation_count":14,"is_preprint":false},{"pmid":"30566575","id":"PMC_30566575","title":"RNA-binding protein QKI regulates contact inhibition via Yes-associate protein in ccRCC.","date":"2019","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/30566575","citation_count":14,"is_preprint":false},{"pmid":"35041461","id":"PMC_35041461","title":"Signaling by the tyrosine kinase Yes promotes liver cancer development.","date":"2022","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/35041461","citation_count":14,"is_preprint":false},{"pmid":"36247165","id":"PMC_36247165","title":"Intermittent compressive force regulates human periodontal ligament cell behavior via yes-associated protein.","date":"2022","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/36247165","citation_count":14,"is_preprint":false},{"pmid":"35601164","id":"PMC_35601164","title":"Yes-associated protein promotes endothelial-to-mesenchymal transition of endothelial cells in choroidal neovascularization fibrosis.","date":"2022","source":"International journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/35601164","citation_count":14,"is_preprint":false},{"pmid":"39505660","id":"PMC_39505660","title":"Yes, polygenic sex determination is a thing!","date":"2024","source":"Trends in genetics : TIG","url":"https://pubmed.ncbi.nlm.nih.gov/39505660","citation_count":13,"is_preprint":false},{"pmid":"35686503","id":"PMC_35686503","title":"Circ_0081143 Contributes to Gastric Cancer Malignant Development and Doxorubicin Resistance by Elevating the Expression of YES1 by Targeting mziR-129-2-3p.","date":"2022","source":"Gut and liver","url":"https://pubmed.ncbi.nlm.nih.gov/35686503","citation_count":13,"is_preprint":false},{"pmid":"33907466","id":"PMC_33907466","title":"Matrine Regulates Proliferation, Apoptosis, Cell Cycle, Migration, and Invasion of Non-Small Cell Lung Cancer Cells Through the circFUT8/miR-944/YES1 Axis.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33907466","citation_count":13,"is_preprint":false},{"pmid":"31278282","id":"PMC_31278282","title":"Etv2 transcriptionally regulates Yes1 and promotes cell proliferation during embryogenesis.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31278282","citation_count":12,"is_preprint":false},{"pmid":"36675179","id":"PMC_36675179","title":"Yes-Associated Protein and Transcriptional Coactivator with PDZ-Binding Motif in Cardiovascular Diseases.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36675179","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49705,"output_tokens":5045,"usd":0.112395,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13441,"output_tokens":3848,"usd":0.081702,"stage2_stop_reason":"end_turn"},"total_usd":0.194097,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"The small peptide SMIM30, encoded by lncRNA LINC00998, drives membrane anchoring of YES1 (and SRC) by directly binding to them, thereby promoting YES1 phosphorylation and activating the downstream MAPK signaling pathway in hepatocellular carcinoma cells.\",\n      \"method\": \"RIP-seq, co-immunoprecipitation/pulldown, functional overexpression/knockdown assays, MAPK pathway readout\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, binding demonstrated by pulldown/co-IP and functional validation by OE/KD with pathway readout, two orthogonal approaches\",\n      \"pmids\": [\"32461121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YES1 (c-Yes tyrosine kinase), rather than Src, is specifically localized at endothelial cell junctions where it becomes activated in a flow-dependent manner, phosphorylates VE-cadherin to regulate its constitutive turnover and endocytosis, and thereby maintains endothelial junction plasticity and vascular integrity. EC-specific YES1 deletion suppressed VE-cadherin phosphorylation and arrested VE-cadherin at junctions, causing loss of collective migration and exaggerated agonist-induced leakage.\",\n      \"method\": \"Endothelial cell-specific YES1 knockout mice, live imaging, phosphorylation assays, VE-cadherin internalization assays, comparison with Src-deficient ECs\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype, multiple orthogonal readouts (localization, phosphorylation, endocytosis, migration, leakage), rigorous controls with Src-KO comparison\",\n      \"pmids\": [\"37936984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YES1 is a substrate and effector of the EphA2 receptor tyrosine kinase: EphA2 activates YES1, which then phosphorylates ANXA2 at Tyr24, leading to ANXA2 activation and increased nuclear distribution of ANXA2 in gastric cancer cells, promoting invasion and migration.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression, site-directed mutagenesis (ANXA2 Tyr24F mutant), in vitro invasion/migration assays, mouse xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted pathway with mutagenesis (Tyr24F rescue), reciprocal functional assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33941853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YES1 signaling promotes nuclear accumulation and transcriptional activity of YAP and TAZ in hepatocellular carcinoma cells and liver tumors. YES1 phosphorylates YAP/TAZ, driving their nuclear accumulation, and YAP/TAZ are required effectors of YES1-dependent oncogenic transformation of hepatocytes.\",\n      \"method\": \"Genetic (transgenic expression of activated YES1 in mouse hepatocytes) and pharmacological interventions, phosphorylation assays, nuclear fractionation, epistasis experiments in cellular and mouse HCC models\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological approaches, in vivo mouse models, epistasis placing YAP/TAZ downstream of YES1, replicated across cellular and animal models\",\n      \"pmids\": [\"35041461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YES1 drives lung cancer growth and metastasis primarily through mTOR signaling. YES1 genetic depletion (CRISPR/Cas9) significantly reduced tumor growth and metastasis in preclinical models, and YES1 gene amplification confers high sensitivity to the SFK inhibitor dasatinib.\",\n      \"method\": \"CRISPR/Cas9 knockout, in vivo tumor and metastasis models, patient-derived xenografts, mTOR signaling pathway analysis by immunoblotting\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR/Cas9 loss-of-function, in vivo models including patient-derived xenografts, defined signaling pathway (mTOR), multiple complementary approaches\",\n      \"pmids\": [\"31166114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YES1 regulates YAP1 transcriptional activity by controlling YAP1 nuclear translocation and serine phosphorylation in YES1-amplified cancer cells, placing YAP1 as a downstream effector of YES1 kinase activity.\",\n      \"method\": \"shRNA knockdown, YES1-specific kinase inhibitor (CH6953755), nuclear fractionation, phosphorylation assays, transcriptional reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, pharmacological and genetic inhibition, multiple assays (nuclear fractionation, phosphorylation, reporter), but no direct in vitro reconstitution\",\n      \"pmids\": [\"31391186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"c-Yes kinase is inactivated by elevation of intracellular calcium levels through a Ca2+-dependent association with specific cellular proteins, which forms complexes not seen with c-Src, and one of these proteins can inhibit c-Yes kinase activity in vitro. This regulation is distinct from c-Src, which is activated under the same conditions.\",\n      \"method\": \"In vitro kinase assays, immunoprecipitation, gradient sedimentation, Ca2+-supplemented cell extracts, protein tyrosine phosphatase treatment, EGTA reversal\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of inhibition, EGTA reversal, multiple cell types tested, direct comparison to c-Src\",\n      \"pmids\": [\"8246968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Yes kinase activity is specifically required for West Nile virus particle maturation: RNAi knockdown of c-Yes (but not c-Src) reduces virus yield, and Yes kinase activity is needed for the viral envelope glycoprotein E to transit beyond the endoplasmic reticulum, enabling virion egress through the secretory pathway.\",\n      \"method\": \"RNA interference knockdown, SFK inhibitor PP2 treatment, endoglycosidase H digestion of viral envelope glycoprotein, electron microscopy, viral titer assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific RNAi knockdown distinguishing YES1 from Src, orthogonal mechanistic assay (EndoH digestion), EM confirmation, multiple complementary approaches\",\n      \"pmids\": [\"16140770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"YES1 (c-Yes) plays a unique and non-redundant role in VEGF-mediated endothelial cell migration: selective knockdown of Yes (but not Src or Fyn) by RNAi significantly decreased VEGF-induced cell migration in human retinal microvascular endothelial cells, while all three kinases were required for VEGF mitogenic signaling.\",\n      \"method\": \"RNA interference selective knockdown of individual Src family kinases, VEGF-induced migration assay, proliferation assay, tube formation assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective RNAi distinguishing YES1 from Src/Fyn, multiple functional readouts, single lab\",\n      \"pmids\": [\"16400523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Yes kinase is specifically activated downstream of the leukotriene B4 high-affinity receptor BLT1 following LTB4 stimulation of neutrophils, and BLT1 endocytosis is required for Yes kinase activation. Yes kinase activation (but not c-Src or other SFKs) is required for LTB4-induced neutrophil degranulation.\",\n      \"method\": \"Src family kinase inhibitor PP1, dominant-negative dynamin (endocytosis block), selective kinase activity assays for individual SFKs, degranulation enzyme release assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and dominant-negative genetic approach, selective kinase activity assays distinguishing YES1 from other SFKs, single lab\",\n      \"pmids\": [\"15749899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mislocalized Scribble (Scrib) scaffolds active YES1 (preferentially in its kinase-active, αC helix-in conformation) in the cytoplasm, enhancing YAP1 phosphorylation at Y357. Scrib HaloPROTAC degradation attenuates YAP1-Y357 phosphorylation, and Snail-induced Scrib mislocalization promotes YAP1 nuclear localization independently of Hippo-regulated YAP-S127 phosphorylation.\",\n      \"method\": \"HaloTag genome engineering, PROTAC degradation, affinity purification mass spectrometry, phosphorylation assays, confocal imaging\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PROTAC-mediated protein degradation with functional phosphorylation readout, AP-MS identification of YES1-Scrib interaction, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33730553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YES1 activation in mouse pachytene spermatocytes in response to heat stress is anti-apoptotic, operating via the ERK/MTA1/p53 cascade. Co-culture with Sertoli cells enhances heat stress-induced YES1 activation through paracrine signaling. Pharmacological inhibition of YES1 with SU6656 dramatically increased heat stress-induced apoptosis.\",\n      \"method\": \"Primary cell culture, YES1 selective inhibitor SU6656, co-culture with Sertoli cells, apoptosis assays, immunoblotting for ERK/MTA1/p53\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with defined pathway readout (ERK/MTA1/p53), single lab, primary cell system\",\n      \"pmids\": [\"24132961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YES1 phosphorylates OCT1 (organic cation transporter 1) on tyrosine residues, and YES1 kinase inhibition by dasatinib suppresses OCT1 transporter activity both in cells and in mice, as demonstrated by modulation of the OCT1 biomarker isobutyryl L-carnitine.\",\n      \"method\": \"Phospho-proteomics screen, genetic and pharmacological inhibition of YES1 (dasatinib), targeted metabolomics for OCT1 biomarker, in vivo mouse studies\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased phospho-proteomics identification plus pharmacological/genetic validation, in vivo confirmation, single lab\",\n      \"pmids\": [\"33790797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Etv2 (an Ets transcription factor) directly binds to the promoter region of YES1 and functions as a transcriptional regulator of YES1 during embryogenesis. Etv2 induction increases YES1 transcript levels dose-dependently, and YES1 is reduced in Etv2 null embryoid bodies.\",\n      \"method\": \"ChIP-seq, RNA-seq, doxycycline-inducible Etv2 ES/EB system, luciferase reporter assay, promoter binding assays, single-cell RNA-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus inducible expression and loss-of-function systems, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31278282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSL3 interacts with YES1 and suppresses its activation (phosphorylation at Tyr419). Decreased active YES1 consequently inhibits YAP1 nuclear colocalization and transcriptional complex formation in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (ACSL3-YES1 interaction), phosphorylation assays (Tyr419), nuclear fractionation, gain- and loss-of-function assays, in vitro and in vivo experiments\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding plus functional phosphorylation readout with downstream YAP1 nuclear localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"38953696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YES1 promotes YAP1 nuclear translocation and drives gastric cancer cell proliferation. In the linc01133/miR-145-5p/YES1 axis, YES1 upregulation increases CDK4, CDK6, and cyclin D1 to promote G1-S phase transition via YAP1 nuclear translocation.\",\n      \"method\": \"ceRNA sponging assays, luciferase reporter assay, YES1 knockdown/overexpression, nuclear fractionation, cell cycle analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, YES1's role in YAP1 nuclear translocation established only indirectly via ceRNA pathway, no direct kinase assay\",\n      \"pmids\": [\"35017464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YES1 amplification leads to resistance to trastuzumab-emtansine (T-DM1) and cross-resistance to all types of HER2-targeted drugs. YES1 activates multiple proliferation-related signaling pathways including EGFR, PI3K, and MAPK. Inhibiting YES1 with dasatinib sensitizes resistant cells in vitro and in vivo.\",\n      \"method\": \"Acquired resistance modeling with escalating T-DM1, gene copy number analysis, siRNA knockdown and stable overexpression, western blotting for signaling pathways, xenograft models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological manipulation, in vivo validation, signaling pathway identification by immunoblotting, single lab\",\n      \"pmids\": [\"32572172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YES1 amplification confers resistance to neratinib (HER2 TKI) in HER2-amplified breast and lung cancers. YES1 activation leads to downregulation of HER2, AKT, and MAPK signaling upon combined dasatinib treatment. Knockdown of YES1 by siRNA or pharmacological inhibition by dasatinib restored neratinib sensitivity.\",\n      \"method\": \"Acquisition of drug resistance by escalating drug exposure, copy number analysis, siRNA knockdown, pharmacological inhibition, in vitro and in vivo (xenograft) studies, signaling pathway analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological approaches, in vivo validation, signaling pathway readout, single lab\",\n      \"pmids\": [\"31856375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YES1 inhibition in SCLC cells causes alterations in the replisome and DNA repair processes, conferring sensitivity to irradiation, in addition to reducing proliferation and inducing apoptosis. YES1 protein is detectable in plasma exosomes from patients and mouse models.\",\n      \"method\": \"Genetic depletion (CRISPR/shRNA), pharmacological inhibition (CH6953755/dasatinib), organoid models, patient-derived xenografts, transcriptomic analysis of replisome/DNA repair pathways, irradiation sensitivity assays\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological interventions, in vivo models, mechanistic pathway (replisome/DNA repair) identified by transcriptomics, single lab\",\n      \"pmids\": [\"35988891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-210 directly targets the 3'UTR of YES1 mRNA and reduces YES1 protein expression, thereby suppressing hepatocellular carcinoma cell proliferation and cell cycle progression.\",\n      \"method\": \"Luciferase reporter assay (3'UTR binding), siRNA knockdown of YES1, miR-210 mimic/inhibitor transfection, flow cytometry cell cycle analysis, proliferation assay\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase validation of 3'UTR targeting plus downstream functional assay, single lab, indirect mechanism\",\n      \"pmids\": [\"26676187\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YES1 is a non-receptor Src family tyrosine kinase that promotes cell proliferation, survival, invasion, and drug resistance by phosphorylating downstream substrates including VE-cadherin (regulating endothelial junction turnover), ANXA2 (at Tyr24, downstream of EphA2), OCT1, and the transcriptional coactivators YAP/TAZ (promoting their nuclear accumulation and transcriptional activity); its kinase activity is regulated by Ca2+-dependent association with inhibitory proteins, by membrane anchoring driven by the peptide SMIM30, and by upstream transcriptional control via the Etv2 transcription factor, while the mislocalized scaffold protein Scrib recruits active YES1 to enhance YAP1-Y357 phosphorylation independently of canonical Hippo signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YES1 is a non-receptor Src-family tyrosine kinase that drives cell proliferation, survival, migration, and oncogenic transformation by phosphorylating distinct substrates in a manner that is non-redundant with c-Src [#1, #8]. A recurrent output of YES1 signaling is control of the transcriptional coactivators YAP/TAZ: YES1 phosphorylates YAP/TAZ and promotes their nuclear accumulation and transcriptional activity, and these effectors are required for YES1-dependent oncogenic transformation of hepatocytes [#3, #5]. YES1 also phosphorylates ANXA2 at Tyr24 downstream of the EphA2 receptor to promote invasion [#2], VE-cadherin to govern endothelial junction turnover, endocytosis, and vascular integrity in a flow-dependent manner [#1], and the transporter OCT1 to regulate its activity [#12]. Beyond YAP/TAZ, YES1 engages mTOR signaling to drive lung tumor growth and metastasis [#4]. Its kinase activity is set by both inhibitory and activating inputs: Ca2+-dependent association with inhibitory proteins suppresses c-Yes activity (distinct from c-Src) [#6], ACSL3 binds YES1 and suppresses its Tyr419 activation [#14], membrane anchoring by the SMIM30 peptide promotes its phosphorylation [#0], and the mislocalized scaffold Scrib recruits the active, \\u03b1C-helix-in conformer to enhance YAP1-Y357 phosphorylation independently of canonical Hippo signaling [#10]; transcriptionally, the Ets factor Etv2 directly binds the YES1 promoter to control its expression during embryogenesis [#13]. Clinically, YES1 amplification confers sensitivity to the SFK inhibitor dasatinib and drives resistance to HER2-targeted therapies, which dasatinib can reverse [#4, #16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that c-Yes is regulated differently from its closest relative c-Src, answering whether SFK members are functionally interchangeable.\",\n      \"evidence\": \"in vitro kinase assays, immunoprecipitation, and Ca2+-supplemented extracts with EGTA reversal in mammalian cells\",\n      \"pmids\": [\"8246968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The identity of the Ca2+-dependent inhibitory protein(s) was not molecularly defined\", \"Physiological contexts triggering this Ca2+-dependent inhibition were not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed YES1 has cellular roles non-redundant with c-Src by defining specific requirements in West Nile virus maturation and in BLT1-driven neutrophil degranulation.\",\n      \"evidence\": \"RNAi knockdown distinguishing Yes from Src, PP2/PP1 inhibitors, dominant-negative dynamin, EndoH digestion, and selective kinase activity assays\",\n      \"pmids\": [\"16140770\", \"15749899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct YES1 substrates in viral glycoprotein trafficking and neutrophil degranulation were not identified\", \"How endocytosis couples to selective Yes activation was not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated a unique YES1 function in VEGF-induced endothelial migration distinct from Src and Fyn, refining the division of labor among SFKs in angiogenesis.\",\n      \"evidence\": \"selective RNAi of individual SFKs with migration, proliferation, and tube formation assays in retinal microvascular endothelial cells\",\n      \"pmids\": [\"16400523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate linking YES1 to migration machinery was identified\", \"Single lab; mechanism downstream of VEGF receptor not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended YES1 function to anti-apoptotic stress signaling in germ cells and introduced a miRNA-based control of YES1 abundance.\",\n      \"evidence\": \"SU6656 inhibition with ERK/MTA1/p53 readout in spermatocytes, and luciferase 3'UTR validation of miR-210 targeting in HCC cells\",\n      \"pmids\": [\"24132961\", \"26676187\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"miR-210 link is indirect with no direct kinase assay\", \"Whether YES1 directly phosphorylates ERK-pathway components was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified YAP1 as a downstream effector of YES1 kinase activity and mTOR as a parallel oncogenic output, defining the core proliferative circuitry exploited in YES1-amplified cancers.\",\n      \"evidence\": \"CRISPR/shRNA depletion, YES1 inhibitor CH6953755, nuclear fractionation, phosphorylation and reporter assays, and PDX models in lung cancer\",\n      \"pmids\": [\"31166114\", \"31391186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YES1 directly versus indirectly phosphorylates YAP1 was not fully resolved at this stage\", \"Relative contributions of YAP1 versus mTOR arms not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed YES1 under direct transcriptional control of Etv2, establishing how YES1 expression is set during development.\",\n      \"evidence\": \"ChIP-seq, doxycycline-inducible Etv2 ES/EB system, luciferase reporter, and Etv2-null embryoid bodies\",\n      \"pmids\": [\"31278282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Etv2-driven YES1 expression in vivo not established\", \"Other transcriptional regulators of YES1 not surveyed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a membrane-anchoring activation mechanism via the SMIM30 micropeptide and clarified YES1 amplification as a driver of resistance to HER2-targeted therapy.\",\n      \"evidence\": \"RIP-seq, co-IP/pulldown with MAPK readout in HCC; T-DM1 acquired-resistance modeling with copy number analysis, siRNA, and dasatinib rescue in xenografts\",\n      \"pmids\": [\"32461121\", \"32572172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SMIM30 binding interface and selectivity for YES1 versus SRC not structurally defined\", \"Which downstream pathway (EGFR/PI3K/MAPK) is rate-limiting for resistance not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped specific YES1 substrate-effector relationships: ANXA2-Tyr24 downstream of EphA2, OCT1 tyrosine phosphorylation, and Scrib-scaffolded YAP1-Y357 phosphorylation independent of Hippo.\",\n      \"evidence\": \"co-IP, Tyr24F mutagenesis and invasion assays (ANXA2); phospho-proteomics with dasatinib and in vivo biomarker (OCT1); HaloPROTAC degradation, AP-MS, and conformation-selective binding (Scrib)\",\n      \"pmids\": [\"33941853\", \"33790797\", \"33730553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of EphA2-YES1-ANXA2 axis beyond gastric cancer not established\", \"Direct kinase-substrate reconstitution for OCT1 and YAP1-Y357 not performed\", \"How Scrib selects the active YES1 conformer mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Solidified YES1 as a YAP/TAZ-activating kinase in hepatocytes and endothelial-junction kinase, and revealed a replisome/DNA-repair vulnerability conferring radiosensitivity.\",\n      \"evidence\": \"transgenic activated-YES1 mouse hepatocytes with epistasis (HCC); EC-specific YES1 knockout mice with live imaging and VE-cadherin internalization; CRISPR/shRNA, CH6953755/dasatinib, organoids and PDX with transcriptomics (SCLC)\",\n      \"pmids\": [\"35041461\", \"37936984\", \"35988891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct YES1 substrate in the replisome/DNA-repair response not identified\", \"Mechanism linking junctional VE-cadherin phosphorylation to collective migration not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ACSL3 as a negative regulator of YES1 activation, adding a brake on the YES1-YAP1 axis.\",\n      \"evidence\": \"co-IP, Tyr419 phosphorylation assays, nuclear fractionation, and gain/loss-of-function in breast cancer cells and in vivo\",\n      \"pmids\": [\"38953696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ACSL3 directly competes with activating inputs or sequesters YES1 not defined\", \"Single lab; reciprocal validation limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the multiple activating and inhibitory inputs (SMIM30, Scrib, EphA2, Ca2+-proteins, ACSL3) converge on a single conformational switch governing YES1 substrate selection across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of YES1 activation states\", \"Substrate-selection rules distinguishing YAP/TAZ versus VE-cadherin versus ANXA2 contexts not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 10, 12]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 16, 17, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SMIM30\", \"ANXA2\", \"YAP1\", \"TAZ\", \"VE-cadherin\", \"Scrib\", \"ACSL3\", \"EphA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}