{"gene":"YES1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":1986,"finding":"YES1 (c-yes/SYN) encodes a protein-tyrosine kinase structurally similar to v-yes and human c-Src, identifying it as a member of the Src family of tyrosine kinases","method":"Molecular cloning and nucleotide sequence analysis of cDNA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct molecular cloning and sequence analysis establishing enzymatic class","pmids":["3526330"],"is_preprint":false},{"year":1993,"finding":"c-Yes kinase is inactivated by elevation of intracellular calcium through a Ca2+-dependent association with specific cellular proteins that inhibit its kinase activity; this mechanism is distinct from c-Src regulation and independent of protein kinase C","method":"In vitro kinase activity assays, gradient sedimentation, co-immunoprecipitation, in vitro reconstitution with Ca2+-supplemented cell extracts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution plus multiple orthogonal methods in a single study","pmids":["8246968"],"is_preprint":false},{"year":1995,"finding":"c-Yes tyrosine kinase activity is elevated in colonic adenomas at greatest risk for cancer (villous architecture, large size, severe dysplasia), demonstrating YES1 activation as an early event in colonic neoplasia","method":"In vitro protein-tyrosine kinase activity assay (enolase phosphorylation and autophosphorylation) on human tissue samples","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 1 — direct enzymatic activity assay; single lab, single method","pmids":["7806032"],"is_preprint":false},{"year":2005,"finding":"c-Yes (but not c-Src) is specifically required for maturation and egress of West Nile virus particles; YES1 knockdown reduces virus yield and prevents viral envelope glycoprotein E trafficking beyond the endoplasmic reticulum without affecting viral RNA or protein synthesis","method":"RNA interference knockdown of c-Yes, endoglycosidase H digestion, electron microscopy, SFK inhibitor PP2 treatment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (siRNA, pharmacological inhibition, endoH digestion, EM) with specific mechanistic readout","pmids":["16140770"],"is_preprint":false},{"year":2005,"finding":"YES1 (Yes kinase) is activated downstream of BLT1 receptor endocytosis following LTB4 stimulation in human neutrophils, and this activation is required for neutrophil degranulation; BLT1 endocytosis is necessary for Yes kinase activation","method":"In vitro kinase activity assays, dominant-negative dynamin transfection, pharmacological inhibition (PP1), endocytosis inhibitors","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — kinase activity assay plus multiple mechanistic interventions establishing pathway order","pmids":["15749899"],"is_preprint":false},{"year":2006,"finding":"c-Yes is the predominant Src family kinase in endothelial cells; the FGFR-1beta isoform (but not FGFR-1alpha) directly associates with and activates c-YES via its SH2 domain recognizing phospho-FGFR-1beta, leading to cortactin activation and SFK-dependent cord formation","method":"Co-immunoprecipitation, SH2/SH3 domain binding assays, stable transfection of FGFR isoforms, kinase activity assays, in vitro cord formation","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1–2 — direct co-IP, domain-specific binding, and functional readouts with multiple orthogonal methods","pmids":["16631103"],"is_preprint":false},{"year":2006,"finding":"YES1 and Src play distinct roles in VEGF-mediated endothelial cell events: YES1 is specifically required for VEGF-induced cell migration, while Fyn (not YES1) is required for tube formation; all three SFKs are required for VEGF mitogenic signaling","method":"RNA interference (selective siRNA knockdown of Src, Fyn, and Yes individually), cell migration, tube formation, and proliferation assays","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 — selective siRNA knockdown with multiple specific functional readouts, distinguishing YES1 from paralogs","pmids":["16400523"],"is_preprint":false},{"year":2013,"finding":"YES1 is a druggable kinase target; homology models of YES1 were generated in active (DFG-in) and inactive conformations, and inhibitors identified by HTS preferentially bind the active conformation","method":"High-throughput enzymatic activity screen, cell-based survival assays, homology modeling and inhibitor docking","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro biochemical assay with structural modeling; single study","pmids":["23787099"],"is_preprint":false},{"year":2013,"finding":"YES1 is a direct target of miR-145 in colon cancer cells; miR-145 binds the 3'-UTR of YES1 mRNA to suppress its expression","method":"Microarray-based target identification, seed site enrichment analysis, direct validation by luciferase reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter assay validating direct 3'-UTR targeting","pmids":["20098684"],"is_preprint":false},{"year":2018,"finding":"YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors in EGFR-mutant lung adenocarcinoma; clones with transposon insertions activating YES1 expression exhibit resistance to all three generations of EGFR inhibitors and sensitivity to YES1 inhibition","method":"Transposon mutagenesis screen, siRNA knockdown, pharmacological inhibition, clinical genomic sequencing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic screen plus siRNA, pharmacological validation, and clinical genomics; multiple orthogonal methods","pmids":["29875142"],"is_preprint":false},{"year":2019,"finding":"YES1 effects on NSCLC growth and metastasis are mainly driven by mTOR signaling; YES1 overexpression induces metastatic spread and CRISPR/Cas9 depletion of YES1 significantly reduces tumor growth and metastasis","method":"CRISPR/Cas9 genetic depletion, in vivo tumor models, patient-derived xenografts, signaling pathway analysis","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 — CRISPR/Cas9 KO with defined signaling pathway (mTOR) and multiple in vivo readouts","pmids":["31166114"],"is_preprint":false},{"year":2019,"finding":"YES1 regulates YAP1 transcriptional activity by controlling its nuclear translocation and serine phosphorylation; a specific YES1 kinase inhibitor (CH6953755) blocks this regulation and exerts antitumor activity in YES1-amplified cancers","method":"shRNA knockdown, YES1-specific kinase inhibitor CH6953755, YAP1 nuclear translocation assays, phosphorylation analysis, in vitro and in vivo tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — pharmacological and genetic inhibition with direct readout of YAP1 phosphorylation and nuclear localization","pmids":["31391186"],"is_preprint":false},{"year":2020,"finding":"The peptide SMIM30 (encoded by lncRNA LINC00998) promotes membrane anchoring of SRC/YES1 non-receptor tyrosine kinases, leading to their phosphorylation and activation of the downstream MAPK signaling pathway in HCC","method":"RIP-seq, cell-based functional assays, co-immunoprecipitation, membrane fractionation, MAPK pathway analysis","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP and fractionation establishing membrane anchoring mechanism; single lab","pmids":["32461121"],"is_preprint":false},{"year":2020,"finding":"YES1 activation induces acquired resistance to neratinib (HER2-targeted therapy) in HER2-amplified breast and lung cancer cells; YES1 amplification was identified in neratinib-resistant lines and dasatinib or siRNA-mediated YES1 inhibition restored sensitivity, with combined dasatinib+neratinib treatment downregulating HER2, AKT and MAPK signaling","method":"Establishment of resistant cell lines, siRNA knockdown, pharmacological inhibition with dasatinib, in vivo combination treatment, Western blot signaling analysis","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological inhibition with defined signaling readouts and in vivo validation","pmids":["31856375"],"is_preprint":false},{"year":2021,"finding":"YES1 phosphorylates the organic cation transporter OCT1 at tyrosine residues, regulating its hepatic uptake activity; pharmacological YES1 inhibition with dasatinib modulates hepatic OCT1 function in mice as shown by metabolomics","method":"Phospho-proteomics screen, genetic and pharmacological YES1 inhibition, metabolomics (isobutyryl L-carnitine as biomarker), mouse models","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — phospho-proteomics plus in vivo functional validation; single study","pmids":["33790797"],"is_preprint":false},{"year":2021,"finding":"Mislocalized Scribble scaffolds the active (open αC-helix-in) conformation of YES1 in epithelial cancer cells, promoting YAP1-Y357 phosphorylation and YAP1 nuclear localization; junction-localized Scrib does not recruit active YES1","method":"HaloTag genome engineering, Snail-induced mislocalization, HaloPROTAC degradation, Halo-ligand affinity purification mass spectrometry, YAP1 phosphorylation assays","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 — genome-engineered fusion, targeted degradation, and AP-MS with direct phosphorylation readout; multiple orthogonal methods","pmids":["33730553"],"is_preprint":false},{"year":2021,"finding":"EphA2 activates YES1, which then phosphorylates ANXA2 at Tyr24, causing ANXA2 activation and increased nuclear distribution, driving gastric cancer invasion and metastasis; reexpression of WT but not Tyr24F mutant ANXA2 rescues YES1-induced invasion","method":"Co-immunoprecipitation, kinase activity assays, site-directed mutagenesis (Tyr24F), knockdown/overexpression, in vitro invasion/migration assays, mouse tumor models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis rescue experiment plus co-IP, functional assays, and in vivo validation establishing pathway order","pmids":["33941853"],"is_preprint":false},{"year":2022,"finding":"YES1 tyrosine kinase phosphorylates YAP and TAZ (YAP/TAZ), promoting their nuclear accumulation and transcriptional activity in HCC; transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis, and YAP/TAZ are required effectors downstream of Yes","method":"Genetic (transgenic mouse, hepatocyte-specific expression) and pharmacological interventions, YAP/TAZ phosphorylation analysis, nuclear localization assays, epistasis experiments","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 — transgenic mouse model establishing sufficiency, plus phosphorylation and epistasis data; multiple orthogonal methods","pmids":["35041461"],"is_preprint":false},{"year":2022,"finding":"YES1 is druggable in SCLC; YES1-inhibited cells reveal alterations in replisome and DNA repair processes that confer sensitivity to irradiation; CH6953755 and dasatinib induce antitumor activity in organoid and xenograft models","method":"Genetic depletion (siRNA/shRNA), pharmacological inhibition, organoid formation, patient-derived xenografts, DNA repair pathway analysis","journal":"Journal of thoracic oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts in genetic and pharmacological models; mechanistic link to DNA repair is single study","pmids":["35988891"],"is_preprint":false},{"year":2022,"finding":"YES1 linc01133 sponges miR-145-5p to upregulate YES1, which promotes YAP1 nuclear translocation and upregulation of cell cycle regulators CDK4, CDK6, and cyclin D1, driving G1-S phase transition in gastric cancer","method":"Dual-luciferase reporter assay, miRNA target validation, YES1 knockdown/overexpression, YAP1 nuclear localization assays, in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — luciferase validation plus nuclear localization and cell cycle readouts; single lab","pmids":["35017464"],"is_preprint":false},{"year":2024,"finding":"ACSL3 interacts with YES1 and suppresses YES1 activation through phosphorylation at Tyr419; decreased active YES1 inhibits YAP1 nuclear colocalization and transcriptional complex formation in breast cancer cells","method":"Co-immunoprecipitation, phosphorylation analysis (Tyr419), gain- and loss-of-function assays, nuclear localization assays, in vitro and in vivo models","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP and phosphorylation data with functional readouts; single lab, single study","pmids":["38953696"],"is_preprint":false},{"year":2024,"finding":"YES1 undergoes post-translational modifications including lipidation and nitrosylation that modulate its catalytic activity, subcellular localization, and substrate binding affinity","method":"Review summarizing experimental findings on YES1 PTMs from multiple studies","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 4 — review-level summary without primary experimental data in this paper","pmids":["38338729"],"is_preprint":false}],"current_model":"YES1 is a Src family non-receptor tyrosine kinase that is activated downstream of receptor tyrosine kinases (e.g., EphA2, FGFR-1beta) and GPCRs (e.g., BLT1); once active, YES1 phosphorylates substrates including YAP/TAZ (promoting their nuclear accumulation and transcriptional activity), ANXA2 (at Tyr24, driving cancer invasion), and OCT1 (regulating transporter activity), and its membrane localization is facilitated by SMIM30 peptide and scaffolded by mislocalized Scribble, while Ca2+-dependent association with cellular proteins can inactivate it; YES1 gene amplification drives resistance to EGFR, HER2, and other targeted therapies primarily through mTOR and YAP/TAZ signaling."},"narrative":{"teleology":[{"year":1986,"claim":"Establishing YES1's identity as a Src family tyrosine kinase resolved the question of what enzymatic activity c-yes encoded and placed it within the broader SFK family.","evidence":"Molecular cloning and nucleotide sequencing of human c-yes cDNA","pmids":["3526330"],"confidence":"High","gaps":["No information on specific substrates or biological functions","Regulatory mechanisms unknown"]},{"year":1993,"claim":"The discovery that intracellular Ca²⁺ elevation inactivates YES1 through association with inhibitory proteins—independent of PKC and distinct from c-Src regulation—established a unique regulatory mechanism for this kinase.","evidence":"In vitro kinase assays, gradient sedimentation, co-immunoprecipitation, and reconstitution with Ca²⁺-supplemented extracts","pmids":["8246968"],"confidence":"High","gaps":["Identity of the Ca²⁺-dependent inhibitory binding partners not determined","Physiological context of Ca²⁺-mediated YES1 inactivation not established"]},{"year":1995,"claim":"Demonstrating elevated YES1 kinase activity in high-risk colonic adenomas provided the first evidence linking YES1 activation to early-stage human neoplasia.","evidence":"In vitro tyrosine kinase activity assay on human colonic adenoma tissue samples","pmids":["7806032"],"confidence":"Medium","gaps":["Causal versus correlative relationship not established","Downstream substrates in colon tissue not identified"]},{"year":2005,"claim":"Two studies revealed non-redundant biological functions of YES1: it is specifically required for West Nile virus particle maturation and egress (distinct from Src), and it is activated downstream of BLT1 receptor endocytosis to mediate neutrophil degranulation, demonstrating YES1-specific roles in viral biology and innate immunity.","evidence":"siRNA knockdown, pharmacological inhibition (PP1/PP2), endoglycosidase H digestion, electron microscopy, dominant-negative dynamin transfection","pmids":["16140770","15749899"],"confidence":"High","gaps":["Direct YES1 substrates in viral trafficking and degranulation pathways not identified","Whether YES1 kinase activity or scaffolding function mediates virus maturation unclear"]},{"year":2006,"claim":"Identifying FGFR-1β as a direct activator of YES1 via its SH2 domain, and showing YES1 is specifically required for VEGF-induced endothelial migration (not tube formation), established YES1 as a non-redundant SFK in angiogenic signaling.","evidence":"Co-immunoprecipitation, SH2/SH3 domain binding assays, selective siRNA knockdown of individual SFKs, endothelial functional assays","pmids":["16631103","16400523"],"confidence":"High","gaps":["Direct endothelial substrates of YES1 beyond cortactin activation not mapped","In vivo angiogenesis phenotype of YES1 loss not tested"]},{"year":2018,"claim":"A transposon mutagenesis screen revealed YES1 amplification as a mechanism of acquired resistance to all three generations of EGFR inhibitors, establishing YES1 as a clinically actionable bypass kinase in EGFR-mutant lung cancer.","evidence":"Transposon mutagenesis screen, siRNA knockdown, pharmacological inhibition, clinical genomic sequencing","pmids":["29875142"],"confidence":"High","gaps":["Precise downstream signaling route from YES1 to EGFR-bypass not fully delineated at this point","Therapeutic window of YES1 inhibition in patients not established"]},{"year":2019,"claim":"Two studies defined the major downstream effector pathways of YES1 in cancer: mTOR signaling drives YES1-dependent NSCLC growth and metastasis, while YES1 regulates YAP1 nuclear translocation and transcriptional activity—establishing the YES1–YAP1 axis as a druggable oncogenic module.","evidence":"CRISPR/Cas9 KO, patient-derived xenografts, shRNA, YES1-specific inhibitor CH6953755, YAP1 nuclear localization assays","pmids":["31166114","31391186"],"confidence":"High","gaps":["Whether mTOR and YAP1 axes are parallel or convergent downstream of YES1 not resolved","Clinical efficacy of YES1-specific inhibitors not yet demonstrated"]},{"year":2020,"claim":"The SMIM30 micropeptide was shown to promote YES1 membrane anchoring and activation, linking a non-coding RNA-encoded peptide to SFK regulation and downstream MAPK signaling in hepatocellular carcinoma; separately, YES1 amplification was identified as a resistance mechanism to HER2-targeted neratinib.","evidence":"Co-immunoprecipitation, membrane fractionation, MAPK pathway analysis; resistant cell line generation, siRNA/dasatinib rescue experiments","pmids":["32461121","31856375"],"confidence":"Medium","gaps":["Mechanism by which SMIM30 facilitates membrane anchoring (direct lipid modification assistance or scaffolding) not clear","Whether SMIM30-YES1 interaction is direct or requires intermediary proteins"]},{"year":2021,"claim":"Three key mechanistic advances clarified YES1 signaling: mislocalized Scribble scaffolds active-conformation YES1 to phosphorylate YAP1-Y357; EphA2 activates YES1 which phosphorylates ANXA2-Y24 to drive gastric cancer invasion; and YES1 phosphorylates OCT1 to regulate hepatic transporter activity.","evidence":"HaloTag genome engineering with HaloPROTAC degradation and AP-MS; site-directed mutagenesis (ANXA2-Y24F) rescue experiments with in vivo models; phospho-proteomics with metabolomics validation in mice","pmids":["33730553","33941853","33790797"],"confidence":"High","gaps":["Full substrate repertoire of YES1 remains unmapped","Structural basis of Scribble–YES1 interaction not determined","Whether OCT1 phosphorylation is relevant in human drug metabolism not confirmed"]},{"year":2022,"claim":"Transgenic expression of activated Yes in mouse hepatocytes demonstrated sufficiency for liver tumorigenesis with YAP/TAZ as required downstream effectors, while YES1 inhibition in SCLC revealed a role in DNA repair and replication, broadening YES1's functional repertoire beyond YAP signaling.","evidence":"Hepatocyte-specific transgenic mice with epistasis experiments; siRNA/shRNA plus pharmacological inhibition in SCLC organoids and xenografts with DNA repair pathway analysis","pmids":["35041461","35988891"],"confidence":"High","gaps":["Direct YES1 substrates in the DNA repair/replisome pathway not identified","Whether YAP/TAZ-independent oncogenic functions contribute to hepatocarcinogenesis not resolved"]},{"year":2024,"claim":"ACSL3 was identified as a negative regulator of YES1 activation, suppressing Tyr419 phosphorylation and thereby inhibiting YAP1 nuclear translocation, adding a metabolic enzyme to the network controlling YES1 activity.","evidence":"Co-immunoprecipitation, Tyr419 phosphorylation analysis, gain- and loss-of-function assays in breast cancer models","pmids":["38953696"],"confidence":"Medium","gaps":["Whether ACSL3 directly dephosphorylates YES1 or acts via a phosphatase is unknown","Mechanism by which a lipid-CoA ligase regulates a tyrosine kinase not elucidated","Single-lab finding awaits independent confirmation"]},{"year":null,"claim":"Key unresolved questions include the full substrate repertoire of YES1, the structural basis for its regulation by Scribble and ACSL3, clinical validation of YES1-specific inhibitors, and the extent to which YES1 non-kinase (scaffolding) functions contribute to its biology.","evidence":"","pmids":[],"confidence":"Low","gaps":["No comprehensive substrate identification study (e.g., analog-sensitive allele) has been performed","No crystal structure of YES1 in complex with any regulatory partner exists","Clinical trial data for YES1-selective inhibitors not yet available"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,11,16,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,14,16,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6,10,11,12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,13,18]}],"complexes":[],"partners":["YAP1","ANXA2","SCRIB","FGFR1","EPHA2","ACSL3","SRC","SMIM30"],"other_free_text":[]},"mechanistic_narrative":"YES1 is a Src family non-receptor tyrosine kinase with distinct signaling roles in endothelial biology, immune cell function, viral maturation, and oncogenesis. YES1 is activated downstream of receptor tyrosine kinases (FGFR-1β, EphA2) and G-protein-coupled receptors (BLT1), and phosphorylates substrates including YAP/TAZ—promoting their nuclear accumulation and transcriptional activity to drive tumorigenesis—and ANXA2 at Tyr24, facilitating cancer cell invasion [PMID:35041461, PMID:31391186, PMID:33941853, PMID:16631103, PMID:15749899]. Its activity is regulated by Ca²⁺-dependent association with inhibitory cellular proteins, by membrane anchoring through the SMIM30 peptide, and by scaffolding via mislocalized Scribble, which stabilizes the active-conformation kinase and channels signaling through YAP1-Y357 phosphorylation [PMID:8246968, PMID:32461121, PMID:33730553]. YES1 gene amplification is a clinically relevant resistance mechanism to EGFR and HER2 inhibitors in lung and breast cancers, operating primarily through mTOR and YAP/TAZ signaling axes [PMID:29875142, PMID:31856375, PMID:31166114]."},"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; ACTL9","url":"https://www.omim.org/entry/619251"},{"mim_id":"612265","title":"FAMILY WITH SEQUENCE SIMILARITY 120, MEMBER A; FAM120A","url":"https://www.omim.org/entry/612265"},{"mim_id":"606608","title":"YES1-ASSOCIATED TRANSCRIPTIONAL REGULATOR; YAP1","url":"https://www.omim.org/entry/606608"},{"mim_id":"312173","title":"RIBOSOMAL PROTEIN L10; RPL10","url":"https://www.omim.org/entry/312173"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YES1"},"hgnc":{"alias_symbol":["Yes","c-yes","HsT441"],"prev_symbol":[]},"alphafold":{"accession":"P07947","domains":[{"cath_id":"2.30.30.40","chopping":"96-153","consensus_level":"high","plddt":92.9119,"start":96,"end":153},{"cath_id":"3.30.505.10","chopping":"156-253","consensus_level":"high","plddt":92.6237,"start":156,"end":253},{"cath_id":"3.30.200.20","chopping":"273-348","consensus_level":"high","plddt":93.5104,"start":273,"end":348},{"cath_id":"1.10.510.10","chopping":"356-527","consensus_level":"high","plddt":92.6074,"start":356,"end":527}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07947","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07947-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07947-F1-predicted_aligned_error_v6.png","plddt_mean":81.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YES1","jax_strain_url":"https://www.jax.org/strain/search?query=YES1"},"sequence":{"accession":"P07947","fasta_url":"https://rest.uniprot.org/uniprotkb/P07947.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07947/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07947"}},"corpus_meta":[{"pmid":"18703216","id":"PMC_18703216","title":"Expression of Yes-associated protein in common solid tumors.","date":"2008","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18703216","citation_count":482,"is_preprint":false},{"pmid":"3526330","id":"PMC_3526330","title":"yes-related protooncogene, syn, belongs to the protein-tyrosine kinase family.","date":"1986","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/3526330","citation_count":243,"is_preprint":false},{"pmid":"32461121","id":"PMC_32461121","title":"Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation.","date":"2020","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/32461121","citation_count":179,"is_preprint":false},{"pmid":"23312954","id":"PMC_23312954","title":"Wnt your brain be inflamed? Yes, it Wnt!","date":"2013","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23312954","citation_count":139,"is_preprint":false},{"pmid":"20098684","id":"PMC_20098684","title":"MicroRNA-145 targets YES and STAT1 in colon cancer cells.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20098684","citation_count":139,"is_preprint":false},{"pmid":"27093644","id":"PMC_27093644","title":"Long noncoding RNA H19 competitively binds miR-17-5p to regulate YES1 expression in thyroid cancer.","date":"2016","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/27093644","citation_count":131,"is_preprint":false},{"pmid":"28818100","id":"PMC_28818100","title":"miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28818100","citation_count":123,"is_preprint":false},{"pmid":"29149457","id":"PMC_29149457","title":"High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis.","date":"2018","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29149457","citation_count":114,"is_preprint":false},{"pmid":"15345057","id":"PMC_15345057","title":"Is HIV-1 RNA dimerization a prerequisite for packaging? Yes, no, probably?","date":"2004","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/15345057","citation_count":101,"is_preprint":false},{"pmid":"25750642","id":"PMC_25750642","title":"Are Platelets Cells? 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this mechanism is distinct from c-Src regulation and independent of protein kinase C\",\n      \"method\": \"In vitro kinase activity assays, gradient sedimentation, co-immunoprecipitation, in vitro reconstitution with Ca2+-supplemented cell extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution plus multiple orthogonal methods in a single study\",\n      \"pmids\": [\"8246968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Yes tyrosine kinase activity is elevated in colonic adenomas at greatest risk for cancer (villous architecture, large size, severe dysplasia), demonstrating YES1 activation as an early event in colonic neoplasia\",\n      \"method\": \"In vitro protein-tyrosine kinase activity assay (enolase phosphorylation and autophosphorylation) on human tissue samples\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct enzymatic activity assay; single lab, single method\",\n      \"pmids\": [\"7806032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Yes (but not c-Src) is specifically required for maturation and egress of West Nile virus particles; YES1 knockdown reduces virus yield and prevents viral envelope glycoprotein E trafficking beyond the endoplasmic reticulum without affecting viral RNA or protein synthesis\",\n      \"method\": \"RNA interference knockdown of c-Yes, endoglycosidase H digestion, electron microscopy, SFK inhibitor PP2 treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (siRNA, pharmacological inhibition, endoH digestion, EM) with specific mechanistic readout\",\n      \"pmids\": [\"16140770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"YES1 (Yes kinase) is activated downstream of BLT1 receptor endocytosis following LTB4 stimulation in human neutrophils, and this activation is required for neutrophil degranulation; BLT1 endocytosis is necessary for Yes kinase activation\",\n      \"method\": \"In vitro kinase activity assays, dominant-negative dynamin transfection, pharmacological inhibition (PP1), endocytosis inhibitors\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — kinase activity assay plus multiple mechanistic interventions establishing pathway order\",\n      \"pmids\": [\"15749899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Yes is the predominant Src family kinase in endothelial cells; the FGFR-1beta isoform (but not FGFR-1alpha) directly associates with and activates c-YES via its SH2 domain recognizing phospho-FGFR-1beta, leading to cortactin activation and SFK-dependent cord formation\",\n      \"method\": \"Co-immunoprecipitation, SH2/SH3 domain binding assays, stable transfection of FGFR isoforms, kinase activity assays, in vitro cord formation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct co-IP, domain-specific binding, and functional readouts with multiple orthogonal methods\",\n      \"pmids\": [\"16631103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"YES1 and Src play distinct roles in VEGF-mediated endothelial cell events: YES1 is specifically required for VEGF-induced cell migration, while Fyn (not YES1) is required for tube formation; all three SFKs are required for VEGF mitogenic signaling\",\n      \"method\": \"RNA interference (selective siRNA knockdown of Src, Fyn, and Yes individually), cell migration, tube formation, and proliferation assays\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — selective siRNA knockdown with multiple specific functional readouts, distinguishing YES1 from paralogs\",\n      \"pmids\": [\"16400523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YES1 is a druggable kinase target; homology models of YES1 were generated in active (DFG-in) and inactive conformations, and inhibitors identified by HTS preferentially bind the active conformation\",\n      \"method\": \"High-throughput enzymatic activity screen, cell-based survival assays, homology modeling and inhibitor docking\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assay with structural modeling; single study\",\n      \"pmids\": [\"23787099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YES1 is a direct target of miR-145 in colon cancer cells; miR-145 binds the 3'-UTR of YES1 mRNA to suppress its expression\",\n      \"method\": \"Microarray-based target identification, seed site enrichment analysis, direct validation by luciferase reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter assay validating direct 3'-UTR targeting\",\n      \"pmids\": [\"20098684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors in EGFR-mutant lung adenocarcinoma; clones with transposon insertions activating YES1 expression exhibit resistance to all three generations of EGFR inhibitors and sensitivity to YES1 inhibition\",\n      \"method\": \"Transposon mutagenesis screen, siRNA knockdown, pharmacological inhibition, clinical genomic sequencing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic screen plus siRNA, pharmacological validation, and clinical genomics; multiple orthogonal methods\",\n      \"pmids\": [\"29875142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YES1 effects on NSCLC growth and metastasis are mainly driven by mTOR signaling; YES1 overexpression induces metastatic spread and CRISPR/Cas9 depletion of YES1 significantly reduces tumor growth and metastasis\",\n      \"method\": \"CRISPR/Cas9 genetic depletion, in vivo tumor models, patient-derived xenografts, signaling pathway analysis\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR/Cas9 KO with defined signaling pathway (mTOR) and multiple in vivo readouts\",\n      \"pmids\": [\"31166114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YES1 regulates YAP1 transcriptional activity by controlling its nuclear translocation and serine phosphorylation; a specific YES1 kinase inhibitor (CH6953755) blocks this regulation and exerts antitumor activity in YES1-amplified cancers\",\n      \"method\": \"shRNA knockdown, YES1-specific kinase inhibitor CH6953755, YAP1 nuclear translocation assays, phosphorylation analysis, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — pharmacological and genetic inhibition with direct readout of YAP1 phosphorylation and nuclear localization\",\n      \"pmids\": [\"31391186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The peptide SMIM30 (encoded by lncRNA LINC00998) promotes membrane anchoring of SRC/YES1 non-receptor tyrosine kinases, leading to their phosphorylation and activation of the downstream MAPK signaling pathway in HCC\",\n      \"method\": \"RIP-seq, cell-based functional assays, co-immunoprecipitation, membrane fractionation, MAPK pathway analysis\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP and fractionation establishing membrane anchoring mechanism; single lab\",\n      \"pmids\": [\"32461121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YES1 activation induces acquired resistance to neratinib (HER2-targeted therapy) in HER2-amplified breast and lung cancer cells; YES1 amplification was identified in neratinib-resistant lines and dasatinib or siRNA-mediated YES1 inhibition restored sensitivity, with combined dasatinib+neratinib treatment downregulating HER2, AKT and MAPK signaling\",\n      \"method\": \"Establishment of resistant cell lines, siRNA knockdown, pharmacological inhibition with dasatinib, in vivo combination treatment, Western blot signaling analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological inhibition with defined signaling readouts and in vivo validation\",\n      \"pmids\": [\"31856375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YES1 phosphorylates the organic cation transporter OCT1 at tyrosine residues, regulating its hepatic uptake activity; pharmacological YES1 inhibition with dasatinib modulates hepatic OCT1 function in mice as shown by metabolomics\",\n      \"method\": \"Phospho-proteomics screen, genetic and pharmacological YES1 inhibition, metabolomics (isobutyryl L-carnitine as biomarker), mouse models\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phospho-proteomics plus in vivo functional validation; single study\",\n      \"pmids\": [\"33790797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mislocalized Scribble scaffolds the active (open αC-helix-in) conformation of YES1 in epithelial cancer cells, promoting YAP1-Y357 phosphorylation and YAP1 nuclear localization; junction-localized Scrib does not recruit active YES1\",\n      \"method\": \"HaloTag genome engineering, Snail-induced mislocalization, HaloPROTAC degradation, Halo-ligand affinity purification mass spectrometry, YAP1 phosphorylation assays\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-engineered fusion, targeted degradation, and AP-MS with direct phosphorylation readout; multiple orthogonal methods\",\n      \"pmids\": [\"33730553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EphA2 activates YES1, which then phosphorylates ANXA2 at Tyr24, causing ANXA2 activation and increased nuclear distribution, driving gastric cancer invasion and metastasis; reexpression of WT but not Tyr24F mutant ANXA2 rescues YES1-induced invasion\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, site-directed mutagenesis (Tyr24F), knockdown/overexpression, in vitro invasion/migration assays, mouse tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis rescue experiment plus co-IP, functional assays, and in vivo validation establishing pathway order\",\n      \"pmids\": [\"33941853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YES1 tyrosine kinase phosphorylates YAP and TAZ (YAP/TAZ), promoting their nuclear accumulation and transcriptional activity in HCC; transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis, and YAP/TAZ are required effectors downstream of Yes\",\n      \"method\": \"Genetic (transgenic mouse, hepatocyte-specific expression) and pharmacological interventions, YAP/TAZ phosphorylation analysis, nuclear localization assays, epistasis experiments\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — transgenic mouse model establishing sufficiency, plus phosphorylation and epistasis data; multiple orthogonal methods\",\n      \"pmids\": [\"35041461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YES1 is druggable in SCLC; YES1-inhibited cells reveal alterations in replisome and DNA repair processes that confer sensitivity to irradiation; CH6953755 and dasatinib induce antitumor activity in organoid and xenograft models\",\n      \"method\": \"Genetic depletion (siRNA/shRNA), pharmacological inhibition, organoid formation, patient-derived xenografts, DNA repair pathway analysis\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts in genetic and pharmacological models; mechanistic link to DNA repair is single study\",\n      \"pmids\": [\"35988891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YES1 linc01133 sponges miR-145-5p to upregulate YES1, which promotes YAP1 nuclear translocation and upregulation of cell cycle regulators CDK4, CDK6, and cyclin D1, driving G1-S phase transition in gastric cancer\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA target validation, YES1 knockdown/overexpression, YAP1 nuclear localization assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — luciferase validation plus nuclear localization and cell cycle readouts; single lab\",\n      \"pmids\": [\"35017464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSL3 interacts with YES1 and suppresses YES1 activation through phosphorylation at Tyr419; decreased active YES1 inhibits YAP1 nuclear colocalization and transcriptional complex formation in breast cancer cells\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation analysis (Tyr419), gain- and loss-of-function assays, nuclear localization assays, in vitro and in vivo models\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP and phosphorylation data with functional readouts; single lab, single study\",\n      \"pmids\": [\"38953696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YES1 undergoes post-translational modifications including lipidation and nitrosylation that modulate its catalytic activity, subcellular localization, and substrate binding affinity\",\n      \"method\": \"Review summarizing experimental findings on YES1 PTMs from multiple studies\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — review-level summary without primary experimental data in this paper\",\n      \"pmids\": [\"38338729\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YES1 is a Src family non-receptor tyrosine kinase that is activated downstream of receptor tyrosine kinases (e.g., EphA2, FGFR-1beta) and GPCRs (e.g., BLT1); once active, YES1 phosphorylates substrates including YAP/TAZ (promoting their nuclear accumulation and transcriptional activity), ANXA2 (at Tyr24, driving cancer invasion), and OCT1 (regulating transporter activity), and its membrane localization is facilitated by SMIM30 peptide and scaffolded by mislocalized Scribble, while Ca2+-dependent association with cellular proteins can inactivate it; YES1 gene amplification drives resistance to EGFR, HER2, and other targeted therapies primarily through mTOR and YAP/TAZ signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YES1 is a Src family non-receptor tyrosine kinase with distinct signaling roles in endothelial biology, immune cell function, viral maturation, and oncogenesis. YES1 is activated downstream of receptor tyrosine kinases (FGFR-1β, EphA2) and G-protein-coupled receptors (BLT1), and phosphorylates substrates including YAP/TAZ—promoting their nuclear accumulation and transcriptional activity to drive tumorigenesis—and ANXA2 at Tyr24, facilitating cancer cell invasion [PMID:35041461, PMID:31391186, PMID:33941853, PMID:16631103, PMID:15749899]. Its activity is regulated by Ca²⁺-dependent association with inhibitory cellular proteins, by membrane anchoring through the SMIM30 peptide, and by scaffolding via mislocalized Scribble, which stabilizes the active-conformation kinase and channels signaling through YAP1-Y357 phosphorylation [PMID:8246968, PMID:32461121, PMID:33730553]. YES1 gene amplification is a clinically relevant resistance mechanism to EGFR and HER2 inhibitors in lung and breast cancers, operating primarily through mTOR and YAP/TAZ signaling axes [PMID:29875142, PMID:31856375, PMID:31166114].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Establishing YES1's identity as a Src family tyrosine kinase resolved the question of what enzymatic activity c-yes encoded and placed it within the broader SFK family.\",\n      \"evidence\": \"Molecular cloning and nucleotide sequencing of human c-yes cDNA\",\n      \"pmids\": [\"3526330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No information on specific substrates or biological functions\", \"Regulatory mechanisms unknown\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"The discovery that intracellular Ca²⁺ elevation inactivates YES1 through association with inhibitory proteins—independent of PKC and distinct from c-Src regulation—established a unique regulatory mechanism for this kinase.\",\n      \"evidence\": \"In vitro kinase assays, gradient sedimentation, co-immunoprecipitation, and reconstitution with Ca²⁺-supplemented extracts\",\n      \"pmids\": [\"8246968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the Ca²⁺-dependent inhibitory binding partners not determined\", \"Physiological context of Ca²⁺-mediated YES1 inactivation not established\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating elevated YES1 kinase activity in high-risk colonic adenomas provided the first evidence linking YES1 activation to early-stage human neoplasia.\",\n      \"evidence\": \"In vitro tyrosine kinase activity assay on human colonic adenoma tissue samples\",\n      \"pmids\": [\"7806032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal versus correlative relationship not established\", \"Downstream substrates in colon tissue not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Two studies revealed non-redundant biological functions of YES1: it is specifically required for West Nile virus particle maturation and egress (distinct from Src), and it is activated downstream of BLT1 receptor endocytosis to mediate neutrophil degranulation, demonstrating YES1-specific roles in viral biology and innate immunity.\",\n      \"evidence\": \"siRNA knockdown, pharmacological inhibition (PP1/PP2), endoglycosidase H digestion, electron microscopy, dominant-negative dynamin transfection\",\n      \"pmids\": [\"16140770\", \"15749899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct YES1 substrates in viral trafficking and degranulation pathways not identified\", \"Whether YES1 kinase activity or scaffolding function mediates virus maturation unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying FGFR-1β as a direct activator of YES1 via its SH2 domain, and showing YES1 is specifically required for VEGF-induced endothelial migration (not tube formation), established YES1 as a non-redundant SFK in angiogenic signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, SH2/SH3 domain binding assays, selective siRNA knockdown of individual SFKs, endothelial functional assays\",\n      \"pmids\": [\"16631103\", \"16400523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct endothelial substrates of YES1 beyond cortactin activation not mapped\", \"In vivo angiogenesis phenotype of YES1 loss not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A transposon mutagenesis screen revealed YES1 amplification as a mechanism of acquired resistance to all three generations of EGFR inhibitors, establishing YES1 as a clinically actionable bypass kinase in EGFR-mutant lung cancer.\",\n      \"evidence\": \"Transposon mutagenesis screen, siRNA knockdown, pharmacological inhibition, clinical genomic sequencing\",\n      \"pmids\": [\"29875142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise downstream signaling route from YES1 to EGFR-bypass not fully delineated at this point\", \"Therapeutic window of YES1 inhibition in patients not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies defined the major downstream effector pathways of YES1 in cancer: mTOR signaling drives YES1-dependent NSCLC growth and metastasis, while YES1 regulates YAP1 nuclear translocation and transcriptional activity—establishing the YES1–YAP1 axis as a druggable oncogenic module.\",\n      \"evidence\": \"CRISPR/Cas9 KO, patient-derived xenografts, shRNA, YES1-specific inhibitor CH6953755, YAP1 nuclear localization assays\",\n      \"pmids\": [\"31166114\", \"31391186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mTOR and YAP1 axes are parallel or convergent downstream of YES1 not resolved\", \"Clinical efficacy of YES1-specific inhibitors not yet demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The SMIM30 micropeptide was shown to promote YES1 membrane anchoring and activation, linking a non-coding RNA-encoded peptide to SFK regulation and downstream MAPK signaling in hepatocellular carcinoma; separately, YES1 amplification was identified as a resistance mechanism to HER2-targeted neratinib.\",\n      \"evidence\": \"Co-immunoprecipitation, membrane fractionation, MAPK pathway analysis; resistant cell line generation, siRNA/dasatinib rescue experiments\",\n      \"pmids\": [\"32461121\", \"31856375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SMIM30 facilitates membrane anchoring (direct lipid modification assistance or scaffolding) not clear\", \"Whether SMIM30-YES1 interaction is direct or requires intermediary proteins\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Three key mechanistic advances clarified YES1 signaling: mislocalized Scribble scaffolds active-conformation YES1 to phosphorylate YAP1-Y357; EphA2 activates YES1 which phosphorylates ANXA2-Y24 to drive gastric cancer invasion; and YES1 phosphorylates OCT1 to regulate hepatic transporter activity.\",\n      \"evidence\": \"HaloTag genome engineering with HaloPROTAC degradation and AP-MS; site-directed mutagenesis (ANXA2-Y24F) rescue experiments with in vivo models; phospho-proteomics with metabolomics validation in mice\",\n      \"pmids\": [\"33730553\", \"33941853\", \"33790797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire of YES1 remains unmapped\", \"Structural basis of Scribble–YES1 interaction not determined\", \"Whether OCT1 phosphorylation is relevant in human drug metabolism not confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transgenic expression of activated Yes in mouse hepatocytes demonstrated sufficiency for liver tumorigenesis with YAP/TAZ as required downstream effectors, while YES1 inhibition in SCLC revealed a role in DNA repair and replication, broadening YES1's functional repertoire beyond YAP signaling.\",\n      \"evidence\": \"Hepatocyte-specific transgenic mice with epistasis experiments; siRNA/shRNA plus pharmacological inhibition in SCLC organoids and xenografts with DNA repair pathway analysis\",\n      \"pmids\": [\"35041461\", \"35988891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct YES1 substrates in the DNA repair/replisome pathway not identified\", \"Whether YAP/TAZ-independent oncogenic functions contribute to hepatocarcinogenesis not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ACSL3 was identified as a negative regulator of YES1 activation, suppressing Tyr419 phosphorylation and thereby inhibiting YAP1 nuclear translocation, adding a metabolic enzyme to the network controlling YES1 activity.\",\n      \"evidence\": \"Co-immunoprecipitation, Tyr419 phosphorylation analysis, gain- and loss-of-function assays in breast cancer models\",\n      \"pmids\": [\"38953696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ACSL3 directly dephosphorylates YES1 or acts via a phosphatase is unknown\", \"Mechanism by which a lipid-CoA ligase regulates a tyrosine kinase not elucidated\", \"Single-lab finding awaits independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full substrate repertoire of YES1, the structural basis for its regulation by Scribble and ACSL3, clinical validation of YES1-specific inhibitors, and the extent to which YES1 non-kinase (scaffolding) functions contribute to its biology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No comprehensive substrate identification study (e.g., analog-sensitive allele) has been performed\", \"No crystal structure of YES1 in complex with any regulatory partner exists\", \"Clinical trial data for YES1-selective inhibitors not yet available\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 11, 16, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 14, 16, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6, 10, 11, 12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 13, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"YAP1\",\n      \"ANXA2\",\n      \"SCRIB\",\n      \"FGFR1\",\n      \"EPHA2\",\n      \"ACSL3\",\n      \"SRC\",\n      \"SMIM30\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}