{"gene":"PTK2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2000,"finding":"FAK associates with activated PDGF- and EGF-receptor signaling complexes via its N-terminal band-4.1-like (FERM) domain, and requires its C-terminal domain for targeting to integrin-receptor clustering sites; kinase-inactive FAK is transphosphorylated at Y397 after EGF stimulation, establishing FAK as a receptor-proximal integrator of growth-factor and integrin signals for cell migration.","method":"Co-immunoprecipitation, domain-deletion constructs, FAK-null fibroblast reconstitution, cell motility assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, FAK-null rescue, multiple domain mutants, independent readouts of migration","pmids":["10806474"],"is_preprint":false},{"year":1999,"finding":"FAK kinase activity, the Tyr-397/SH2-binding site, and the first proline-rich SH3-binding region in the FAK C-terminal domain are each individually required for full FAK-mediated fibronectin-stimulated cell migration; direct paxillin binding to FAK is not required. The dominant-negative C-terminal fragment FRNK blocks FAK-mediated migration only when localized to focal contacts.","method":"FAK-null fibroblast reconstitution with point/deletion mutants, FRNK overexpression, cell migration assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutant rescue in null cells, multiple orthogonal mutants, specific phenotypic readout","pmids":["10413676"],"is_preprint":false},{"year":1999,"finding":"FAK and p130Cas define a directionally persistent cell-migration pathway that is distinct from a Shc/MAP-kinase-dependent random-motility pathway; both pathways are down-regulated by tumor suppressor PTEN, which directly dephosphorylates Shc.","method":"Overexpression of FAK, p130Cas, dominant-negative Shc, and constitutively active MEK1 in PTEN-reconstituted U87-MG cells; migration directionality assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis/overexpression in defined genetic background, two orthogonal pathways dissected, single lab","pmids":["10427092"],"is_preprint":false},{"year":2003,"finding":"FAK Y397 phosphorylation and FAK kinase activity are required for cell invasion but not for integrin-stimulated motility; invasion involves formation of a FAK-Src-p130Cas-Dock180 signaling complex, elevated Rac and JNK activation, and increased MMP expression and activity. Transient FAK accumulation at lamellipodia is linked to the invasive phenotype.","method":"FAK-null cells reconstituted with FAK mutants, v-Src transformation, Co-IP of FAK-Src-p130Cas-Dock180 complex, Rac and JNK activity assays, MMP zymography, invasion assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, FAK-null rescue, complex identification by Co-IP, distinct motility vs invasion pathways","pmids":["12615911"],"is_preprint":false},{"year":2004,"finding":"A specific sequence in the FAK FERM domain is required for cell-adhesion-dependent activation of FAK in vivo; point mutations in this sequence reduce tyrosine phosphorylation and Src family kinase binding without affecting intrinsic catalytic activity in vitro. Purified FERM domain interacts directly with full-length FAK in vitro.","method":"FERM domain point mutagenesis, in vitro kinase assay, Co-IP/pulldown, cell migration assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution of FERM–FAK interaction, mutagenesis, in-cell signaling readouts, single lab","pmids":["15169899"],"is_preprint":false},{"year":2014,"finding":"FAK autophosphorylation at Tyr-397 requires site-specific dimerization of FAK mediated by association of the N-terminal FERM domains; dimers are stabilized by a FERM–FAT interaction; paxillin plays a dual role by recruiting FAK to focal adhesions and reinforcing the FAT:FERM interaction; dimerization requires local enrichment at focal adhesions.","method":"X-ray crystallography, small-angle X-ray scattering (SAXS), biochemical dimerization assays, FAK autophosphorylation assays, paxillin interaction studies, functional cell-based assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, SAXS, in vitro biochemistry, and functional validation in one study","pmids":["24480479"],"is_preprint":false},{"year":2008,"finding":"FAK contains two nuclear export signal (NES) sequences: NES1 in the F1 lobe of the FERM domain and NES2 in the kinase domain; only NES2 demonstrates full biological nuclear export activity. Both are evolutionarily conserved and present in the FAK-related kinase Pyk2.","method":"NES sequence identification, mutational analysis, nuclear export activity assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional nuclear export assay, single lab","pmids":["18549812"],"is_preprint":false},{"year":2004,"finding":"Cdk5 phosphorylates FAK at Serine 732 in vitro and in the developing brain; S732 phosphorylation regulates a centrosome-associated microtubule structure to promote nuclear translocation during neuronal migration without directly affecting FAK kinase activity, and prevents accumulation of FAK at the centrosome.","method":"In vitro kinase assay (Cdk5 + FAK), phospho-specific antibody (pS732), S732A unphosphorylatable FAK mutant, neuronal migration assays","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphorylation assay with mutagenesis, phospho-specific antibody in vivo, single lab","pmids":["14712065"],"is_preprint":false},{"year":2009,"finding":"FAK mediates activation-loop-independent phosphorylation of IGF-1R, promotes Akt and ERK activation downstream of IGF-1R, and is required for IGF-1R stability; FAK-null MEFs display reduced IGF-1R phosphorylation and stability compared to wild-type MEFs.","method":"FAK-null vs wild-type MEFs, FAK siRNA knockdown, autophosphorylation assays with IGF-1R mutants, immunoblot for Akt/ERK, IGF-1R stability assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null cells plus siRNA, multiple readouts, single lab","pmids":["19545541"],"is_preprint":false},{"year":2020,"finding":"FAK directly phosphorylates HDAC5 at Tyr-642 in osteocytes, a post-translational modification that controls HDAC5 subcellular localization; fluid-flow shear stress triggers FAK dephosphorylation, promoting HDAC4/5 nuclear translocation and Sost (Sclerostin) suppression for bone formation.","method":"Direct phosphorylation assay (FAK + HDAC5), phospho-specific antibody, pharmacological FAK inhibition in vitro and in vivo, HDAC4/5 nuclear translocation imaging, Sost mRNA measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct kinase assay identifying specific phosphorylation site, supported by inhibitor studies in vitro and in vivo with defined molecular readout","pmids":["32612176"],"is_preprint":false},{"year":2021,"finding":"FAK is required for YAP phosphorylation at Tyr-357 in intrahepatic cholangiocarcinoma cells; FAK ablation strongly delayed Akt/YAP-driven iCCA initiation and suppressed tumor progression, establishing FAK as a central upstream regulator of YAP in this context.","method":"Conditional FAK knockout mice, FAK overexpression mice, in vitro cell line studies with FAK inhibitor, phospho-Y357 YAP immunoblot","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus overexpression in vivo, phosphorylation site identified, single lab","pmids":["34052254"],"is_preprint":false},{"year":2021,"finding":"FAK inhibition blocks β-catenin activation by reducing tyrosine-654 phosphorylation of β-catenin, preferentially targeting cancer stem cells; a constitutively active β-catenin mutant reversed FAK-inhibitor-mediated CSC targeting, placing β-catenin downstream of FAK in CSC regulation.","method":"FAK inhibitors (VS-4718, VS-6063), immunoblot for pY654-β-catenin, constitutively active β-catenin rescue, CSC assays (tumorsphere, ALDH, limiting dilution), xenograft models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus genetic rescue, specific phosphorylation site identified, multiple CSC readouts, single lab","pmids":["28881682"],"is_preprint":false},{"year":2017,"finding":"LFA-1 cross-linking activates FAK1 (PTK2), which phosphorylates LAT at a single site (Y171) to create LAT-GRB2-SKAP1 complexes distinct from canonical LAT-Gads-SLP-76 complexes; these complexes decrease T-cell–DC dwell times and reduce T-cell proliferation, establishing FAK as a mediator of LFA-1-induced T-cell de-adhesion.","method":"LFA-1 cross-linking, Co-IP, LAT Y171 mutant, FAK1 kinase assay, T-cell:DC conjugate formation assays, proliferation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific mutagenesis, functional T-cell assays, single lab","pmids":["28699640"],"is_preprint":false},{"year":2019,"finding":"PTK2/FAK phosphorylates SQSTM1/p62 at Ser-403 via activation of TBK1; inhibition of PTK2 reduced ubiquitin aggregate accumulation and attenuated TARDBP-induced cytotoxicity in neuronal cells, and PTK2 inhibition rescued TARDBP proteinopathy phenotypes in a Drosophila model.","method":"Kinase inhibitor screening, immunoblot for pS403-SQSTM1, SQSTM1-S403A non-phosphorylatable mutant rescue, Drosophila TARDBP model, TBK1 co-manipulation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell-based and in vivo (Drosophila) experiments, site-specific mutant rescue, TBK1 epistasis, single lab","pmids":["31690171"],"is_preprint":false},{"year":2022,"finding":"DUSP22 directly interacts with FAK and dephosphorylates FAK at Tyr-397 and Tyr-576/577, thereby suppressing downstream ERK1/2 and NF-κB signaling; disruption of DUSP22-FAK binding abolishes DUSP22-mediated amelioration of NASH progression.","method":"Co-IP (DUSP22–FAK interaction), phospho-FAK immunoblot, DUSP22 knockout and transgenic mice, AAV gene therapy, in vitro phosphatase assay implied","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies interaction, specific phosphorylation sites measured, genetic models in vivo, single lab","pmids":["36209205"],"is_preprint":false},{"year":2016,"finding":"FAK depletion in cancer-associated fibroblasts (CAFs) increases chemokine production, which activates CCR1/CCR2 on cancer cells, leading to protein kinase A activation and enhanced malignant cell glycolysis; this paracrine mechanism is independent of genetic mutations in cancer cells.","method":"Conditional FAK knockout in CAF subpopulation (mouse model), proteomic/phosphoproteomic analysis, CCR1/CCR2 receptor blocking, PKA activity measurement, glycolysis assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic FAK depletion in specific cell type, multi-omics plus pathway rescue, single lab","pmids":["32157087"],"is_preprint":false},{"year":2021,"finding":"FAK activation in vascular smooth muscle cells (SMCs) stabilizes DNMT3A in the cytoplasm; pharmacological or genetic FAK catalytic inhibition forces FAK nuclear localization, where nuclear FAK promotes DNMT3A ubiquitination and proteasomal degradation via E3 ligase TRAF6, causing DNA hypomethylation of contractile gene promoters and maintaining SMC differentiation.","method":"FAK inhibitors, conditional FAK genetic inhibition, RNA-sequencing of injured femoral arteries, DNMT3A ubiquitination assays, DNA methylation analysis of contractile gene promoters, TRAF6 co-manipulation","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (genetic/pharmacological FAK inhibition, ubiquitination assay, methylation), specific E3 ligase identified, single lab","pmids":["34702049"],"is_preprint":false},{"year":2009,"finding":"ARHGAP21 interacts with the C-terminal region of FAK in glioblastoma cells; ARHGAP21 depletion increases FAK phosphorylation, Cdc42 activity, MMP-2 production, and cell migration, indicating ARHGAP21 negatively regulates FAK signaling.","method":"Co-IP (ARHGAP21–FAK), shRNA knockdown of ARHGAP21, immunofluorescence, FAK phosphorylation assay, Cdc42 activity assay, MMP-2 zymography, migration assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus loss-of-function with multiple downstream readouts, single lab","pmids":["19268501"],"is_preprint":false},{"year":2017,"finding":"PDE4D promotes FAK-mediated melanoma invasion by interacting with FAK through the scaffolding protein RACK1; inhibition of PDE4 activity or disruption of PDE4D–FAK interaction reduces invasion; PDE4D–FAK interaction is detectable in situ in metastatic melanoma.","method":"Co-IP (PDE4D–FAK via RACK1), PDE4 inhibition, disruption of PDE4D–FAK interaction, invasion assays, in situ analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP identifies ternary complex, functional invasion assay with inhibitor, in situ validation, single lab","pmids":["28092671"],"is_preprint":false},{"year":2013,"finding":"FAK directly interacts with p53 in both cytoplasm and nucleus; FAK inhibits p53 transcriptional activity (p21, Bax, Mdm-2 targets) through protein–protein interaction; a 7-amino-acid site on p53 mediates the interaction with FAK.","method":"Co-immunoprecipitation, pulldown assay, confocal microscopy co-localization, p53 transcriptional reporter assays, site-directed mutagenesis of p53","journal":"Anti-cancer agents in medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pulldown, confocal co-localization, functional transcription assay, single lab","pmids":["21355845"],"is_preprint":false},{"year":2021,"finding":"FAK regulates Drp1 phosphorylation and mitochondrial Drp1 levels in cardiomyocytes; extracellular fibronectin activates the FAK-ERK1/2-Drp1 pathway to promote mitochondrial fission, increase oxygen consumption rate and ATP production; adrenergic agonists also activate this pathway to stimulate cardiomyocyte respiration.","method":"FAK inhibition, ERK1/2 inhibition, Drp1 phosphorylation immunoblot, mitochondrial morphology imaging, oxygen consumption rate (Seahorse), ATP assay in neonatal rat ventricular myocytes","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple metabolic readouts, single lab","pmids":["34739186"],"is_preprint":false},{"year":2024,"finding":"Disruption of the talin-binding site on FAK or elimination of FAK catalytic activity prevents YAP nuclear localization and transcriptional activity without altering nuclear size or traction forces, whereas disruption of vinculin-talin binding reduces nuclear size and traction forces before affecting YAP; this defines a nuclear-tension-independent mechanism by which FAK controls YAP nuclear localization.","method":"Domain-specific FAK mutants (talin-binding site), FAK catalytic inhibition, vinculin-talin interaction disruption, YAP nuclear localization quantification, traction force microscopy, nuclear size measurement in fibroblasts and hMSCs on deformable substrates","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple domain-specific mutants with orthogonal mechanical and transcriptional readouts, single lab","pmids":["38547833"],"is_preprint":false},{"year":2016,"finding":"SMARCE1 interacts with and potentiates HIF1A transcriptional activity upon loss of cell attachment, resulting in rapid PTK2/FAK activation; PTK2 and HIF1A are each required for SMARCE1-mediated anoikis resistance, acting through ERK/AKT activation and BIM suppression.","method":"Co-IP (SMARCE1–HIF1A), ChIP assay, SMARCE1/HIF1A/PTK2 knockdown, anoikis assay, ERK/AKT/BIM immunoblot, xenograft lung metastasis model","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, epistatic knockdowns, in vivo metastasis model, single lab","pmids":["27495308"],"is_preprint":false},{"year":2016,"finding":"Fibronectin induces macrophage migration through a signaling pathway in which SFK activity is required upstream of FAK activation, and FAK in turn drives ligand-independent phosphorylation and activation of CSF-1R (c-FMS); both FAK and CSF-1R are required for FN-induced macrophage migration.","method":"FAK phosphorylation immunoblot, SFK/FAK inhibitors, CSF-1R genetic knockdown and pharmacological inhibition, Co-IP (CSF-1R–β1 integrin interaction), migration assays in murine and human macrophages","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by sequential inhibition, Co-IP, both genetic and pharmacological approaches, single lab","pmids":["27588738"],"is_preprint":false},{"year":2013,"finding":"FAK directly interacts with VEGFR-3 in cancer cells; disruption of this interaction with small molecule C4 causes dephosphorylation of both VEGFR-3 and FAK, reduces cell viability, causes cell-cycle arrest and apoptosis, and reduces tumor growth in murine pancreatic cancer models.","method":"Co-IP (FAK–VEGFR-3), small molecule C4 disruption, phospho-FAK/VEGFR-3 immunoblot, cell viability/apoptosis assays, subcutaneous and orthotopic murine tumor models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies complex, targeted disruption with functional readouts in vitro and in vivo, single lab","pmids":["24142503"],"is_preprint":false},{"year":2016,"finding":"FAK is required for FGF/heparin-mediated down-regulation of smooth muscle alpha-actin (myofibroblast de-differentiation); FAK-null MEFs show reduced FGFR surface expression and FGF signaling, establishing FAK as necessary for FGF signal transduction but not for TGF-β-dependent myofibroblast differentiation.","method":"FAK shRNA knockdown, FAK-/- MEFs, FGFR surface expression assay, FGF signaling readouts (ERK), alpha-SMA immunostaining, stress fiber quantification","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent loss-of-function approaches (shRNA + genetic null), receptor surface expression and signaling readouts, single lab","pmids":["16585062"],"is_preprint":false}],"current_model":"PTK2/FAK is an autoinhibited, non-receptor tyrosine kinase that localizes to focal adhesion complexes where local enrichment drives site-specific FERM-domain-mediated dimerization, enabling autophosphorylation at Tyr-397; this creates a Src SH2-docking site that initiates a kinase-dependent signaling cascade (involving p130Cas-Dock180-Rac, JNK, ERK, PI3K-Akt) required for directed cell migration, invasion, and survival, while kinase-independent nuclear FAK phosphorylates HDAC5 (Tyr-642) and regulates p53 and transcription-factor ubiquitination; FAK additionally integrates growth-factor-receptor (EGFR, PDGFR, IGF-1R) and integrin signals, phosphorylates substrates including β-catenin (Tyr-654), SQSTM1/p62 (via TBK1), and Drp1 (via ERK1/2), and is negatively regulated by DUSP22-mediated dephosphorylation of Tyr-397/576/577 and by ARHGAP21 binding to its C-terminal domain."},"narrative":{"mechanistic_narrative":"PTK2/FAK is a non-receptor tyrosine kinase that integrates integrin and growth-factor-receptor signals at focal adhesions to drive directed cell migration, invasion, and survival [PMID:10806474, PMID:12615911]. Adhesion-dependent activation is mediated by its N-terminal FERM domain, which engages activated PDGF- and EGF-receptor complexes and directs assembly at integrin clustering sites, while the C-terminal domain governs focal-adhesion targeting; FERM-domain point mutations abolish in-cell activation and Src-family kinase binding without altering intrinsic catalysis [PMID:10806474, PMID:15169899]. Mechanistically, autophosphorylation at Tyr-397 requires local enrichment at focal adhesions that promotes site-specific FERM-mediated dimerization, stabilized by a FERM–FAT interaction and reinforced by paxillin recruitment [PMID:24480479]. Tyr-397 phosphorylation and kinase activity are selectively required for invasion through assembly of a FAK–Src–p130Cas–Dock180 complex that activates Rac and JNK and elevates MMP activity, defining an invasion pathway distinct from integrin-stimulated motility [PMID:12615911]. FAK also transactivates receptor tyrosine kinases by activation-loop-independent phosphorylation, promoting IGF-1R stability and downstream Akt/ERK signaling and CSF-1R activation during fibronectin-induced migration [PMID:19545541, PMID:27588738]. Beyond the cytoplasm, catalytic inhibition forces FAK nuclear localization where it controls protein turnover and transcription, promoting TRAF6-dependent DNMT3A ubiquitination to maintain smooth-muscle differentiation and binding p53 to suppress its transcriptional activity [PMID:34702049, PMID:21355845]. FAK phosphorylates a diverse substrate set including HDAC5 (Tyr-642), β-catenin (Tyr-654), and—via ERK1/2—Drp1 to drive mitochondrial fission, and acts upstream of YAP nuclear localization through a talin-binding, catalysis-dependent mechanism [PMID:32612176, PMID:28881682, PMID:34739186, PMID:38547833]. FAK signaling is restrained by DUSP22, which dephosphorylates Tyr-397 and Tyr-576/577, and by ARHGAP21 binding to its C-terminal region [PMID:36209205, PMID:19268501].","teleology":[{"year":1999,"claim":"Established which FAK modules are functionally required for migration, separating kinase activity, the Tyr-397/SH2 site, and SH3-binding regions from dispensable direct paxillin binding.","evidence":"Systematic point/deletion mutant rescue in FAK-null fibroblasts with FRNK dominant-negative and migration assays","pmids":["10413676"],"confidence":"High","gaps":["Did not define how Tyr-397 phosphorylation is triggered upstream","Mechanism of FRNK focal-contact localization requirement unresolved"]},{"year":1999,"claim":"Defined FAK/p130Cas as a directionally persistent migration pathway distinct from Shc/MAPK random motility, placing FAK within a PTEN-regulated migration network.","evidence":"Overexpression epistasis in PTEN-reconstituted U87-MG cells with directionality assays","pmids":["10427092"],"confidence":"Medium","gaps":["Overexpression-based, single genetic background","Molecular link between FAK and directional persistence not detailed"]},{"year":2000,"claim":"Showed FAK is a receptor-proximal integrator, with the FERM domain binding activated growth-factor receptors and the C-terminus directing integrin-site targeting.","evidence":"Co-IP, domain-deletion constructs, FAK-null reconstitution, motility assays","pmids":["10806474"],"confidence":"High","gaps":["Structural basis of FERM–receptor binding not resolved","Whether transphosphorylation is intermolecular not directly shown"]},{"year":2003,"claim":"Distinguished invasion from motility mechanistically by identifying a kinase-dependent FAK–Src–p130Cas–Dock180–Rac–JNK–MMP axis.","evidence":"FAK-null rescue with mutants, v-Src transformation, Co-IP, Rac/JNK assays, MMP zymography, invasion assays","pmids":["12615911"],"confidence":"High","gaps":["Spatial regulation of lamellipodial FAK accumulation not fully defined","Direct versus indirect MMP regulation unresolved"]},{"year":2004,"claim":"Localized adhesion-dependent activation to a specific FERM-domain sequence required for Src binding and in-cell tyrosine phosphorylation, distinct from intrinsic catalysis.","evidence":"FERM point mutagenesis, in vitro kinase assay, pulldown of FERM–FAK interaction, migration assays","pmids":["15169899"],"confidence":"High","gaps":["Did not show the dimeric/oligomeric nature of activation","Conformational change mechanism not yet defined"]},{"year":2004,"claim":"Identified a kinase-activity-independent regulatory phosphorylation by Cdk5 at Ser-732 controlling centrosomal microtubules and nuclear translocation in neuronal migration.","evidence":"In vitro Cdk5 kinase assay, pS732 antibody, S732A mutant, neuronal migration assays","pmids":["14712065"],"confidence":"Medium","gaps":["Single lab","Effector linking pS732 to centrosomal microtubule structure not identified"]},{"year":2008,"claim":"Provided a molecular basis for FAK nuclear-cytoplasmic shuttling by mapping two conserved nuclear export signals.","evidence":"NES identification, mutational analysis, nuclear export activity assays","pmids":["18549812"],"confidence":"Medium","gaps":["Nuclear import mechanism not addressed","Physiological triggers of export not defined"]},{"year":2009,"claim":"Extended FAK function to receptor-tyrosine-kinase transactivation by showing it drives activation-loop-independent IGF-1R phosphorylation and stability.","evidence":"FAK-null vs WT MEFs, siRNA, IGF-1R autophosphorylation mutants, Akt/ERK and stability assays","pmids":["19545541"],"confidence":"Medium","gaps":["Whether FAK directly phosphorylates IGF-1R not definitively shown","Single lab"]},{"year":2014,"claim":"Resolved the activation mechanism: Tyr-397 autophosphorylation requires focal-adhesion-enriched, FERM-mediated dimerization stabilized by FERM–FAT contacts and paxillin.","evidence":"X-ray crystallography, SAXS, dimerization and autophosphorylation biochemistry, paxillin interaction and cell assays","pmids":["24480479"],"confidence":"High","gaps":["Dynamics of dimer assembly in live cells not directly captured","How force/enrichment is sensed not fully defined"]},{"year":2013,"claim":"Demonstrated a kinase-independent nuclear function: direct p53 binding that suppresses p53 transcriptional output.","evidence":"Reciprocal Co-IP, pulldown, confocal co-localization, p53 reporter assays, p53 site mutagenesis","pmids":["21355845"],"confidence":"Medium","gaps":["Single lab","Structural detail of the 7-residue interaction surface limited"]},{"year":2013,"claim":"Identified a FAK–VEGFR-3 complex whose disruption co-inactivates both kinases and suppresses tumor growth, expanding the RTK partner set.","evidence":"Co-IP, small-molecule C4 disruption, phospho-immunoblot, viability/apoptosis assays, murine pancreatic tumor models","pmids":["24142503"],"confidence":"Medium","gaps":["Directionality of the phosphorylation interdependence unclear","Single lab"]},{"year":2016,"claim":"Linked FAK to anoikis resistance and metastasis downstream of SMARCE1/HIF1A via ERK/AKT and BIM suppression.","evidence":"Co-IP, ChIP, epistatic knockdowns, anoikis assay, xenograft metastasis model","pmids":["27495308"],"confidence":"Medium","gaps":["How attachment loss triggers PTK2 activation not defined","Single lab"]},{"year":2016,"claim":"Placed FAK in a fibronectin–SFK–FAK–CSF-1R cascade required for macrophage migration.","evidence":"Sequential SFK/FAK/CSF-1R inhibition, Co-IP, genetic and pharmacological approaches, migration assays","pmids":["27588738"],"confidence":"Medium","gaps":["Whether FAK directly phosphorylates CSF-1R not shown","Single lab"]},{"year":2016,"claim":"Showed FAK is required for FGFR surface expression and FGF signaling during myofibroblast de-differentiation, independent of TGF-β.","evidence":"shRNA and FAK-null MEFs, FGFR surface assay, ERK readouts, α-SMA/stress-fiber quantification","pmids":["16585062"],"confidence":"Medium","gaps":["Mechanism by which FAK controls FGFR surface levels unresolved","Single lab"]},{"year":2016,"claim":"Revealed a non-cell-autonomous role: stromal FAK loss reprograms cancer-cell metabolism via chemokine–CCR1/CCR2–PKA–glycolysis paracrine signaling.","evidence":"CAF-specific conditional FAK knockout, phosphoproteomics, receptor blockade, PKA and glycolysis assays","pmids":["32157087"],"confidence":"Medium","gaps":["FAK substrates controlling chemokine output not identified","Single lab"]},{"year":2017,"claim":"Expanded FAK substrate scope in immune signaling, showing LFA-1-activated FAK phosphorylates LAT at Y171 to form de-adhesion complexes.","evidence":"LFA-1 cross-linking, Co-IP, LAT Y171 mutant, FAK kinase assay, T-cell:DC conjugate and proliferation assays","pmids":["28699640"],"confidence":"Medium","gaps":["Single lab","Selectivity over canonical LAT kinases not fully defined"]},{"year":2017,"claim":"Identified RACK1-scaffolded PDE4D as a FAK partner promoting melanoma invasion.","evidence":"Co-IP of PDE4D–FAK via RACK1, PDE4 inhibition, interaction disruption, invasion assays, in situ analysis","pmids":["28092671"],"confidence":"Medium","gaps":["Mechanistic effect of PDE4D on FAK activity not defined","Single lab"]},{"year":2019,"claim":"Connected FAK to protein-aggregate clearance: it phosphorylates SQSTM1/p62 at Ser-403 via TBK1, and its inhibition rescues TARDBP proteinopathy.","evidence":"Inhibitor screen, pS403 immunoblot, S403A rescue, TBK1 epistasis, Drosophila TARDBP model","pmids":["31690171"],"confidence":"Medium","gaps":["Whether FAK acts directly on TBK1 not resolved","Single lab"]},{"year":2020,"claim":"Established direct FAK phosphorylation of HDAC5 at Tyr-642 controlling its localization and mechanically responsive bone gene regulation.","evidence":"Direct kinase assay, phospho-specific antibody, FAK inhibition in vitro and in vivo, HDAC4/5 translocation imaging, Sost mRNA","pmids":["32612176"],"confidence":"High","gaps":["How shear stress triggers FAK dephosphorylation not detailed","Single lab"]},{"year":2021,"claim":"Defined a nuclear, catalysis-restraining FAK function: catalytic inhibition drives nuclear FAK to promote TRAF6-dependent DNMT3A degradation and maintain SMC differentiation.","evidence":"FAK inhibitors, conditional genetic inhibition, RNA-seq, DNMT3A ubiquitination assays, methylation analysis, TRAF6 manipulation","pmids":["34702049"],"confidence":"Medium","gaps":["Whether FAK directly ubiquitinates DNMT3A or scaffolds TRAF6 unclear","Single lab"]},{"year":2021,"claim":"Placed FAK upstream of YAP via Tyr-357 phosphorylation in cholangiocarcinoma initiation.","evidence":"Conditional FAK knockout and overexpression mice, FAK inhibitor in cell lines, pY357-YAP immunoblot","pmids":["34052254"],"confidence":"Medium","gaps":["Directness of YAP phosphorylation by FAK not established","Single lab"]},{"year":2021,"claim":"Identified FAK control of β-catenin Tyr-654 phosphorylation as a cancer-stem-cell-selective vulnerability.","evidence":"FAK inhibitors, pY654-β-catenin immunoblot, constitutively active β-catenin rescue, CSC assays, xenografts","pmids":["28881682"],"confidence":"Medium","gaps":["Whether FAK directly phosphorylates β-catenin not shown","Single lab"]},{"year":2021,"claim":"Linked FAK to mitochondrial dynamics through a fibronectin–FAK–ERK1/2–Drp1 fission pathway regulating cardiomyocyte respiration.","evidence":"FAK/ERK inhibition, Drp1 phospho-immunoblot, mitochondrial imaging, Seahorse OCR, ATP assays","pmids":["34739186"],"confidence":"Medium","gaps":["Mechanism of Drp1 mitochondrial recruitment not defined","Single lab"]},{"year":2022,"claim":"Identified DUSP22 as a direct negative regulator dephosphorylating FAK Tyr-397 and Tyr-576/577 to suppress ERK1/2 and NF-κB.","evidence":"Co-IP, phospho-FAK immunoblot, DUSP22 knockout/transgenic mice, AAV gene therapy","pmids":["36209205"],"confidence":"Medium","gaps":["Direct phosphatase activity inferred rather than reconstituted","Single lab"]},{"year":2024,"claim":"Dissected FAK's mechanotransduction role, showing talin-binding and catalytic activity control YAP nuclear localization independent of nuclear tension and traction forces.","evidence":"Domain-specific FAK mutants, catalytic inhibition, vinculin-talin disruption, YAP localization, traction force microscopy","pmids":["38547833"],"confidence":"Medium","gaps":["Molecular intermediary between FAK and YAP transport not identified","Single lab"]},{"year":null,"claim":"How the spatial switch between cytoplasmic/focal-adhesion FAK kinase signaling and nuclear kinase-independent functions is coordinated in vivo, and which substrate phosphorylations are direct versus indirect, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Directness of many reported 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Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Phosphorylates NEDD9 following integrin stimulation (PubMed:9360983). Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription","subcellular_location":"Cell junction, focal adhesion; Cell membrane; Cytoplasm, perinuclear region; Cytoplasm, cell cortex; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Nucleus; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q05397/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTK2","classification":"Not Classified","n_dependent_lines":671,"n_total_lines":1208,"dependency_fraction":0.5554635761589404},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000169398","cell_line_id":"CID001253","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"focal_adhesions","grade":3}],"interactors":[{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"RBM25","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001253","total_profiled":1310},"omim":[{"mim_id":"620403","title":"INKA-BOX ACTIN REGULATOR 2; INKA2","url":"https://www.omim.org/entry/620403"},{"mim_id":"620392","title":"ACTIN-BINDING TRANSCRIPTION MODULATOR; ABITRAM","url":"https://www.omim.org/entry/620392"},{"mim_id":"620036","title":"IMMEDIATE-EARLY RESPONSE GENE 2; IER2","url":"https://www.omim.org/entry/620036"},{"mim_id":"618888","title":"CAS SCAFFOLD PROTEIN FAMILY, MEMBER 4; CASS4","url":"https://www.omim.org/entry/618888"},{"mim_id":"618699","title":"CILIARY DYSKINESIA, PRIMARY, 43; CILD43","url":"https://www.omim.org/entry/618699"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTK2"},"hgnc":{"alias_symbol":["FAK","FADK","FAK1","PPP1R71"],"prev_symbol":[]},"alphafold":{"accession":"Q05397","domains":[{"cath_id":"3.10.20.90","chopping":"33-129","consensus_level":"medium","plddt":88.9801,"start":33,"end":129},{"cath_id":"2.30.29.30","chopping":"257-353","consensus_level":"medium","plddt":91.0825,"start":257,"end":353},{"cath_id":"3.30.200.20","chopping":"414-502","consensus_level":"medium","plddt":84.7687,"start":414,"end":502},{"cath_id":"1.10.510.10","chopping":"517-696","consensus_level":"medium","plddt":88.6665,"start":517,"end":696},{"cath_id":"1.20.120.330","chopping":"924-1048","consensus_level":"high","plddt":89.824,"start":924,"end":1048}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05397","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q05397-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q05397-F1-predicted_aligned_error_v6.png","plddt_mean":74.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTK2","jax_strain_url":"https://www.jax.org/strain/search?query=PTK2"},"sequence":{"accession":"Q05397","fasta_url":"https://rest.uniprot.org/uniprotkb/Q05397.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q05397/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05397"}},"corpus_meta":[{"pmid":"25098269","id":"PMC_25098269","title":"FAK in cancer: mechanistic findings and clinical applications.","date":"2014","source":"Nature reviews. 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collagen synthesis by fibroblasts and osteoblasts.","date":"2016","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/27881487","citation_count":30,"is_preprint":false},{"pmid":"33322030","id":"PMC_33322030","title":"Involvement of the FAK Network in Pathologies Related to Altered Mechanotransduction.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33322030","citation_count":28,"is_preprint":false},{"pmid":"30820814","id":"PMC_30820814","title":"Simulated microgravity inhibits the viability and migration of glioma via FAK/RhoA/Rock and FAK/Nek2 signaling.","date":"2019","source":"In vitro cellular & developmental biology. 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kinase (FAK) in cancer therapy: A recent update on inhibitors and PROTAC degraders.","date":"2024","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39029337","citation_count":25,"is_preprint":false},{"pmid":"34827680","id":"PMC_34827680","title":"FAK Inhibition Attenuates Corneal Fibroblast Differentiation In Vitro.","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/34827680","citation_count":25,"is_preprint":false},{"pmid":"22934707","id":"PMC_22934707","title":"FAK and Nanog cross talk with p53 in cancer stem cells.","date":"2013","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22934707","citation_count":25,"is_preprint":false},{"pmid":"24142503","id":"PMC_24142503","title":"The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and inhibits pancreatic cancer growth.","date":"2013","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/24142503","citation_count":25,"is_preprint":false},{"pmid":"12957821","id":"PMC_12957821","title":"PYK2 and FAK in osteoclasts.","date":"2003","source":"Frontiers in bioscience : a journal and virtual library","url":"https://pubmed.ncbi.nlm.nih.gov/12957821","citation_count":23,"is_preprint":false},{"pmid":"24578181","id":"PMC_24578181","title":"New insights into FAK function and regulation during spermatogenesis.","date":"2014","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/24578181","citation_count":22,"is_preprint":false},{"pmid":"34739186","id":"PMC_34739186","title":"FAK regulates cardiomyocyte mitochondrial fission and function through Drp1.","date":"2021","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/34739186","citation_count":21,"is_preprint":false},{"pmid":"12942446","id":"PMC_12942446","title":"[Focal adhesion kinase (FAK), a multifunctional 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signals for cell migration.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion constructs, FAK-null fibroblast reconstitution, cell motility assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, FAK-null rescue, multiple domain mutants, independent readouts of migration\",\n      \"pmids\": [\"10806474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FAK kinase activity, the Tyr-397/SH2-binding site, and the first proline-rich SH3-binding region in the FAK C-terminal domain are each individually required for full FAK-mediated fibronectin-stimulated cell migration; direct paxillin binding to FAK is not required. The dominant-negative C-terminal fragment FRNK blocks FAK-mediated migration only when localized to focal contacts.\",\n      \"method\": \"FAK-null fibroblast reconstitution with point/deletion mutants, FRNK overexpression, cell migration assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutant rescue in null cells, multiple orthogonal mutants, specific phenotypic readout\",\n      \"pmids\": [\"10413676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FAK and p130Cas define a directionally persistent cell-migration pathway that is distinct from a Shc/MAP-kinase-dependent random-motility pathway; both pathways are down-regulated by tumor suppressor PTEN, which directly dephosphorylates Shc.\",\n      \"method\": \"Overexpression of FAK, p130Cas, dominant-negative Shc, and constitutively active MEK1 in PTEN-reconstituted U87-MG cells; migration directionality assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis/overexpression in defined genetic background, two orthogonal pathways dissected, single lab\",\n      \"pmids\": [\"10427092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FAK Y397 phosphorylation and FAK kinase activity are required for cell invasion but not for integrin-stimulated motility; invasion involves formation of a FAK-Src-p130Cas-Dock180 signaling complex, elevated Rac and JNK activation, and increased MMP expression and activity. Transient FAK accumulation at lamellipodia is linked to the invasive phenotype.\",\n      \"method\": \"FAK-null cells reconstituted with FAK mutants, v-Src transformation, Co-IP of FAK-Src-p130Cas-Dock180 complex, Rac and JNK activity assays, MMP zymography, invasion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, FAK-null rescue, complex identification by Co-IP, distinct motility vs invasion pathways\",\n      \"pmids\": [\"12615911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A specific sequence in the FAK FERM domain is required for cell-adhesion-dependent activation of FAK in vivo; point mutations in this sequence reduce tyrosine phosphorylation and Src family kinase binding without affecting intrinsic catalytic activity in vitro. Purified FERM domain interacts directly with full-length FAK in vitro.\",\n      \"method\": \"FERM domain point mutagenesis, in vitro kinase assay, Co-IP/pulldown, cell migration assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution of FERM–FAK interaction, mutagenesis, in-cell signaling readouts, single lab\",\n      \"pmids\": [\"15169899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FAK autophosphorylation at Tyr-397 requires site-specific dimerization of FAK mediated by association of the N-terminal FERM domains; dimers are stabilized by a FERM–FAT interaction; paxillin plays a dual role by recruiting FAK to focal adhesions and reinforcing the FAT:FERM interaction; dimerization requires local enrichment at focal adhesions.\",\n      \"method\": \"X-ray crystallography, small-angle X-ray scattering (SAXS), biochemical dimerization assays, FAK autophosphorylation assays, paxillin interaction studies, functional cell-based assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, SAXS, in vitro biochemistry, and functional validation in one study\",\n      \"pmids\": [\"24480479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FAK contains two nuclear export signal (NES) sequences: NES1 in the F1 lobe of the FERM domain and NES2 in the kinase domain; only NES2 demonstrates full biological nuclear export activity. Both are evolutionarily conserved and present in the FAK-related kinase Pyk2.\",\n      \"method\": \"NES sequence identification, mutational analysis, nuclear export activity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional nuclear export assay, single lab\",\n      \"pmids\": [\"18549812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cdk5 phosphorylates FAK at Serine 732 in vitro and in the developing brain; S732 phosphorylation regulates a centrosome-associated microtubule structure to promote nuclear translocation during neuronal migration without directly affecting FAK kinase activity, and prevents accumulation of FAK at the centrosome.\",\n      \"method\": \"In vitro kinase assay (Cdk5 + FAK), phospho-specific antibody (pS732), S732A unphosphorylatable FAK mutant, neuronal migration assays\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphorylation assay with mutagenesis, phospho-specific antibody in vivo, single lab\",\n      \"pmids\": [\"14712065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FAK mediates activation-loop-independent phosphorylation of IGF-1R, promotes Akt and ERK activation downstream of IGF-1R, and is required for IGF-1R stability; FAK-null MEFs display reduced IGF-1R phosphorylation and stability compared to wild-type MEFs.\",\n      \"method\": \"FAK-null vs wild-type MEFs, FAK siRNA knockdown, autophosphorylation assays with IGF-1R mutants, immunoblot for Akt/ERK, IGF-1R stability assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null cells plus siRNA, multiple readouts, single lab\",\n      \"pmids\": [\"19545541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAK directly phosphorylates HDAC5 at Tyr-642 in osteocytes, a post-translational modification that controls HDAC5 subcellular localization; fluid-flow shear stress triggers FAK dephosphorylation, promoting HDAC4/5 nuclear translocation and Sost (Sclerostin) suppression for bone formation.\",\n      \"method\": \"Direct phosphorylation assay (FAK + HDAC5), phospho-specific antibody, pharmacological FAK inhibition in vitro and in vivo, HDAC4/5 nuclear translocation imaging, Sost mRNA measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct kinase assay identifying specific phosphorylation site, supported by inhibitor studies in vitro and in vivo with defined molecular readout\",\n      \"pmids\": [\"32612176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAK is required for YAP phosphorylation at Tyr-357 in intrahepatic cholangiocarcinoma cells; FAK ablation strongly delayed Akt/YAP-driven iCCA initiation and suppressed tumor progression, establishing FAK as a central upstream regulator of YAP in this context.\",\n      \"method\": \"Conditional FAK knockout mice, FAK overexpression mice, in vitro cell line studies with FAK inhibitor, phospho-Y357 YAP immunoblot\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus overexpression in vivo, phosphorylation site identified, single lab\",\n      \"pmids\": [\"34052254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAK inhibition blocks β-catenin activation by reducing tyrosine-654 phosphorylation of β-catenin, preferentially targeting cancer stem cells; a constitutively active β-catenin mutant reversed FAK-inhibitor-mediated CSC targeting, placing β-catenin downstream of FAK in CSC regulation.\",\n      \"method\": \"FAK inhibitors (VS-4718, VS-6063), immunoblot for pY654-β-catenin, constitutively active β-catenin rescue, CSC assays (tumorsphere, ALDH, limiting dilution), xenograft models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus genetic rescue, specific phosphorylation site identified, multiple CSC readouts, single lab\",\n      \"pmids\": [\"28881682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LFA-1 cross-linking activates FAK1 (PTK2), which phosphorylates LAT at a single site (Y171) to create LAT-GRB2-SKAP1 complexes distinct from canonical LAT-Gads-SLP-76 complexes; these complexes decrease T-cell–DC dwell times and reduce T-cell proliferation, establishing FAK as a mediator of LFA-1-induced T-cell de-adhesion.\",\n      \"method\": \"LFA-1 cross-linking, Co-IP, LAT Y171 mutant, FAK1 kinase assay, T-cell:DC conjugate formation assays, proliferation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific mutagenesis, functional T-cell assays, single lab\",\n      \"pmids\": [\"28699640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTK2/FAK phosphorylates SQSTM1/p62 at Ser-403 via activation of TBK1; inhibition of PTK2 reduced ubiquitin aggregate accumulation and attenuated TARDBP-induced cytotoxicity in neuronal cells, and PTK2 inhibition rescued TARDBP proteinopathy phenotypes in a Drosophila model.\",\n      \"method\": \"Kinase inhibitor screening, immunoblot for pS403-SQSTM1, SQSTM1-S403A non-phosphorylatable mutant rescue, Drosophila TARDBP model, TBK1 co-manipulation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell-based and in vivo (Drosophila) experiments, site-specific mutant rescue, TBK1 epistasis, single lab\",\n      \"pmids\": [\"31690171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DUSP22 directly interacts with FAK and dephosphorylates FAK at Tyr-397 and Tyr-576/577, thereby suppressing downstream ERK1/2 and NF-κB signaling; disruption of DUSP22-FAK binding abolishes DUSP22-mediated amelioration of NASH progression.\",\n      \"method\": \"Co-IP (DUSP22–FAK interaction), phospho-FAK immunoblot, DUSP22 knockout and transgenic mice, AAV gene therapy, in vitro phosphatase assay implied\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies interaction, specific phosphorylation sites measured, genetic models in vivo, single lab\",\n      \"pmids\": [\"36209205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAK depletion in cancer-associated fibroblasts (CAFs) increases chemokine production, which activates CCR1/CCR2 on cancer cells, leading to protein kinase A activation and enhanced malignant cell glycolysis; this paracrine mechanism is independent of genetic mutations in cancer cells.\",\n      \"method\": \"Conditional FAK knockout in CAF subpopulation (mouse model), proteomic/phosphoproteomic analysis, CCR1/CCR2 receptor blocking, PKA activity measurement, glycolysis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic FAK depletion in specific cell type, multi-omics plus pathway rescue, single lab\",\n      \"pmids\": [\"32157087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAK activation in vascular smooth muscle cells (SMCs) stabilizes DNMT3A in the cytoplasm; pharmacological or genetic FAK catalytic inhibition forces FAK nuclear localization, where nuclear FAK promotes DNMT3A ubiquitination and proteasomal degradation via E3 ligase TRAF6, causing DNA hypomethylation of contractile gene promoters and maintaining SMC differentiation.\",\n      \"method\": \"FAK inhibitors, conditional FAK genetic inhibition, RNA-sequencing of injured femoral arteries, DNMT3A ubiquitination assays, DNA methylation analysis of contractile gene promoters, TRAF6 co-manipulation\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (genetic/pharmacological FAK inhibition, ubiquitination assay, methylation), specific E3 ligase identified, single lab\",\n      \"pmids\": [\"34702049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ARHGAP21 interacts with the C-terminal region of FAK in glioblastoma cells; ARHGAP21 depletion increases FAK phosphorylation, Cdc42 activity, MMP-2 production, and cell migration, indicating ARHGAP21 negatively regulates FAK signaling.\",\n      \"method\": \"Co-IP (ARHGAP21–FAK), shRNA knockdown of ARHGAP21, immunofluorescence, FAK phosphorylation assay, Cdc42 activity assay, MMP-2 zymography, migration assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus loss-of-function with multiple downstream readouts, single lab\",\n      \"pmids\": [\"19268501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDE4D promotes FAK-mediated melanoma invasion by interacting with FAK through the scaffolding protein RACK1; inhibition of PDE4 activity or disruption of PDE4D–FAK interaction reduces invasion; PDE4D–FAK interaction is detectable in situ in metastatic melanoma.\",\n      \"method\": \"Co-IP (PDE4D–FAK via RACK1), PDE4 inhibition, disruption of PDE4D–FAK interaction, invasion assays, in situ analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP identifies ternary complex, functional invasion assay with inhibitor, in situ validation, single lab\",\n      \"pmids\": [\"28092671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FAK directly interacts with p53 in both cytoplasm and nucleus; FAK inhibits p53 transcriptional activity (p21, Bax, Mdm-2 targets) through protein–protein interaction; a 7-amino-acid site on p53 mediates the interaction with FAK.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay, confocal microscopy co-localization, p53 transcriptional reporter assays, site-directed mutagenesis of p53\",\n      \"journal\": \"Anti-cancer agents in medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pulldown, confocal co-localization, functional transcription assay, single lab\",\n      \"pmids\": [\"21355845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAK regulates Drp1 phosphorylation and mitochondrial Drp1 levels in cardiomyocytes; extracellular fibronectin activates the FAK-ERK1/2-Drp1 pathway to promote mitochondrial fission, increase oxygen consumption rate and ATP production; adrenergic agonists also activate this pathway to stimulate cardiomyocyte respiration.\",\n      \"method\": \"FAK inhibition, ERK1/2 inhibition, Drp1 phosphorylation immunoblot, mitochondrial morphology imaging, oxygen consumption rate (Seahorse), ATP assay in neonatal rat ventricular myocytes\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple metabolic readouts, single lab\",\n      \"pmids\": [\"34739186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disruption of the talin-binding site on FAK or elimination of FAK catalytic activity prevents YAP nuclear localization and transcriptional activity without altering nuclear size or traction forces, whereas disruption of vinculin-talin binding reduces nuclear size and traction forces before affecting YAP; this defines a nuclear-tension-independent mechanism by which FAK controls YAP nuclear localization.\",\n      \"method\": \"Domain-specific FAK mutants (talin-binding site), FAK catalytic inhibition, vinculin-talin interaction disruption, YAP nuclear localization quantification, traction force microscopy, nuclear size measurement in fibroblasts and hMSCs on deformable substrates\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple domain-specific mutants with orthogonal mechanical and transcriptional readouts, single lab\",\n      \"pmids\": [\"38547833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SMARCE1 interacts with and potentiates HIF1A transcriptional activity upon loss of cell attachment, resulting in rapid PTK2/FAK activation; PTK2 and HIF1A are each required for SMARCE1-mediated anoikis resistance, acting through ERK/AKT activation and BIM suppression.\",\n      \"method\": \"Co-IP (SMARCE1–HIF1A), ChIP assay, SMARCE1/HIF1A/PTK2 knockdown, anoikis assay, ERK/AKT/BIM immunoblot, xenograft lung metastasis model\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, epistatic knockdowns, in vivo metastasis model, single lab\",\n      \"pmids\": [\"27495308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fibronectin induces macrophage migration through a signaling pathway in which SFK activity is required upstream of FAK activation, and FAK in turn drives ligand-independent phosphorylation and activation of CSF-1R (c-FMS); both FAK and CSF-1R are required for FN-induced macrophage migration.\",\n      \"method\": \"FAK phosphorylation immunoblot, SFK/FAK inhibitors, CSF-1R genetic knockdown and pharmacological inhibition, Co-IP (CSF-1R–β1 integrin interaction), migration assays in murine and human macrophages\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by sequential inhibition, Co-IP, both genetic and pharmacological approaches, single lab\",\n      \"pmids\": [\"27588738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FAK directly interacts with VEGFR-3 in cancer cells; disruption of this interaction with small molecule C4 causes dephosphorylation of both VEGFR-3 and FAK, reduces cell viability, causes cell-cycle arrest and apoptosis, and reduces tumor growth in murine pancreatic cancer models.\",\n      \"method\": \"Co-IP (FAK–VEGFR-3), small molecule C4 disruption, phospho-FAK/VEGFR-3 immunoblot, cell viability/apoptosis assays, subcutaneous and orthotopic murine tumor models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies complex, targeted disruption with functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"24142503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAK is required for FGF/heparin-mediated down-regulation of smooth muscle alpha-actin (myofibroblast de-differentiation); FAK-null MEFs show reduced FGFR surface expression and FGF signaling, establishing FAK as necessary for FGF signal transduction but not for TGF-β-dependent myofibroblast differentiation.\",\n      \"method\": \"FAK shRNA knockdown, FAK-/- MEFs, FGFR surface expression assay, FGF signaling readouts (ERK), alpha-SMA immunostaining, stress fiber quantification\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent loss-of-function approaches (shRNA + genetic null), receptor surface expression and signaling readouts, single lab\",\n      \"pmids\": [\"16585062\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTK2/FAK is an autoinhibited, non-receptor tyrosine kinase that localizes to focal adhesion complexes where local enrichment drives site-specific FERM-domain-mediated dimerization, enabling autophosphorylation at Tyr-397; this creates a Src SH2-docking site that initiates a kinase-dependent signaling cascade (involving p130Cas-Dock180-Rac, JNK, ERK, PI3K-Akt) required for directed cell migration, invasion, and survival, while kinase-independent nuclear FAK phosphorylates HDAC5 (Tyr-642) and regulates p53 and transcription-factor ubiquitination; FAK additionally integrates growth-factor-receptor (EGFR, PDGFR, IGF-1R) and integrin signals, phosphorylates substrates including β-catenin (Tyr-654), SQSTM1/p62 (via TBK1), and Drp1 (via ERK1/2), and is negatively regulated by DUSP22-mediated dephosphorylation of Tyr-397/576/577 and by ARHGAP21 binding to its C-terminal domain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTK2/FAK is a non-receptor tyrosine kinase that integrates integrin and growth-factor-receptor signals at focal adhesions to drive directed cell migration, invasion, and survival [#0, #3]. Adhesion-dependent activation is mediated by its N-terminal FERM domain, which engages activated PDGF- and EGF-receptor complexes and directs assembly at integrin clustering sites, while the C-terminal domain governs focal-adhesion targeting; FERM-domain point mutations abolish in-cell activation and Src-family kinase binding without altering intrinsic catalysis [#0, #4]. Mechanistically, autophosphorylation at Tyr-397 requires local enrichment at focal adhesions that promotes site-specific FERM-mediated dimerization, stabilized by a FERM–FAT interaction and reinforced by paxillin recruitment [#5]. Tyr-397 phosphorylation and kinase activity are selectively required for invasion through assembly of a FAK–Src–p130Cas–Dock180 complex that activates Rac and JNK and elevates MMP activity, defining an invasion pathway distinct from integrin-stimulated motility [#3]. FAK also transactivates receptor tyrosine kinases by activation-loop-independent phosphorylation, promoting IGF-1R stability and downstream Akt/ERK signaling and CSF-1R activation during fibronectin-induced migration [#8, #23]. Beyond the cytoplasm, catalytic inhibition forces FAK nuclear localization where it controls protein turnover and transcription, promoting TRAF6-dependent DNMT3A ubiquitination to maintain smooth-muscle differentiation and binding p53 to suppress its transcriptional activity [#16, #19]. FAK phosphorylates a diverse substrate set including HDAC5 (Tyr-642), β-catenin (Tyr-654), and—via ERK1/2—Drp1 to drive mitochondrial fission, and acts upstream of YAP nuclear localization through a talin-binding, catalysis-dependent mechanism [#9, #11, #20, #21]. FAK signaling is restrained by DUSP22, which dephosphorylates Tyr-397 and Tyr-576/577, and by ARHGAP21 binding to its C-terminal region [#14, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established which FAK modules are functionally required for migration, separating kinase activity, the Tyr-397/SH2 site, and SH3-binding regions from dispensable direct paxillin binding.\",\n      \"evidence\": \"Systematic point/deletion mutant rescue in FAK-null fibroblasts with FRNK dominant-negative and migration assays\",\n      \"pmids\": [\"10413676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how Tyr-397 phosphorylation is triggered upstream\", \"Mechanism of FRNK focal-contact localization requirement unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined FAK/p130Cas as a directionally persistent migration pathway distinct from Shc/MAPK random motility, placing FAK within a PTEN-regulated migration network.\",\n      \"evidence\": \"Overexpression epistasis in PTEN-reconstituted U87-MG cells with directionality assays\",\n      \"pmids\": [\"10427092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based, single genetic background\", \"Molecular link between FAK and directional persistence not detailed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed FAK is a receptor-proximal integrator, with the FERM domain binding activated growth-factor receptors and the C-terminus directing integrin-site targeting.\",\n      \"evidence\": \"Co-IP, domain-deletion constructs, FAK-null reconstitution, motility assays\",\n      \"pmids\": [\"10806474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FERM–receptor binding not resolved\", \"Whether transphosphorylation is intermolecular not directly shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Distinguished invasion from motility mechanistically by identifying a kinase-dependent FAK–Src–p130Cas–Dock180–Rac–JNK–MMP axis.\",\n      \"evidence\": \"FAK-null rescue with mutants, v-Src transformation, Co-IP, Rac/JNK assays, MMP zymography, invasion assays\",\n      \"pmids\": [\"12615911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial regulation of lamellipodial FAK accumulation not fully defined\", \"Direct versus indirect MMP regulation unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Localized adhesion-dependent activation to a specific FERM-domain sequence required for Src binding and in-cell tyrosine phosphorylation, distinct from intrinsic catalysis.\",\n      \"evidence\": \"FERM point mutagenesis, in vitro kinase assay, pulldown of FERM–FAK interaction, migration assays\",\n      \"pmids\": [\"15169899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show the dimeric/oligomeric nature of activation\", \"Conformational change mechanism not yet defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a kinase-activity-independent regulatory phosphorylation by Cdk5 at Ser-732 controlling centrosomal microtubules and nuclear translocation in neuronal migration.\",\n      \"evidence\": \"In vitro Cdk5 kinase assay, pS732 antibody, S732A mutant, neuronal migration assays\",\n      \"pmids\": [\"14712065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Effector linking pS732 to centrosomal microtubule structure not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided a molecular basis for FAK nuclear-cytoplasmic shuttling by mapping two conserved nuclear export signals.\",\n      \"evidence\": \"NES identification, mutational analysis, nuclear export activity assays\",\n      \"pmids\": [\"18549812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear import mechanism not addressed\", \"Physiological triggers of export not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended FAK function to receptor-tyrosine-kinase transactivation by showing it drives activation-loop-independent IGF-1R phosphorylation and stability.\",\n      \"evidence\": \"FAK-null vs WT MEFs, siRNA, IGF-1R autophosphorylation mutants, Akt/ERK and stability assays\",\n      \"pmids\": [\"19545541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FAK directly phosphorylates IGF-1R not definitively shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the activation mechanism: Tyr-397 autophosphorylation requires focal-adhesion-enriched, FERM-mediated dimerization stabilized by FERM–FAT contacts and paxillin.\",\n      \"evidence\": \"X-ray crystallography, SAXS, dimerization and autophosphorylation biochemistry, paxillin interaction and cell assays\",\n      \"pmids\": [\"24480479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of dimer assembly in live cells not directly captured\", \"How force/enrichment is sensed not fully defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a kinase-independent nuclear function: direct p53 binding that suppresses p53 transcriptional output.\",\n      \"evidence\": \"Reciprocal Co-IP, pulldown, confocal co-localization, p53 reporter assays, p53 site mutagenesis\",\n      \"pmids\": [\"21355845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural detail of the 7-residue interaction surface limited\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a FAK–VEGFR-3 complex whose disruption co-inactivates both kinases and suppresses tumor growth, expanding the RTK partner set.\",\n      \"evidence\": \"Co-IP, small-molecule C4 disruption, phospho-immunoblot, viability/apoptosis assays, murine pancreatic tumor models\",\n      \"pmids\": [\"24142503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of the phosphorylation interdependence unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked FAK to anoikis resistance and metastasis downstream of SMARCE1/HIF1A via ERK/AKT and BIM suppression.\",\n      \"evidence\": \"Co-IP, ChIP, epistatic knockdowns, anoikis assay, xenograft metastasis model\",\n      \"pmids\": [\"27495308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How attachment loss triggers PTK2 activation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed FAK in a fibronectin–SFK–FAK–CSF-1R cascade required for macrophage migration.\",\n      \"evidence\": \"Sequential SFK/FAK/CSF-1R inhibition, Co-IP, genetic and pharmacological approaches, migration assays\",\n      \"pmids\": [\"27588738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FAK directly phosphorylates CSF-1R not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed FAK is required for FGFR surface expression and FGF signaling during myofibroblast de-differentiation, independent of TGF-β.\",\n      \"evidence\": \"shRNA and FAK-null MEFs, FGFR surface assay, ERK readouts, α-SMA/stress-fiber quantification\",\n      \"pmids\": [\"16585062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FAK controls FGFR surface levels unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-cell-autonomous role: stromal FAK loss reprograms cancer-cell metabolism via chemokine–CCR1/CCR2–PKA–glycolysis paracrine signaling.\",\n      \"evidence\": \"CAF-specific conditional FAK knockout, phosphoproteomics, receptor blockade, PKA and glycolysis assays\",\n      \"pmids\": [\"32157087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FAK substrates controlling chemokine output not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded FAK substrate scope in immune signaling, showing LFA-1-activated FAK phosphorylates LAT at Y171 to form de-adhesion complexes.\",\n      \"evidence\": \"LFA-1 cross-linking, Co-IP, LAT Y171 mutant, FAK kinase assay, T-cell:DC conjugate and proliferation assays\",\n      \"pmids\": [\"28699640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Selectivity over canonical LAT kinases not fully defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified RACK1-scaffolded PDE4D as a FAK partner promoting melanoma invasion.\",\n      \"evidence\": \"Co-IP of PDE4D–FAK via RACK1, PDE4 inhibition, interaction disruption, invasion assays, in situ analysis\",\n      \"pmids\": [\"28092671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic effect of PDE4D on FAK activity not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected FAK to protein-aggregate clearance: it phosphorylates SQSTM1/p62 at Ser-403 via TBK1, and its inhibition rescues TARDBP proteinopathy.\",\n      \"evidence\": \"Inhibitor screen, pS403 immunoblot, S403A rescue, TBK1 epistasis, Drosophila TARDBP model\",\n      \"pmids\": [\"31690171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FAK acts directly on TBK1 not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established direct FAK phosphorylation of HDAC5 at Tyr-642 controlling its localization and mechanically responsive bone gene regulation.\",\n      \"evidence\": \"Direct kinase assay, phospho-specific antibody, FAK inhibition in vitro and in vivo, HDAC4/5 translocation imaging, Sost mRNA\",\n      \"pmids\": [\"32612176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How shear stress triggers FAK dephosphorylation not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a nuclear, catalysis-restraining FAK function: catalytic inhibition drives nuclear FAK to promote TRAF6-dependent DNMT3A degradation and maintain SMC differentiation.\",\n      \"evidence\": \"FAK inhibitors, conditional genetic inhibition, RNA-seq, DNMT3A ubiquitination assays, methylation analysis, TRAF6 manipulation\",\n      \"pmids\": [\"34702049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FAK directly ubiquitinates DNMT3A or scaffolds TRAF6 unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed FAK upstream of YAP via Tyr-357 phosphorylation in cholangiocarcinoma initiation.\",\n      \"evidence\": \"Conditional FAK knockout and overexpression mice, FAK inhibitor in cell lines, pY357-YAP immunoblot\",\n      \"pmids\": [\"34052254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of YAP phosphorylation by FAK not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified FAK control of β-catenin Tyr-654 phosphorylation as a cancer-stem-cell-selective vulnerability.\",\n      \"evidence\": \"FAK inhibitors, pY654-β-catenin immunoblot, constitutively active β-catenin rescue, CSC assays, xenografts\",\n      \"pmids\": [\"28881682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FAK directly phosphorylates β-catenin not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked FAK to mitochondrial dynamics through a fibronectin–FAK–ERK1/2–Drp1 fission pathway regulating cardiomyocyte respiration.\",\n      \"evidence\": \"FAK/ERK inhibition, Drp1 phospho-immunoblot, mitochondrial imaging, Seahorse OCR, ATP assays\",\n      \"pmids\": [\"34739186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Drp1 mitochondrial recruitment not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified DUSP22 as a direct negative regulator dephosphorylating FAK Tyr-397 and Tyr-576/577 to suppress ERK1/2 and NF-κB.\",\n      \"evidence\": \"Co-IP, phospho-FAK immunoblot, DUSP22 knockout/transgenic mice, AAV gene therapy\",\n      \"pmids\": [\"36209205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphatase activity inferred rather than reconstituted\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected FAK's mechanotransduction role, showing talin-binding and catalytic activity control YAP nuclear localization independent of nuclear tension and traction forces.\",\n      \"evidence\": \"Domain-specific FAK mutants, catalytic inhibition, vinculin-talin disruption, YAP localization, traction force microscopy\",\n      \"pmids\": [\"38547833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular intermediary between FAK and YAP transport not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the spatial switch between cytoplasmic/focal-adhesion FAK kinase signaling and nuclear kinase-independent functions is coordinated in vivo, and which substrate phosphorylations are direct versus indirect, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of many reported substrate phosphorylations (YAP, β-catenin, CSF-1R, IGF-1R) not established\", \"In vivo regulation of nuclear FAK localization incompletely defined\", \"Integration of force-sensing with biochemical activation not fully reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 9, 12]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5, 9, 20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [19, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 19, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 11, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 19, 21]}\n    ],\n    \"complexes\": [\"FAK-Src-p130Cas-Dock180 invasion complex\"],\n    \"partners\": [\"SRC\", \"BCAR1\", \"PXN\", \"PDGFRA\", \"EGFR\", \"IGF1R\", \"DUSP22\", \"ARHGAP21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}