{"gene":"DOK1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1997,"finding":"p62(dok)/DOK1 was identified as a novel protein constitutively tyrosine-phosphorylated in CML progenitor cells by p210(bcr-abl), and its association with p120 RasGAP correlates with its tyrosine phosphorylation state. DOK1 is also rapidly phosphorylated downstream of c-Kit receptor activation.","method":"Protein purification, co-immunoprecipitation, SDS-PAGE","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — foundational discovery paper, reciprocal co-IP, multiple cell systems, >300 citations","pmids":["9008160"],"is_preprint":false},{"year":2000,"finding":"Tyrosine-phosphorylated p62(dok) directly inhibits RasGAP catalytic activity. p210(bcr-abl) directly phosphorylates p62(dok) at C-terminal tyrosine residues, and five tyrosine residues are involved in RasGAP binding in vitro.","method":"In vitro kinase assay, in vitro RasGAP activity assay, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of enzymatic inhibition, direct phosphorylation assay with mutagenesis","pmids":["10688886"],"is_preprint":false},{"year":2000,"finding":"DOK1 negatively regulates BCR signaling and is indispensable for FcγRIIB-mediated negative regulation of B cell proliferation. DOK1 tyrosine phosphorylation is Lyn-dependent upon BCR or BCR/FcγRIIB cross-linking, and loss of dok gene results in sustained MAP kinase activation.","method":"Homologous recombination knockout, co-immunoprecipitation, kinase assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, Lyn-dependency established, replicated by independent lab","pmids":["10640270"],"is_preprint":false},{"year":2000,"finding":"FcγRIIB-BCR coaggregation leads to increased DOK1 tyrosine phosphorylation and RasGAP binding. SHIP recruits DOK1 via its phosphotyrosine-binding (PTB) domain, and DOK1 contains all structural information required to mediate FcγRIIB inhibitory effect on Erk activation.","method":"Co-immunoprecipitation, chimeric receptor functional assay, phosphorylation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus chimeric receptor rescue experiment, two orthogonal approaches","pmids":["10755621"],"is_preprint":false},{"year":1999,"finding":"DOK1 undergoes tyrosine phosphorylation in response to cell adhesion to extracellular matrix (mediated by Src family kinases) and insulin. The PH domain is required for membrane localization and tyrosine phosphorylation. Phosphorylation at Y361 mediates NCK binding, and overexpression of wild-type DOK1 (but not PH-domain or Y361F mutants) enhances insulin-stimulated cell migration.","method":"Dominant-negative mutant overexpression, co-immunoprecipitation, cell migration assays, subcellular fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including mutagenesis, localization, and functional migration assay","pmids":["10202139"],"is_preprint":false},{"year":2000,"finding":"DOK1 inhibits cellular transformation by Src tyrosine kinase. Both the PTB domain and C-terminal tail (residues 336-363) are necessary for this inhibitory activity. DOK1 homodimerizes through its PTB domain and Y146, and mutations blocking homodimerization reduce Dok1's ability to inhibit Src transformation.","method":"Combinatorial peptide library, transformation assay, co-immunoprecipitation, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — combinatorial peptide library plus mutagenesis plus functional transformation assay","pmids":["11042170"],"is_preprint":false},{"year":2001,"finding":"DOK1 acts as a negative regulator of growth factor-induced Ras/MAPK signaling and cell proliferation. Loss of p62(dok) in mice results in increased proliferation and sustained Ras/MAPK activation after growth factor removal, and accelerates p210(bcr-abl)-induced myeloproliferative disease.","method":"Gene knockout (homologous recombination), retroviral bone marrow transduction, MAPK activation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined signaling and disease phenotype, replicated by independent lab","pmids":["11489947"],"is_preprint":false},{"year":2001,"finding":"Plasma membrane recruitment of DOK1 via PI3-kinase-dependent binding of its PH domain to 3'-phosphorylated phosphoinositides is essential for its negative regulatory function on the PDGFR/MAPK pathway. This negative effect can occur independently of DOK1's ability to associate with RasGAP and Nck.","method":"Retroviral reconstitution in knockout cells, PI3K inhibitor treatment, membrane targeting constructs, cell proliferation assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — reconstitution in KO cells, pharmacological inhibition, domain-specific mutants, multiple orthogonal methods","pmids":["11489946"],"is_preprint":false},{"year":2001,"finding":"Dok-1 and Dok-2 double knockout mice spontaneously develop CML-like myeloproliferative disease with aberrant Ras/MAP kinase activation, demonstrating that these proteins are critical tumor suppressors in the hematopoietic compartment.","method":"Double gene knockout, bone marrow transplantation, MAPK activation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — double KO with strong disease phenotype, replicated by independent lab (PMID 15611294)","pmids":["15611295","15611294"],"is_preprint":false},{"year":2001,"finding":"The insulin receptor directly phosphorylates p62(dok) at Y362 and Y398. Y362 phosphorylation mediates NCK binding, Y362/Y398 phosphorylation mediates GAP binding, and these sites are essential for DOK1 to inhibit insulin-stimulated Ras and Akt activation.","method":"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, Ras and Akt activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis plus functional signaling readouts","pmids":["11551902"],"is_preprint":false},{"year":2002,"finding":"DOK1 interacts with RET receptor tyrosine kinase (identified by yeast two-hybrid). Y361 in DOK1 is the binding site for Nck; Y295, Y314, Y361, Y376, Y397, and Y408 are involved in RasGAP binding. RasGAP binding to DOK1 is required to suppress Ras/Erk activation by RET-MEN2B, while Nck binding to Y361 is necessary for JNK and c-Jun activation.","method":"Yeast two-hybrid, site-directed mutagenesis, co-immunoprecipitation, kinase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — mutagenesis of multiple sites with defined functional consequences, replicated in multiple RET contexts","pmids":["12087092"],"is_preprint":false},{"year":2002,"finding":"DOK1 acts as an adaptor linking activin receptors (serine/threonine kinase receptors) to Smad proteins. DOK1 associates with both type I and II activin receptors and with Smad3, facilitating Smad3/Smad4 association, without requiring DOK1 tyrosine phosphorylation.","method":"Co-immunoprecipitation, gene trap screen, apoptosis assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-IP showing association with receptors and Smads, novel and unexpected mechanism","pmids":["11927552"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of the DOK1 PTB domain alone and in complex with a phosphopeptide from RET receptor reveals that the RET phosphopeptide binds to a surface groove between strand β5 and the C-terminal α-helix of the PTB domain. DOK1 PTB domain does not recognize peptides from TrkA or IL-4 receptor recognized by Shc and IRS1.","method":"X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with defined molecular binding surface","pmids":["14607833"],"is_preprint":false},{"year":2004,"finding":"c-Abl tyrosine kinase phosphorylates DOK1 at Y361 upon cell adhesion, promoting DOK1 association with the SH2/SH3 adaptor Nck. This c-Abl/DOK1/Nck pathway is critical for filopodia formation during cell spreading; fibroblasts lacking c-Abl, DOK1, or Nck have fewer filopodia. DOK1 and c-Abl were both detected in filopodia of spreading cells.","method":"Mass spectrometry substrate identification, site-directed mutagenesis, knockout fibroblasts, live imaging, co-immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — unbiased substrate identification, multiple KO rescue experiments, localization, mutagenesis","pmids":["15148308"],"is_preprint":false},{"year":2004,"finding":"IKKβ associates with and phosphorylates DOK1 at S439, S443, S446, and S450 in response to TNF-α, IL-1, or γ-radiation. This serine phosphorylation is required for DOK1's ability to inhibit PDGF-induced ERK1/2 phosphorylation, cell growth inhibition, and promotion of cell motility.","method":"In vitro kinase assay, phospho-specific antisera, site-directed mutagenesis, cell proliferation and migration assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus phospho-specific antibody validation plus mutagenesis plus functional readouts","pmids":["15574499"],"is_preprint":false},{"year":2004,"finding":"DOK1 negatively regulates PDGF-stimulated c-myc induction by recruiting Csk to active Src kinases (attenuating their activity), and negatively regulates PDGF-induced MAPK activation by acting on RasGAP and other binding partners. Both pathways contribute to DOK1's inhibitory effect on mitogenesis.","method":"Knockout cells, binding-deficient DOK1 mutants, Src kinase assays, proliferation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — KO reconstitution with domain mutants, two independent pathways defined","pmids":["16537894"],"is_preprint":false},{"year":2004,"finding":"DOK1 tyrosine residues Y336 and Y340 are essential for negative regulation of Ras-Erk signaling downstream of PTKs (Lyn, Fyn) and for inhibiting v-Abl-induced cellular transformation, but are dispensable for RasGAP binding, indicating DOK1 recruits additional unidentified molecules that cooperate with RasGAP.","method":"C-terminal deletion mutants, Tyr→Phe substitutions, Ras/Erk activation assays, transformation assays","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1/2 — systematic mutagenesis with clear functional separation of binding and signaling activities","pmids":["15189452"],"is_preprint":false},{"year":2004,"finding":"DOK1 mediates SHP-2 binding to the αVβ3 integrin β3 subunit in response to IGF-I in vascular smooth muscle cells. DOK1 binds both β3 and SHP-2, and disrupting either interaction prevents IGF-I-dependent Akt and MAPK phosphorylation and cell migration/proliferation.","method":"Co-immunoprecipitation, blocking peptides, DOK1 binding-mutant expression, signaling assays, migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal approaches in a single lab study","pmids":["15546884"],"is_preprint":false},{"year":2005,"finding":"DOK1 and DOK2 are essential negative regulators downstream of TLR4 in macrophages. LPS induces DOK1 tyrosine phosphorylation; knockout macrophages show elevated Erk activation and hyperproduction of TNF-α. This negative regulation requires DOK1 tyrosine phosphorylation (Tyr/Phe mutant loses activity).","method":"Knockout mice, forced expression with phosphorylation mutants, cytokine production assays, kinase activation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined signaling phenotype, phosphorylation-mutant rescue, replicated across multiple TLR agonists","pmids":["15699069"],"is_preprint":false},{"year":2006,"finding":"DOK1 shuttles between the nucleus and cytoplasm via a functional nuclear export signal (NES: 348LLKAKLTDPKED359) dependent on CRM1. Src-induced tyrosine phosphorylation and IKKβ-dependent serine phosphorylation both promote cytoplasmic retention. Cytoplasmic localization is required for DOK1's functions in inhibiting cell proliferation and promoting cell spreading and motility.","method":"Leptomycin B treatment, NES mutant expression, live cell imaging, Src/IKKβ co-expression, functional assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — pharmacological inhibition, mutagenesis, multiple functional readouts, direct localization experiments","pmids":["16705178"],"is_preprint":false},{"year":2007,"finding":"NMR spectroscopy and X-ray crystallography reveal that unphosphorylated β3 integrin tail binds more strongly to talin than DOK1 PTB domain, but phosphorylation of Y747 in the β3 tail switches the preference, allowing DOK1 to bind much more strongly than talin, acting as an integrin activation switch.","method":"NMR spectroscopy (15N-1H HSQC titrations), X-ray crystallography, affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — structural and biophysical characterization with quantitative affinity measurements","pmids":["18156175"],"is_preprint":false},{"year":2008,"finding":"DOK1 promotes adipocyte hypertrophy by counteracting ERK-mediated inhibitory phosphorylation of PPARγ at S112. DOK1-deficient embryonic fibroblasts show increased ERK activity and elevated PPARγ-S112 phosphorylation, impairing adipogenic differentiation. Mutation of PPARγ-S112 blocks the lean phenotype caused by DOK1 ablation.","method":"Knockout mice, embryonic fibroblast differentiation assays, ERK activation assays, PPARγ phosphorylation assays, rescue experiments","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — KO mice plus rescue with PPARγ mutant, multiple orthogonal methods, clear molecular mechanism","pmids":["18204460"],"is_preprint":false},{"year":2009,"finding":"DOK1 and DOK2 PH domains bind phosphatidylinositol 5-phosphate (PtdIns5P) in vitro. PtdIns5P production in T cells correlates with and regulates DOK tyrosine phosphorylation in vivo upon TCR triggering.","method":"In vitro lipid binding assay, PtdIns5P manipulation in T cells, phosphorylation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro binding assay plus in vivo correlation with functional consequence","pmids":["19299694"],"is_preprint":false},{"year":2009,"finding":"CD45 recruits DOK1 via its SH2 domain (requiring DOK1-Y296), promotes DOK1 membrane targeting, and through DOK1, negatively regulates JAK2/STAT3/5 phosphorylation downstream of IL-3 and IFN-α stimulation.","method":"Co-immunoprecipitation, Y296F point mutant, stable DOK1 expression, DOK1 siRNA, JAK/STAT phosphorylation assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — single lab, multiple approaches including point mutant, RNAi, and stable expression","pmids":["19481264"],"is_preprint":false},{"year":2011,"finding":"Oncogenic tyrosine kinases (p210bcr-abl and oncogenic Src) target DOK1 for degradation through the ubiquitin-proteasome pathway via lysine-dependent polyubiquitination, in a manner dependent on their tyrosine kinase activity. A DOK1 mutant largely refractory to this degradation shows enhanced suppression of oncogenic transformation.","method":"Proteasome inhibitor treatment, ubiquitination assays, lysine-mutant DOK1, transformation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1/2 — ubiquitination reconstitution, proteasome inhibitor, mutagenesis, functional transformation readout","pmids":["21536658"],"is_preprint":false},{"year":2000,"finding":"SHIP1 forms a complex with DOK1 in BCR-ABL-transformed hematopoietic cells. Both the SH2 domain of SHIP1 and the PTB domain of DOK1 are required for complex formation, which is mutually exclusive with DOK1-RasGAP association. The DOK1/SHIP1 complex is only detected in the cytosolic fraction.","method":"Co-immunoprecipitation, domain-deletion mutants, subcellular fractionation","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 — domain-mapping of complex with co-IP, single lab","pmids":["10822173"],"is_preprint":false},{"year":2000,"finding":"Lck phosphorylates DOK1 (p62dok) downstream of CD2 (but not CD3) receptor stimulation in T cells. Phospho-DOK1 binds the SH2 domain of Lck in vitro, suggesting a feedback interaction.","method":"Lck/EGFR chimeric receptor system, JCaM1.6 cells, in vitro SH2 binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — engineered chimeric kinase system plus knockout Lck-deficient cells","pmids":["10799545"],"is_preprint":false},{"year":2000,"finding":"Tec protein tyrosine kinase directly phosphorylates DOK1 in vivo and in vitro and mediates signaling from the B cell antigen receptor to DOK1. This requires the Tec homology and SH2 domains of Tec plus kinase activity. DOK1 expression inhibits Ras activity in 293 cells, and dominant-negative Tec blocks BCR-induced DOK1 phosphorylation.","method":"In vitro kinase assay, dominant-negative mutants, Ras activity assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1/2 — in vitro kinase assay plus dominant-negative experiments","pmids":["10823839"],"is_preprint":false},{"year":1999,"finding":"SHP-1 is constitutively associated with p62(DOK)/DOK1 in macrophages and is a direct DOK1 phosphatase. The interaction occurs independently of DOK1 tyrosine phosphorylation (constitutive), but the SHP-1 catalytic domain associates directly and inducibly with tyrosine-phosphorylated DOK1. DOK1 is a major CSF-1R-associated tyrosine-phosphorylated protein in macrophages.","method":"Far Western analysis, co-immunoprecipitation, SHP-1-deficient motheaten mouse macrophages, catalytic mutant SHP-1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — catalytic mutant trapping, KO macrophages, far Western, multiple orthogonal approaches","pmids":["10585470"],"is_preprint":false},{"year":2000,"finding":"SH2D1A (XLP gene product) associates with DOK1 at phosphorylated Y449 via its SH2 domain; an XLP-associated SH2D1A mutant fails to associate with DOK1. Overexpression of SH2D1A activates NF-κB through a mechanism requiring IKKβ but not the SH2 domain.","method":"Co-immunoprecipitation, XLP mutant analysis, NF-κB reporter assay, dominant-negative IKKβ","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — phospho-site identified, XLP mutant validation, functional NF-κB readout","pmids":["10852966"],"is_preprint":false},{"year":2002,"finding":"DOK1 phosphorylation at Y295 and Y361 allows the SH2 domains of p120 RasGAP to bind, suppressing CrkI-driven Ras pathway activity. Abl family kinases phosphorylate these DOK1 tyrosines in the context of CrkI-transformed cells to restrain localized Ras activation.","method":"Co-immunoprecipitation, mutagenesis, FRET Ras activation sensor, RasGAP knockdown, transformation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with functional readout, FRET imaging, RasGAP knockdown","pmids":["25043303"],"is_preprint":false},{"year":2014,"finding":"DOK1 regulates PDGF-BB-induced glioma cell invasion and migration through a p130Cas-Rap1 signaling pathway. DOK1 tyrosine phosphorylation (at Y362 and Y398) is required for PDGF-BB-induced p130Cas tyrosine phosphorylation and Rap1 activation. DOK1 colocalizes with phospho-p130Cas at the cell membrane.","method":"siRNA knockdown, phosphorylation-deficient DOK1 mutant (DOK1FF), Rap1 activation assay, 3D spheroid invasion assay, co-localization imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — KD plus phospho-mutant with multiple signaling and functional readouts","pmids":["24762811"],"is_preprint":false},{"year":2014,"finding":"BRK (breast tumor kinase/PTK6) interacts with and phosphorylates DOK1 specifically at Y362, leading to ubiquitin-proteasome-mediated DOK1 degradation to promote cell proliferation and migration.","method":"Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, proteasome inhibitor treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1/2 — in vitro kinase assay with specific phosphosite identification, ubiquitination assay","pmids":["24523872"],"is_preprint":false},{"year":2023,"finding":"RasGAP SH2 domains generate distinct binding interactions with doubly phosphorylated DOK1 (and p190RhoGAP and EphB4). RasGAP-DOK1 binding involves dual SH2 domain engagement with high affinity, but these interactions do not alter RasGAP catalytic activity, implying RasGAP uses SH2 domains for spatial-temporal Ras regulation rather than allosteric activation.","method":"Affinity measurements, small-angle X-ray scattering (SAXS), RasGAP activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — quantitative affinity measurements, SAXS, enzymatic assay; single study","pmids":["37507023"],"is_preprint":false},{"year":2002,"finding":"p62(dok)/DOK1 is tyrosine-phosphorylated and forms a complex with SHIP and RasGAP upon FcγRIIB/FcεRI coaggregation in mast cells. Recruitment of DOK1 to FcεRI is sufficient to inhibit FcεRI-induced calcium mobilization and ERK1/2 activation. Both the PH/PTB domains and the C-terminal proline/tyrosine-rich region can independently mediate inhibition.","method":"Co-immunoprecipitation, chimeric receptor expression, calcium mobilization assay, ERK activation assay, knockout mast cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — chimeric receptor gain-of-function, KO validation, multiple signaling readouts","pmids":["11970986"],"is_preprint":false},{"year":2025,"finding":"14-3-3ζ interacts with the PTB domain of DOK1 even in the absence of phosphorylated integrin β tails. The 14-3-3ζ/DOK1 binary complex can simultaneously bind phosphorylated integrin β2 and β3 cytoplasmic tails, with different phosphorylated motifs preferentially recognized by each protein, constituting a bi-molecular switch in integrin regulation.","method":"NMR spectroscopy, co-immunoprecipitation, integrin tail peptide binding assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 — NMR chemical shift mapping, biophysical binding measurements, single study","pmids":["30243836"],"is_preprint":false},{"year":2009,"finding":"Proteomics of integrin αIIbβ3 outside-in signaling in platelets identified DOK1 and DOK3 as tyrosine-phosphorylated proteins upon platelet spreading on fibrinogen. DOK1 phosphorylation downstream of αIIbβ3 is Src kinase-independent (unlike GPVI-dependent phosphorylation). Both DOK1 and DOK3 inducibly interact with Grb2 and SHIP-1 in fibrinogen-spread platelets.","method":"Proteomics/mass spectrometry, Src kinase inhibitors, co-immunoprecipitation, platelet spreading assay","journal":"Journal of thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased proteomics plus pharmacological validation in human platelets","pmids":["19682241"],"is_preprint":false},{"year":2016,"finding":"DOK1 deficiency in platelets leads to increased clot retraction, enhanced PLCγ2 phosphorylation, and augmented spreading on fibrinogen after thrombin stimulation, demonstrating that DOK1 negatively regulates integrin αIIbβ3 outside-in (but not inside-out) signaling. Dok-1-/- mice show shortened bleeding times and accelerated arterial thrombosis.","method":"Dok-1 knockout mice, platelet aggregation assay, JON/A binding assay, clot retraction assay, PLCγ2 phosphorylation, intravital thrombosis model","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — clean KO, multiple orthogonal assays, in vivo thrombosis model","pmids":["26790499"],"is_preprint":false}],"current_model":"DOK1 is a multi-domain adaptor/docking protein (containing PH, PTB, and C-terminal tyrosine/serine phosphorylation sites) that is phosphorylated on tyrosines by numerous receptor and non-receptor tyrosine kinases (including BCR-ABL, c-Kit, insulin receptor, c-Abl, Lck, Tec, BRK, and RET) and on serines by IKKβ; once tyrosine-phosphorylated and membrane-recruited (via PI3K-dependent PH-domain binding to phosphoinositides), DOK1 assembles signaling complexes with RasGAP, NCK, Csk, SHIP1, SHP-2, and other effectors to act as a negative regulator of Ras/ERK and JAK/STAT signaling, suppress cell proliferation and oncogenic transformation, and promote cell migration, while its nuclear export by CRM1 and ubiquitin-proteasome-mediated degradation by oncogenic kinases provide additional layers of regulation."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of DOK1 as a BCR-ABL and c-Kit substrate that associates with RasGAP established the founding paradigm of DOK1 as a tyrosine-phosphorylated docking protein linking oncogenic kinases to Ras pathway regulation.","evidence":"Protein purification and co-IP from CML progenitor cells and c-Kit-stimulated cells","pmids":["9008160"],"confidence":"High","gaps":["Identity of the kinase(s) phosphorylating DOK1 in normal hematopoiesis was unknown","Functional consequence of DOK1-RasGAP association on Ras activity was not tested","No in vivo loss-of-function data"]},{"year":1999,"claim":"Demonstration that DOK1 requires its PH domain for membrane localization and tyrosine phosphorylation, and that phospho-Y361 recruits NCK to promote cell migration, defined the modular logic of DOK1 signaling: membrane recruitment precedes phosphorylation, which templates distinct effector outputs.","evidence":"Mutagenesis of PH domain and Y361F, subcellular fractionation, insulin-stimulated migration assay in overexpression system","pmids":["10202139"],"confidence":"High","gaps":["The lipid ligand for the PH domain was not identified","Endogenous DOK1 localization dynamics not shown"]},{"year":1999,"claim":"Discovery that SHP-1 constitutively associates with DOK1 and directly dephosphorylates it in macrophages revealed a phosphatase-based feedback loop controlling DOK1 activation state.","evidence":"Far Western, co-IP from SHP-1-deficient motheaten macrophages, catalytic-mutant trapping","pmids":["10585470"],"confidence":"High","gaps":["Specific tyrosine sites dephosphorylated by SHP-1 not mapped","Functional consequence of SHP-1 loss on DOK1-dependent signaling outputs not tested"]},{"year":2000,"claim":"Reconstitution of DOK1 as a direct inhibitor of RasGAP catalytic activity and mapping of five RasGAP-binding tyrosines provided the first biochemical mechanism for how DOK1 dampens Ras signaling.","evidence":"In vitro RasGAP activity assay with purified phospho-DOK1, site-directed mutagenesis","pmids":["10688886"],"confidence":"High","gaps":["Later work (PMID:37507023) challenged whether RasGAP catalytic activity is allosterically regulated by DOK1 binding","Cellular context dependency not explored"]},{"year":2000,"claim":"Genetic knockout revealed DOK1 as indispensable for FcγRIIB-mediated inhibition of B cell proliferation and showed that DOK1 loss causes sustained MAP kinase activation, establishing DOK1 as a physiological negative regulator rather than just a BCR-ABL substrate.","evidence":"Dok-1 homologous recombination knockout mice, BCR/FcγRIIB co-crosslinking, MAPK assays","pmids":["10640270","10755621"],"confidence":"High","gaps":["Relative contribution of DOK1 vs DOK2 in B cell inhibition not resolved","Whether DOK1 acts identically in all inhibitory receptor pathways unknown"]},{"year":2000,"claim":"Identification of SHIP1-DOK1 and DOK1-RasGAP as mutually exclusive complexes, together with multiple kinase inputs (Lck, Tec), revealed that DOK1 serves as a combinatorial signaling hub whose effector output depends on which upstream kinase phosphorylates it and which complex it enters.","evidence":"Co-IP with domain-deletion mutants, subcellular fractionation, chimeric kinase systems, dominant-negative Tec","pmids":["10822173","10799545","10823839"],"confidence":"Medium","gaps":["Quantitative selectivity between SHIP1 vs RasGAP binding not measured","Whether complex exclusivity holds in all cell types not tested"]},{"year":2001,"claim":"Reconstitution experiments in DOK1-null cells showed that PI3K-dependent PH-domain membrane recruitment is essential for DOK1's negative regulation of PDGFR/MAPK signaling and that this can occur independently of RasGAP and NCK binding, implying additional effector pathways.","evidence":"Retroviral reconstitution in KO MEFs, PI3K inhibitor, membrane-targeting domain chimeras","pmids":["11489946","11489947"],"confidence":"High","gaps":["Identity of the RasGAP/NCK-independent effector unknown","Specific PI(3,4,5)P3 vs PI(3,4)P2 dependence not resolved"]},{"year":2001,"claim":"Dok-1/Dok-2 double knockout mice spontaneously developed CML-like myeloproliferative disease with aberrant Ras/MAPK activation, definitively establishing both proteins as hematopoietic tumor suppressors.","evidence":"Double gene knockout, bone marrow transplantation, replicated by two independent groups","pmids":["15611295","15611294"],"confidence":"High","gaps":["Individual contribution of DOK1 vs DOK2 to tumor suppression not separated","Human genetic evidence for DOK1 loss in CML not provided"]},{"year":2002,"claim":"Mapping of DOK1's interaction with RET and systematic mutagenesis of six C-terminal tyrosines delineated a tyrosine code: RasGAP binding (Y295, Y314, Y361, Y376, Y397, Y408) suppresses Ras/Erk, while NCK binding (Y361) activates JNK/c-Jun, showing DOK1 routes different signaling outcomes through distinct phosphotyrosines.","evidence":"Yeast two-hybrid, site-directed mutagenesis, kinase and JNK/Erk activation assays","pmids":["12087092"],"confidence":"High","gaps":["In vivo relevance of DOK1-RET signaling axis not demonstrated","Whether all six tyrosines are simultaneously phosphorylated unknown"]},{"year":2003,"claim":"Crystal structure of the DOK1 PTB domain in complex with a RET phosphopeptide revealed the molecular basis for receptor selectivity, showing binding occurs via a groove between β5 and the C-terminal α-helix distinct from Shc/IRS1 PTB recognition.","evidence":"X-ray crystallography at atomic resolution","pmids":["14607833"],"confidence":"High","gaps":["Full-length DOK1 structure unavailable","How PH domain orientation relative to PTB domain affects receptor engagement unknown"]},{"year":2004,"claim":"Identification of c-Abl as the kinase phosphorylating DOK1-Y361 during cell adhesion, and demonstration that the c-Abl/DOK1/NCK pathway drives filopodia formation, connected DOK1 to cytoskeletal remodeling beyond its role as a purely inhibitory signal dampener.","evidence":"Mass spectrometry substrate identification, KO fibroblasts, live imaging of spreading cells","pmids":["15148308"],"confidence":"High","gaps":["Downstream effectors of NCK linking DOK1 to actin polymerization not identified","Whether this pathway operates in hematopoietic cells not tested"]},{"year":2004,"claim":"Discovery that IKKβ phosphorylates DOK1 at four C-terminal serines in response to TNF-α/IL-1 revealed cross-talk between NF-κB and RTK signaling, with serine phosphorylation required for DOK1's ability to inhibit PDGF-induced ERK activation and promote cell motility.","evidence":"In vitro kinase assay, phospho-specific antibodies, serine-to-alanine mutagenesis, proliferation and migration assays","pmids":["15574499"],"confidence":"High","gaps":["Whether IKKβ and tyrosine kinase phosphorylation are cooperative or sequential unknown","Structural basis for serine phosphorylation-dependent activation not determined"]},{"year":2004,"claim":"Demonstration that DOK1 recruits Csk to attenuate Src kinase activity and suppress PDGF-induced c-myc, in parallel with RasGAP-mediated MAPK inhibition, established that DOK1 operates through at least two independent inhibitory arms to block mitogenesis.","evidence":"KO reconstitution with binding-deficient DOK1 mutants, Src kinase activity assays","pmids":["16537894"],"confidence":"High","gaps":["Direct Csk-DOK1 binding interface not mapped","Quantitative contribution of each arm to proliferation control not determined"]},{"year":2005,"claim":"Extension of DOK1's inhibitory role to innate immunity showed that DOK1/DOK2 are essential negative regulators of TLR4-Erk signaling in macrophages, preventing TNF-α hyperproduction, broadening DOK1's role beyond receptor tyrosine kinase pathways.","evidence":"Dok-1/Dok-2 KO macrophages, forced expression of phosphorylation-deficient DOK1, cytokine assays","pmids":["15699069"],"confidence":"High","gaps":["How TLR4 (a non-tyrosine kinase receptor) triggers DOK1 tyrosine phosphorylation not defined","Whether DOK1 acts on TLR4-proximal or distal signaling steps unclear"]},{"year":2006,"claim":"Identification of a CRM1-dependent NES in DOK1 and demonstration that both Src-mediated tyrosine and IKKβ-mediated serine phosphorylation promote cytoplasmic retention resolved how DOK1 subcellular localization is regulated and why cytoplasmic localization is required for its anti-proliferative and pro-migratory functions.","evidence":"Leptomycin B treatment, NES mutagenesis, live cell imaging, functional assays","pmids":["16705178"],"confidence":"High","gaps":["Nuclear function of DOK1, if any, not characterized","Whether nuclear-cytoplasmic shuttling is dynamically regulated during cell cycle unknown"]},{"year":2007,"claim":"Structural and biophysical studies showed that phosphorylation of integrin β3-Y747 switches binding preference from talin to the DOK1 PTB domain, establishing DOK1 as a phosphorylation-dependent integrin activation switch.","evidence":"NMR titrations and X-ray crystallography with quantitative affinity measurements","pmids":["18156175"],"confidence":"High","gaps":["In vivo validation of this switch in platelet or endothelial integrin signaling not provided at the time","Whether DOK1 binding actively inactivates integrin or simply displaces talin not resolved"]},{"year":2008,"claim":"DOK1 was linked to metabolic regulation: DOK1-null mice are lean because elevated ERK activity causes inhibitory phosphorylation of PPARγ-S112, impairing adipogenesis—a phenotype rescued by PPARγ-S112A mutation.","evidence":"KO mice, MEF adipogenesis assay, ERK and PPARγ phosphorylation, genetic rescue","pmids":["18204460"],"confidence":"High","gaps":["Whether DOK1 acts cell-autonomously in adipocytes or through systemic effects not fully resolved","Upstream kinase phosphorylating DOK1 in adipocyte precursors not identified"]},{"year":2011,"claim":"Discovery that oncogenic kinases (BCR-ABL, Src) target DOK1 for lysine-dependent polyubiquitination and proteasomal degradation provided a mechanism by which oncogenes neutralize DOK1 tumor suppression, and a degradation-resistant DOK1 mutant showed enhanced anti-transformation activity.","evidence":"Ubiquitination assays, proteasome inhibitor, lysine-to-arginine mutants, transformation assays","pmids":["21536658"],"confidence":"High","gaps":["The E3 ubiquitin ligase responsible not identified","Whether this degradation pathway operates in primary human leukemias unknown"]},{"year":2016,"claim":"DOK1-knockout platelet studies demonstrated that DOK1 negatively regulates integrin αIIbβ3 outside-in signaling, controlling PLCγ2 phosphorylation, clot retraction, and in vivo thrombosis, directly validating the structural prediction that DOK1 modulates integrin signaling in a physiological context.","evidence":"Dok-1 KO mice, platelet aggregation, clot retraction, intravital thrombosis model","pmids":["26790499"],"confidence":"High","gaps":["Mechanism by which DOK1 restrains PLCγ2 phosphorylation not defined","Whether DOK1 acts through Csk or RasGAP in platelets not tested"]},{"year":2023,"claim":"Quantitative binding and enzymatic studies revealed that while RasGAP SH2 domains engage doubly phosphorylated DOK1 with high affinity, this binding does not allosterically alter RasGAP catalytic activity, suggesting DOK1 regulates Ras spatiotemporally by relocalizing RasGAP rather than activating it.","evidence":"Affinity measurements, SAXS, in vitro RasGAP activity assay","pmids":["37507023"],"confidence":"Medium","gaps":["Contradicts earlier claim (PMID:10688886) that DOK1 inhibits RasGAP activity; resolution unclear","Spatial redistribution model not validated in cells","Single study without independent replication"]},{"year":null,"claim":"Key unresolved questions include the identity of the E3 ligase mediating DOK1 degradation, the nuclear function (if any) of DOK1, the full set of effectors recruited by Y336/Y340 that operate independently of RasGAP, and whether DOK1 loss or silencing is causally linked to human cancers.","evidence":"","pmids":[],"confidence":"Low","gaps":["E3 ubiquitin ligase for DOK1 not identified","Nuclear role of DOK1 uncharacterized","No human genetic evidence for DOK1 as a tumor suppressor in patients"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4,9,10,11,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,6,15,16,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,7,20,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,6,7,9,10,15,18,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,18,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,24]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[36,37]}],"complexes":[],"partners":["RASA1","NCK1","SHIP1","CSK","SHP1","SHP2","GRB2","YWHAZ"],"other_free_text":[]},"mechanistic_narrative":"DOK1 is a multi-domain docking protein that functions as a broad negative regulator of Ras/ERK, JAK/STAT, and Akt signaling downstream of diverse receptor and non-receptor tyrosine kinases in hematopoietic, mesenchymal, and epithelial cells. Upon tyrosine phosphorylation by kinases including BCR-ABL, c-Abl, Lck, Tec, RET, insulin receptor, and Src family members, DOK1 is recruited to the plasma membrane via PI3K-dependent PH-domain binding to phosphoinositides and assembles inhibitory signaling complexes through its phosphorylated C-terminal tyrosines—recruiting RasGAP (via Y295/Y314/Y361/Y376/Y397/Y408), NCK (via Y361), Csk, SHIP1, and SHP-1/SHP-2—to attenuate mitogenic signaling, suppress oncogenic transformation, and modulate cell migration and integrin outside-in signaling [PMID:9008160, PMID:10688886, PMID:10640270, PMID:11489947, PMID:15148308, PMID:26790499]. Dok-1/Dok-2 double-knockout mice spontaneously develop CML-like myeloproliferative disease, establishing DOK1 as a bona fide tumor suppressor in the hematopoietic compartment [PMID:15611295]. DOK1 activity is regulated at multiple levels: CRM1-dependent nucleocytoplasmic shuttling controls its cytoplasmic availability, IKKβ-mediated serine phosphorylation modulates its signaling output, and oncogenic kinases target it for ubiquitin-proteasome-mediated degradation to overcome its tumor-suppressive function [PMID:16705178, PMID:15574499, PMID:21536658]."},"prefetch_data":{"uniprot":{"accession":"Q99704","full_name":"Docking protein 1","aliases":["Downstream of tyrosine kinase 1","p62(dok)","pp62"],"length_aa":481,"mass_kda":52.4,"function":"DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK1 appears to be a negative regulator of the insulin signaling pathway. Modulates integrin activation by competing with talin for the same binding site on ITGB3","subcellular_location":"Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q99704/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOK1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DOK1","total_profiled":1310},"omim":[{"mim_id":"617797","title":"SRC-RELATED KINASE LACKING C-TERMINAL REGULATORY TYROSINE AND N-TERMINAL MYRISTYLATION SITES; SRMS","url":"https://www.omim.org/entry/617797"},{"mim_id":"611435","title":"DOCKING PROTEIN 3; DOK3","url":"https://www.omim.org/entry/611435"},{"mim_id":"611402","title":"DOCKING PROTEIN 6; DOK6","url":"https://www.omim.org/entry/611402"},{"mim_id":"604997","title":"DOCKING PROTEIN 2; DOK2","url":"https://www.omim.org/entry/604997"},{"mim_id":"604590","title":"Fc FRAGMENT OF IgG RECEPTOR IIb; FCGR2B","url":"https://www.omim.org/entry/604590"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DOK1"},"hgnc":{"alias_symbol":["p62dok"],"prev_symbol":[]},"alphafold":{"accession":"Q99704","domains":[{"cath_id":"2.30.29.30","chopping":"7-48_61-119","consensus_level":"high","plddt":89.8789,"start":7,"end":119},{"cath_id":"2.30.29.30","chopping":"154-257","consensus_level":"high","plddt":93.7483,"start":154,"end":257}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99704","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99704-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99704-F1-predicted_aligned_error_v6.png","plddt_mean":67.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DOK1","jax_strain_url":"https://www.jax.org/strain/search?query=DOK1"},"sequence":{"accession":"Q99704","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99704.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99704/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99704"}},"corpus_meta":[{"pmid":"9008160","id":"PMC_9008160","title":"p62(dok): 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Burkitt's lymphoma cell lines.","date":"2005","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/16338067","citation_count":12,"is_preprint":false},{"pmid":"15655368","id":"PMC_15655368","title":"Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation.","date":"2005","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/15655368","citation_count":11,"is_preprint":false},{"pmid":"26790499","id":"PMC_26790499","title":"Dok-1 negatively regulates platelet integrin αIIbβ3 outside-in signalling and inhibits thrombosis in mice.","date":"2016","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/26790499","citation_count":11,"is_preprint":false},{"pmid":"14705142","id":"PMC_14705142","title":"High-level expression of Dok-1 in neurons of the primate prefrontal cortex and hippocampus.","date":"2004","source":"Journal of neuroscience 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/30243836","citation_count":9,"is_preprint":false},{"pmid":"37507023","id":"PMC_37507023","title":"Diverse p120RasGAP interactions with doubly phosphorylated partners EphB4, p190RhoGAP, and Dok1.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37507023","citation_count":8,"is_preprint":false},{"pmid":"27664281","id":"PMC_27664281","title":"Dok-1 and Dok-2 Regulate the Formation of Memory CD8+ T Cells.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27664281","citation_count":8,"is_preprint":false},{"pmid":"22370159","id":"PMC_22370159","title":"The inositol 5-phosphatase SHIP-1 and adaptors Dok-1 and 2 play central roles in CD4-mediated inhibitory signaling.","date":"2012","source":"Immunology 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p62Dok tyrosine phosphorylation by CD3 in Jurkat T cells.","date":"2000","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11093148","citation_count":6,"is_preprint":false},{"pmid":"15541476","id":"PMC_15541476","title":"Germline mutations in Dok1 do not predispose to chronic lymphocytic leukemia.","date":"2005","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/15541476","citation_count":6,"is_preprint":false},{"pmid":"34941983","id":"PMC_34941983","title":"Expression of the EGFR-RAS Inhibitory Proteins DOK1 and MTMR7 and its Significance in Colorectal Adenoma and Adenoma Recurrence.","date":"2021","source":"Journal of gastrointestinal and liver diseases : JGLD","url":"https://pubmed.ncbi.nlm.nih.gov/34941983","citation_count":6,"is_preprint":false},{"pmid":"22736313","id":"PMC_22736313","title":"Dok-1 overexpression promotes development of γδ natural killer T cells.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22736313","citation_count":6,"is_preprint":false},{"pmid":"31919752","id":"PMC_31919752","title":"Analysis of the DOK1 gene in breast cancer.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31919752","citation_count":5,"is_preprint":false},{"pmid":"27450811","id":"PMC_27450811","title":"Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27450811","citation_count":5,"is_preprint":false},{"pmid":"39513119","id":"PMC_39513119","title":"DOK1 facilitates the advancement of ccRCC.","date":"2024","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39513119","citation_count":4,"is_preprint":false},{"pmid":"35421591","id":"PMC_35421591","title":"Dok-1 regulates mast cell degranulation negatively through inhibiting calcium-dependent F-actin disassembly.","date":"2022","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/35421591","citation_count":4,"is_preprint":false},{"pmid":"38956389","id":"PMC_38956389","title":"DOK1 and DOK2 regulate CD8 T cell signaling and memory formation without affecting tumor cell killing.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38956389","citation_count":4,"is_preprint":false},{"pmid":"27265473","id":"PMC_27265473","title":"Expression of DOK1, 2, and 3 genes in HTLV-1-infected T cells.","date":"2016","source":"Acta virologica","url":"https://pubmed.ncbi.nlm.nih.gov/27265473","citation_count":3,"is_preprint":false},{"pmid":"11054720","id":"PMC_11054720","title":"In vitro-generated stem cell leukaemia showing altered cell cycle progression with distinct signalling of the tyrosine-phosphorylated rasGAP-associated p62(dok) protein.","date":"2000","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11054720","citation_count":3,"is_preprint":false},{"pmid":"14747716","id":"PMC_14747716","title":"Expression, crystallization and preliminary X-ray studies of the recombinant PTB domain of mouse dok1 protein.","date":"2004","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/14747716","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45854,"output_tokens":8732,"usd":0.134271},"stage2":{"model":"claude-opus-4-6","input_tokens":12709,"output_tokens":4935,"usd":0.28038},"total_usd":0.414651,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"p62(dok)/DOK1 was identified as a novel protein constitutively tyrosine-phosphorylated in CML progenitor cells by p210(bcr-abl), and its association with p120 RasGAP correlates with its tyrosine phosphorylation state. DOK1 is also rapidly phosphorylated downstream of c-Kit receptor activation.\",\n      \"method\": \"Protein purification, co-immunoprecipitation, SDS-PAGE\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational discovery paper, reciprocal co-IP, multiple cell systems, >300 citations\",\n      \"pmids\": [\"9008160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Tyrosine-phosphorylated p62(dok) directly inhibits RasGAP catalytic activity. p210(bcr-abl) directly phosphorylates p62(dok) at C-terminal tyrosine residues, and five tyrosine residues are involved in RasGAP binding in vitro.\",\n      \"method\": \"In vitro kinase assay, in vitro RasGAP activity assay, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of enzymatic inhibition, direct phosphorylation assay with mutagenesis\",\n      \"pmids\": [\"10688886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DOK1 negatively regulates BCR signaling and is indispensable for FcγRIIB-mediated negative regulation of B cell proliferation. DOK1 tyrosine phosphorylation is Lyn-dependent upon BCR or BCR/FcγRIIB cross-linking, and loss of dok gene results in sustained MAP kinase activation.\",\n      \"method\": \"Homologous recombination knockout, co-immunoprecipitation, kinase assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, Lyn-dependency established, replicated by independent lab\",\n      \"pmids\": [\"10640270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FcγRIIB-BCR coaggregation leads to increased DOK1 tyrosine phosphorylation and RasGAP binding. SHIP recruits DOK1 via its phosphotyrosine-binding (PTB) domain, and DOK1 contains all structural information required to mediate FcγRIIB inhibitory effect on Erk activation.\",\n      \"method\": \"Co-immunoprecipitation, chimeric receptor functional assay, phosphorylation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus chimeric receptor rescue experiment, two orthogonal approaches\",\n      \"pmids\": [\"10755621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"DOK1 undergoes tyrosine phosphorylation in response to cell adhesion to extracellular matrix (mediated by Src family kinases) and insulin. The PH domain is required for membrane localization and tyrosine phosphorylation. Phosphorylation at Y361 mediates NCK binding, and overexpression of wild-type DOK1 (but not PH-domain or Y361F mutants) enhances insulin-stimulated cell migration.\",\n      \"method\": \"Dominant-negative mutant overexpression, co-immunoprecipitation, cell migration assays, subcellular fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including mutagenesis, localization, and functional migration assay\",\n      \"pmids\": [\"10202139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DOK1 inhibits cellular transformation by Src tyrosine kinase. Both the PTB domain and C-terminal tail (residues 336-363) are necessary for this inhibitory activity. DOK1 homodimerizes through its PTB domain and Y146, and mutations blocking homodimerization reduce Dok1's ability to inhibit Src transformation.\",\n      \"method\": \"Combinatorial peptide library, transformation assay, co-immunoprecipitation, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — combinatorial peptide library plus mutagenesis plus functional transformation assay\",\n      \"pmids\": [\"11042170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DOK1 acts as a negative regulator of growth factor-induced Ras/MAPK signaling and cell proliferation. Loss of p62(dok) in mice results in increased proliferation and sustained Ras/MAPK activation after growth factor removal, and accelerates p210(bcr-abl)-induced myeloproliferative disease.\",\n      \"method\": \"Gene knockout (homologous recombination), retroviral bone marrow transduction, MAPK activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined signaling and disease phenotype, replicated by independent lab\",\n      \"pmids\": [\"11489947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Plasma membrane recruitment of DOK1 via PI3-kinase-dependent binding of its PH domain to 3'-phosphorylated phosphoinositides is essential for its negative regulatory function on the PDGFR/MAPK pathway. This negative effect can occur independently of DOK1's ability to associate with RasGAP and Nck.\",\n      \"method\": \"Retroviral reconstitution in knockout cells, PI3K inhibitor treatment, membrane targeting constructs, cell proliferation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution in KO cells, pharmacological inhibition, domain-specific mutants, multiple orthogonal methods\",\n      \"pmids\": [\"11489946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Dok-1 and Dok-2 double knockout mice spontaneously develop CML-like myeloproliferative disease with aberrant Ras/MAP kinase activation, demonstrating that these proteins are critical tumor suppressors in the hematopoietic compartment.\",\n      \"method\": \"Double gene knockout, bone marrow transplantation, MAPK activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double KO with strong disease phenotype, replicated by independent lab (PMID 15611294)\",\n      \"pmids\": [\"15611295\", \"15611294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The insulin receptor directly phosphorylates p62(dok) at Y362 and Y398. Y362 phosphorylation mediates NCK binding, Y362/Y398 phosphorylation mediates GAP binding, and these sites are essential for DOK1 to inhibit insulin-stimulated Ras and Akt activation.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, Ras and Akt activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus functional signaling readouts\",\n      \"pmids\": [\"11551902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DOK1 interacts with RET receptor tyrosine kinase (identified by yeast two-hybrid). Y361 in DOK1 is the binding site for Nck; Y295, Y314, Y361, Y376, Y397, and Y408 are involved in RasGAP binding. RasGAP binding to DOK1 is required to suppress Ras/Erk activation by RET-MEN2B, while Nck binding to Y361 is necessary for JNK and c-Jun activation.\",\n      \"method\": \"Yeast two-hybrid, site-directed mutagenesis, co-immunoprecipitation, kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis of multiple sites with defined functional consequences, replicated in multiple RET contexts\",\n      \"pmids\": [\"12087092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DOK1 acts as an adaptor linking activin receptors (serine/threonine kinase receptors) to Smad proteins. DOK1 associates with both type I and II activin receptors and with Smad3, facilitating Smad3/Smad4 association, without requiring DOK1 tyrosine phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, gene trap screen, apoptosis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP showing association with receptors and Smads, novel and unexpected mechanism\",\n      \"pmids\": [\"11927552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of the DOK1 PTB domain alone and in complex with a phosphopeptide from RET receptor reveals that the RET phosphopeptide binds to a surface groove between strand β5 and the C-terminal α-helix of the PTB domain. DOK1 PTB domain does not recognize peptides from TrkA or IL-4 receptor recognized by Shc and IRS1.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with defined molecular binding surface\",\n      \"pmids\": [\"14607833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"c-Abl tyrosine kinase phosphorylates DOK1 at Y361 upon cell adhesion, promoting DOK1 association with the SH2/SH3 adaptor Nck. This c-Abl/DOK1/Nck pathway is critical for filopodia formation during cell spreading; fibroblasts lacking c-Abl, DOK1, or Nck have fewer filopodia. DOK1 and c-Abl were both detected in filopodia of spreading cells.\",\n      \"method\": \"Mass spectrometry substrate identification, site-directed mutagenesis, knockout fibroblasts, live imaging, co-immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — unbiased substrate identification, multiple KO rescue experiments, localization, mutagenesis\",\n      \"pmids\": [\"15148308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IKKβ associates with and phosphorylates DOK1 at S439, S443, S446, and S450 in response to TNF-α, IL-1, or γ-radiation. This serine phosphorylation is required for DOK1's ability to inhibit PDGF-induced ERK1/2 phosphorylation, cell growth inhibition, and promotion of cell motility.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antisera, site-directed mutagenesis, cell proliferation and migration assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus phospho-specific antibody validation plus mutagenesis plus functional readouts\",\n      \"pmids\": [\"15574499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DOK1 negatively regulates PDGF-stimulated c-myc induction by recruiting Csk to active Src kinases (attenuating their activity), and negatively regulates PDGF-induced MAPK activation by acting on RasGAP and other binding partners. Both pathways contribute to DOK1's inhibitory effect on mitogenesis.\",\n      \"method\": \"Knockout cells, binding-deficient DOK1 mutants, Src kinase assays, proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO reconstitution with domain mutants, two independent pathways defined\",\n      \"pmids\": [\"16537894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DOK1 tyrosine residues Y336 and Y340 are essential for negative regulation of Ras-Erk signaling downstream of PTKs (Lyn, Fyn) and for inhibiting v-Abl-induced cellular transformation, but are dispensable for RasGAP binding, indicating DOK1 recruits additional unidentified molecules that cooperate with RasGAP.\",\n      \"method\": \"C-terminal deletion mutants, Tyr→Phe substitutions, Ras/Erk activation assays, transformation assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — systematic mutagenesis with clear functional separation of binding and signaling activities\",\n      \"pmids\": [\"15189452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DOK1 mediates SHP-2 binding to the αVβ3 integrin β3 subunit in response to IGF-I in vascular smooth muscle cells. DOK1 binds both β3 and SHP-2, and disrupting either interaction prevents IGF-I-dependent Akt and MAPK phosphorylation and cell migration/proliferation.\",\n      \"method\": \"Co-immunoprecipitation, blocking peptides, DOK1 binding-mutant expression, signaling assays, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches in a single lab study\",\n      \"pmids\": [\"15546884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DOK1 and DOK2 are essential negative regulators downstream of TLR4 in macrophages. LPS induces DOK1 tyrosine phosphorylation; knockout macrophages show elevated Erk activation and hyperproduction of TNF-α. This negative regulation requires DOK1 tyrosine phosphorylation (Tyr/Phe mutant loses activity).\",\n      \"method\": \"Knockout mice, forced expression with phosphorylation mutants, cytokine production assays, kinase activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined signaling phenotype, phosphorylation-mutant rescue, replicated across multiple TLR agonists\",\n      \"pmids\": [\"15699069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DOK1 shuttles between the nucleus and cytoplasm via a functional nuclear export signal (NES: 348LLKAKLTDPKED359) dependent on CRM1. Src-induced tyrosine phosphorylation and IKKβ-dependent serine phosphorylation both promote cytoplasmic retention. Cytoplasmic localization is required for DOK1's functions in inhibiting cell proliferation and promoting cell spreading and motility.\",\n      \"method\": \"Leptomycin B treatment, NES mutant expression, live cell imaging, Src/IKKβ co-expression, functional assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition, mutagenesis, multiple functional readouts, direct localization experiments\",\n      \"pmids\": [\"16705178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NMR spectroscopy and X-ray crystallography reveal that unphosphorylated β3 integrin tail binds more strongly to talin than DOK1 PTB domain, but phosphorylation of Y747 in the β3 tail switches the preference, allowing DOK1 to bind much more strongly than talin, acting as an integrin activation switch.\",\n      \"method\": \"NMR spectroscopy (15N-1H HSQC titrations), X-ray crystallography, affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and biophysical characterization with quantitative affinity measurements\",\n      \"pmids\": [\"18156175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DOK1 promotes adipocyte hypertrophy by counteracting ERK-mediated inhibitory phosphorylation of PPARγ at S112. DOK1-deficient embryonic fibroblasts show increased ERK activity and elevated PPARγ-S112 phosphorylation, impairing adipogenic differentiation. Mutation of PPARγ-S112 blocks the lean phenotype caused by DOK1 ablation.\",\n      \"method\": \"Knockout mice, embryonic fibroblast differentiation assays, ERK activation assays, PPARγ phosphorylation assays, rescue experiments\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice plus rescue with PPARγ mutant, multiple orthogonal methods, clear molecular mechanism\",\n      \"pmids\": [\"18204460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DOK1 and DOK2 PH domains bind phosphatidylinositol 5-phosphate (PtdIns5P) in vitro. PtdIns5P production in T cells correlates with and regulates DOK tyrosine phosphorylation in vivo upon TCR triggering.\",\n      \"method\": \"In vitro lipid binding assay, PtdIns5P manipulation in T cells, phosphorylation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding assay plus in vivo correlation with functional consequence\",\n      \"pmids\": [\"19299694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD45 recruits DOK1 via its SH2 domain (requiring DOK1-Y296), promotes DOK1 membrane targeting, and through DOK1, negatively regulates JAK2/STAT3/5 phosphorylation downstream of IL-3 and IFN-α stimulation.\",\n      \"method\": \"Co-immunoprecipitation, Y296F point mutant, stable DOK1 expression, DOK1 siRNA, JAK/STAT phosphorylation assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab, multiple approaches including point mutant, RNAi, and stable expression\",\n      \"pmids\": [\"19481264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Oncogenic tyrosine kinases (p210bcr-abl and oncogenic Src) target DOK1 for degradation through the ubiquitin-proteasome pathway via lysine-dependent polyubiquitination, in a manner dependent on their tyrosine kinase activity. A DOK1 mutant largely refractory to this degradation shows enhanced suppression of oncogenic transformation.\",\n      \"method\": \"Proteasome inhibitor treatment, ubiquitination assays, lysine-mutant DOK1, transformation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — ubiquitination reconstitution, proteasome inhibitor, mutagenesis, functional transformation readout\",\n      \"pmids\": [\"21536658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHIP1 forms a complex with DOK1 in BCR-ABL-transformed hematopoietic cells. Both the SH2 domain of SHIP1 and the PTB domain of DOK1 are required for complex formation, which is mutually exclusive with DOK1-RasGAP association. The DOK1/SHIP1 complex is only detected in the cytosolic fraction.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mutants, subcellular fractionation\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — domain-mapping of complex with co-IP, single lab\",\n      \"pmids\": [\"10822173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Lck phosphorylates DOK1 (p62dok) downstream of CD2 (but not CD3) receptor stimulation in T cells. Phospho-DOK1 binds the SH2 domain of Lck in vitro, suggesting a feedback interaction.\",\n      \"method\": \"Lck/EGFR chimeric receptor system, JCaM1.6 cells, in vitro SH2 binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — engineered chimeric kinase system plus knockout Lck-deficient cells\",\n      \"pmids\": [\"10799545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Tec protein tyrosine kinase directly phosphorylates DOK1 in vivo and in vitro and mediates signaling from the B cell antigen receptor to DOK1. This requires the Tec homology and SH2 domains of Tec plus kinase activity. DOK1 expression inhibits Ras activity in 293 cells, and dominant-negative Tec blocks BCR-induced DOK1 phosphorylation.\",\n      \"method\": \"In vitro kinase assay, dominant-negative mutants, Ras activity assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assay plus dominant-negative experiments\",\n      \"pmids\": [\"10823839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SHP-1 is constitutively associated with p62(DOK)/DOK1 in macrophages and is a direct DOK1 phosphatase. The interaction occurs independently of DOK1 tyrosine phosphorylation (constitutive), but the SHP-1 catalytic domain associates directly and inducibly with tyrosine-phosphorylated DOK1. DOK1 is a major CSF-1R-associated tyrosine-phosphorylated protein in macrophages.\",\n      \"method\": \"Far Western analysis, co-immunoprecipitation, SHP-1-deficient motheaten mouse macrophages, catalytic mutant SHP-1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — catalytic mutant trapping, KO macrophages, far Western, multiple orthogonal approaches\",\n      \"pmids\": [\"10585470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SH2D1A (XLP gene product) associates with DOK1 at phosphorylated Y449 via its SH2 domain; an XLP-associated SH2D1A mutant fails to associate with DOK1. Overexpression of SH2D1A activates NF-κB through a mechanism requiring IKKβ but not the SH2 domain.\",\n      \"method\": \"Co-immunoprecipitation, XLP mutant analysis, NF-κB reporter assay, dominant-negative IKKβ\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phospho-site identified, XLP mutant validation, functional NF-κB readout\",\n      \"pmids\": [\"10852966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DOK1 phosphorylation at Y295 and Y361 allows the SH2 domains of p120 RasGAP to bind, suppressing CrkI-driven Ras pathway activity. Abl family kinases phosphorylate these DOK1 tyrosines in the context of CrkI-transformed cells to restrain localized Ras activation.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, FRET Ras activation sensor, RasGAP knockdown, transformation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with functional readout, FRET imaging, RasGAP knockdown\",\n      \"pmids\": [\"25043303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOK1 regulates PDGF-BB-induced glioma cell invasion and migration through a p130Cas-Rap1 signaling pathway. DOK1 tyrosine phosphorylation (at Y362 and Y398) is required for PDGF-BB-induced p130Cas tyrosine phosphorylation and Rap1 activation. DOK1 colocalizes with phospho-p130Cas at the cell membrane.\",\n      \"method\": \"siRNA knockdown, phosphorylation-deficient DOK1 mutant (DOK1FF), Rap1 activation assay, 3D spheroid invasion assay, co-localization imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD plus phospho-mutant with multiple signaling and functional readouts\",\n      \"pmids\": [\"24762811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRK (breast tumor kinase/PTK6) interacts with and phosphorylates DOK1 specifically at Y362, leading to ubiquitin-proteasome-mediated DOK1 degradation to promote cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, proteasome inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assay with specific phosphosite identification, ubiquitination assay\",\n      \"pmids\": [\"24523872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RasGAP SH2 domains generate distinct binding interactions with doubly phosphorylated DOK1 (and p190RhoGAP and EphB4). RasGAP-DOK1 binding involves dual SH2 domain engagement with high affinity, but these interactions do not alter RasGAP catalytic activity, implying RasGAP uses SH2 domains for spatial-temporal Ras regulation rather than allosteric activation.\",\n      \"method\": \"Affinity measurements, small-angle X-ray scattering (SAXS), RasGAP activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — quantitative affinity measurements, SAXS, enzymatic assay; single study\",\n      \"pmids\": [\"37507023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p62(dok)/DOK1 is tyrosine-phosphorylated and forms a complex with SHIP and RasGAP upon FcγRIIB/FcεRI coaggregation in mast cells. Recruitment of DOK1 to FcεRI is sufficient to inhibit FcεRI-induced calcium mobilization and ERK1/2 activation. Both the PH/PTB domains and the C-terminal proline/tyrosine-rich region can independently mediate inhibition.\",\n      \"method\": \"Co-immunoprecipitation, chimeric receptor expression, calcium mobilization assay, ERK activation assay, knockout mast cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chimeric receptor gain-of-function, KO validation, multiple signaling readouts\",\n      \"pmids\": [\"11970986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"14-3-3ζ interacts with the PTB domain of DOK1 even in the absence of phosphorylated integrin β tails. The 14-3-3ζ/DOK1 binary complex can simultaneously bind phosphorylated integrin β2 and β3 cytoplasmic tails, with different phosphorylated motifs preferentially recognized by each protein, constituting a bi-molecular switch in integrin regulation.\",\n      \"method\": \"NMR spectroscopy, co-immunoprecipitation, integrin tail peptide binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR chemical shift mapping, biophysical binding measurements, single study\",\n      \"pmids\": [\"30243836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Proteomics of integrin αIIbβ3 outside-in signaling in platelets identified DOK1 and DOK3 as tyrosine-phosphorylated proteins upon platelet spreading on fibrinogen. DOK1 phosphorylation downstream of αIIbβ3 is Src kinase-independent (unlike GPVI-dependent phosphorylation). Both DOK1 and DOK3 inducibly interact with Grb2 and SHIP-1 in fibrinogen-spread platelets.\",\n      \"method\": \"Proteomics/mass spectrometry, Src kinase inhibitors, co-immunoprecipitation, platelet spreading assay\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomics plus pharmacological validation in human platelets\",\n      \"pmids\": [\"19682241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DOK1 deficiency in platelets leads to increased clot retraction, enhanced PLCγ2 phosphorylation, and augmented spreading on fibrinogen after thrombin stimulation, demonstrating that DOK1 negatively regulates integrin αIIbβ3 outside-in (but not inside-out) signaling. Dok-1-/- mice show shortened bleeding times and accelerated arterial thrombosis.\",\n      \"method\": \"Dok-1 knockout mice, platelet aggregation assay, JON/A binding assay, clot retraction assay, PLCγ2 phosphorylation, intravital thrombosis model\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO, multiple orthogonal assays, in vivo thrombosis model\",\n      \"pmids\": [\"26790499\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOK1 is a multi-domain adaptor/docking protein (containing PH, PTB, and C-terminal tyrosine/serine phosphorylation sites) that is phosphorylated on tyrosines by numerous receptor and non-receptor tyrosine kinases (including BCR-ABL, c-Kit, insulin receptor, c-Abl, Lck, Tec, BRK, and RET) and on serines by IKKβ; once tyrosine-phosphorylated and membrane-recruited (via PI3K-dependent PH-domain binding to phosphoinositides), DOK1 assembles signaling complexes with RasGAP, NCK, Csk, SHIP1, SHP-2, and other effectors to act as a negative regulator of Ras/ERK and JAK/STAT signaling, suppress cell proliferation and oncogenic transformation, and promote cell migration, while its nuclear export by CRM1 and ubiquitin-proteasome-mediated degradation by oncogenic kinases provide additional layers of regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DOK1 is a multi-domain docking protein that functions as a broad negative regulator of Ras/ERK, JAK/STAT, and Akt signaling downstream of diverse receptor and non-receptor tyrosine kinases in hematopoietic, mesenchymal, and epithelial cells. Upon tyrosine phosphorylation by kinases including BCR-ABL, c-Abl, Lck, Tec, RET, insulin receptor, and Src family members, DOK1 is recruited to the plasma membrane via PI3K-dependent PH-domain binding to phosphoinositides and assembles inhibitory signaling complexes through its phosphorylated C-terminal tyrosines—recruiting RasGAP (via Y295/Y314/Y361/Y376/Y397/Y408), NCK (via Y361), Csk, SHIP1, and SHP-1/SHP-2—to attenuate mitogenic signaling, suppress oncogenic transformation, and modulate cell migration and integrin outside-in signaling [PMID:9008160, PMID:10688886, PMID:10640270, PMID:11489947, PMID:15148308, PMID:26790499]. Dok-1/Dok-2 double-knockout mice spontaneously develop CML-like myeloproliferative disease, establishing DOK1 as a bona fide tumor suppressor in the hematopoietic compartment [PMID:15611295]. DOK1 activity is regulated at multiple levels: CRM1-dependent nucleocytoplasmic shuttling controls its cytoplasmic availability, IKKβ-mediated serine phosphorylation modulates its signaling output, and oncogenic kinases target it for ubiquitin-proteasome-mediated degradation to overcome its tumor-suppressive function [PMID:16705178, PMID:15574499, PMID:21536658].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of DOK1 as a BCR-ABL and c-Kit substrate that associates with RasGAP established the founding paradigm of DOK1 as a tyrosine-phosphorylated docking protein linking oncogenic kinases to Ras pathway regulation.\",\n      \"evidence\": \"Protein purification and co-IP from CML progenitor cells and c-Kit-stimulated cells\",\n      \"pmids\": [\"9008160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase(s) phosphorylating DOK1 in normal hematopoiesis was unknown\", \"Functional consequence of DOK1-RasGAP association on Ras activity was not tested\", \"No in vivo loss-of-function data\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that DOK1 requires its PH domain for membrane localization and tyrosine phosphorylation, and that phospho-Y361 recruits NCK to promote cell migration, defined the modular logic of DOK1 signaling: membrane recruitment precedes phosphorylation, which templates distinct effector outputs.\",\n      \"evidence\": \"Mutagenesis of PH domain and Y361F, subcellular fractionation, insulin-stimulated migration assay in overexpression system\",\n      \"pmids\": [\"10202139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The lipid ligand for the PH domain was not identified\", \"Endogenous DOK1 localization dynamics not shown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery that SHP-1 constitutively associates with DOK1 and directly dephosphorylates it in macrophages revealed a phosphatase-based feedback loop controlling DOK1 activation state.\",\n      \"evidence\": \"Far Western, co-IP from SHP-1-deficient motheaten macrophages, catalytic-mutant trapping\",\n      \"pmids\": [\"10585470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific tyrosine sites dephosphorylated by SHP-1 not mapped\", \"Functional consequence of SHP-1 loss on DOK1-dependent signaling outputs not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Reconstitution of DOK1 as a direct inhibitor of RasGAP catalytic activity and mapping of five RasGAP-binding tyrosines provided the first biochemical mechanism for how DOK1 dampens Ras signaling.\",\n      \"evidence\": \"In vitro RasGAP activity assay with purified phospho-DOK1, site-directed mutagenesis\",\n      \"pmids\": [\"10688886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Later work (PMID:37507023) challenged whether RasGAP catalytic activity is allosterically regulated by DOK1 binding\", \"Cellular context dependency not explored\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic knockout revealed DOK1 as indispensable for FcγRIIB-mediated inhibition of B cell proliferation and showed that DOK1 loss causes sustained MAP kinase activation, establishing DOK1 as a physiological negative regulator rather than just a BCR-ABL substrate.\",\n      \"evidence\": \"Dok-1 homologous recombination knockout mice, BCR/FcγRIIB co-crosslinking, MAPK assays\",\n      \"pmids\": [\"10640270\", \"10755621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of DOK1 vs DOK2 in B cell inhibition not resolved\", \"Whether DOK1 acts identically in all inhibitory receptor pathways unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of SHIP1-DOK1 and DOK1-RasGAP as mutually exclusive complexes, together with multiple kinase inputs (Lck, Tec), revealed that DOK1 serves as a combinatorial signaling hub whose effector output depends on which upstream kinase phosphorylates it and which complex it enters.\",\n      \"evidence\": \"Co-IP with domain-deletion mutants, subcellular fractionation, chimeric kinase systems, dominant-negative Tec\",\n      \"pmids\": [\"10822173\", \"10799545\", \"10823839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative selectivity between SHIP1 vs RasGAP binding not measured\", \"Whether complex exclusivity holds in all cell types not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstitution experiments in DOK1-null cells showed that PI3K-dependent PH-domain membrane recruitment is essential for DOK1's negative regulation of PDGFR/MAPK signaling and that this can occur independently of RasGAP and NCK binding, implying additional effector pathways.\",\n      \"evidence\": \"Retroviral reconstitution in KO MEFs, PI3K inhibitor, membrane-targeting domain chimeras\",\n      \"pmids\": [\"11489946\", \"11489947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the RasGAP/NCK-independent effector unknown\", \"Specific PI(3,4,5)P3 vs PI(3,4)P2 dependence not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Dok-1/Dok-2 double knockout mice spontaneously developed CML-like myeloproliferative disease with aberrant Ras/MAPK activation, definitively establishing both proteins as hematopoietic tumor suppressors.\",\n      \"evidence\": \"Double gene knockout, bone marrow transplantation, replicated by two independent groups\",\n      \"pmids\": [\"15611295\", \"15611294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of DOK1 vs DOK2 to tumor suppression not separated\", \"Human genetic evidence for DOK1 loss in CML not provided\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping of DOK1's interaction with RET and systematic mutagenesis of six C-terminal tyrosines delineated a tyrosine code: RasGAP binding (Y295, Y314, Y361, Y376, Y397, Y408) suppresses Ras/Erk, while NCK binding (Y361) activates JNK/c-Jun, showing DOK1 routes different signaling outcomes through distinct phosphotyrosines.\",\n      \"evidence\": \"Yeast two-hybrid, site-directed mutagenesis, kinase and JNK/Erk activation assays\",\n      \"pmids\": [\"12087092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of DOK1-RET signaling axis not demonstrated\", \"Whether all six tyrosines are simultaneously phosphorylated unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Crystal structure of the DOK1 PTB domain in complex with a RET phosphopeptide revealed the molecular basis for receptor selectivity, showing binding occurs via a groove between β5 and the C-terminal α-helix distinct from Shc/IRS1 PTB recognition.\",\n      \"evidence\": \"X-ray crystallography at atomic resolution\",\n      \"pmids\": [\"14607833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length DOK1 structure unavailable\", \"How PH domain orientation relative to PTB domain affects receptor engagement unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of c-Abl as the kinase phosphorylating DOK1-Y361 during cell adhesion, and demonstration that the c-Abl/DOK1/NCK pathway drives filopodia formation, connected DOK1 to cytoskeletal remodeling beyond its role as a purely inhibitory signal dampener.\",\n      \"evidence\": \"Mass spectrometry substrate identification, KO fibroblasts, live imaging of spreading cells\",\n      \"pmids\": [\"15148308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of NCK linking DOK1 to actin polymerization not identified\", \"Whether this pathway operates in hematopoietic cells not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that IKKβ phosphorylates DOK1 at four C-terminal serines in response to TNF-α/IL-1 revealed cross-talk between NF-κB and RTK signaling, with serine phosphorylation required for DOK1's ability to inhibit PDGF-induced ERK activation and promote cell motility.\",\n      \"evidence\": \"In vitro kinase assay, phospho-specific antibodies, serine-to-alanine mutagenesis, proliferation and migration assays\",\n      \"pmids\": [\"15574499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IKKβ and tyrosine kinase phosphorylation are cooperative or sequential unknown\", \"Structural basis for serine phosphorylation-dependent activation not determined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that DOK1 recruits Csk to attenuate Src kinase activity and suppress PDGF-induced c-myc, in parallel with RasGAP-mediated MAPK inhibition, established that DOK1 operates through at least two independent inhibitory arms to block mitogenesis.\",\n      \"evidence\": \"KO reconstitution with binding-deficient DOK1 mutants, Src kinase activity assays\",\n      \"pmids\": [\"16537894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Csk-DOK1 binding interface not mapped\", \"Quantitative contribution of each arm to proliferation control not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extension of DOK1's inhibitory role to innate immunity showed that DOK1/DOK2 are essential negative regulators of TLR4-Erk signaling in macrophages, preventing TNF-α hyperproduction, broadening DOK1's role beyond receptor tyrosine kinase pathways.\",\n      \"evidence\": \"Dok-1/Dok-2 KO macrophages, forced expression of phosphorylation-deficient DOK1, cytokine assays\",\n      \"pmids\": [\"15699069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TLR4 (a non-tyrosine kinase receptor) triggers DOK1 tyrosine phosphorylation not defined\", \"Whether DOK1 acts on TLR4-proximal or distal signaling steps unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of a CRM1-dependent NES in DOK1 and demonstration that both Src-mediated tyrosine and IKKβ-mediated serine phosphorylation promote cytoplasmic retention resolved how DOK1 subcellular localization is regulated and why cytoplasmic localization is required for its anti-proliferative and pro-migratory functions.\",\n      \"evidence\": \"Leptomycin B treatment, NES mutagenesis, live cell imaging, functional assays\",\n      \"pmids\": [\"16705178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear function of DOK1, if any, not characterized\", \"Whether nuclear-cytoplasmic shuttling is dynamically regulated during cell cycle unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Structural and biophysical studies showed that phosphorylation of integrin β3-Y747 switches binding preference from talin to the DOK1 PTB domain, establishing DOK1 as a phosphorylation-dependent integrin activation switch.\",\n      \"evidence\": \"NMR titrations and X-ray crystallography with quantitative affinity measurements\",\n      \"pmids\": [\"18156175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of this switch in platelet or endothelial integrin signaling not provided at the time\", \"Whether DOK1 binding actively inactivates integrin or simply displaces talin not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"DOK1 was linked to metabolic regulation: DOK1-null mice are lean because elevated ERK activity causes inhibitory phosphorylation of PPARγ-S112, impairing adipogenesis—a phenotype rescued by PPARγ-S112A mutation.\",\n      \"evidence\": \"KO mice, MEF adipogenesis assay, ERK and PPARγ phosphorylation, genetic rescue\",\n      \"pmids\": [\"18204460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOK1 acts cell-autonomously in adipocytes or through systemic effects not fully resolved\", \"Upstream kinase phosphorylating DOK1 in adipocyte precursors not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that oncogenic kinases (BCR-ABL, Src) target DOK1 for lysine-dependent polyubiquitination and proteasomal degradation provided a mechanism by which oncogenes neutralize DOK1 tumor suppression, and a degradation-resistant DOK1 mutant showed enhanced anti-transformation activity.\",\n      \"evidence\": \"Ubiquitination assays, proteasome inhibitor, lysine-to-arginine mutants, transformation assays\",\n      \"pmids\": [\"21536658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ubiquitin ligase responsible not identified\", \"Whether this degradation pathway operates in primary human leukemias unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"DOK1-knockout platelet studies demonstrated that DOK1 negatively regulates integrin αIIbβ3 outside-in signaling, controlling PLCγ2 phosphorylation, clot retraction, and in vivo thrombosis, directly validating the structural prediction that DOK1 modulates integrin signaling in a physiological context.\",\n      \"evidence\": \"Dok-1 KO mice, platelet aggregation, clot retraction, intravital thrombosis model\",\n      \"pmids\": [\"26790499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DOK1 restrains PLCγ2 phosphorylation not defined\", \"Whether DOK1 acts through Csk or RasGAP in platelets not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Quantitative binding and enzymatic studies revealed that while RasGAP SH2 domains engage doubly phosphorylated DOK1 with high affinity, this binding does not allosterically alter RasGAP catalytic activity, suggesting DOK1 regulates Ras spatiotemporally by relocalizing RasGAP rather than activating it.\",\n      \"evidence\": \"Affinity measurements, SAXS, in vitro RasGAP activity assay\",\n      \"pmids\": [\"37507023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contradicts earlier claim (PMID:10688886) that DOK1 inhibits RasGAP activity; resolution unclear\", \"Spatial redistribution model not validated in cells\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the E3 ligase mediating DOK1 degradation, the nuclear function (if any) of DOK1, the full set of effectors recruited by Y336/Y340 that operate independently of RasGAP, and whether DOK1 loss or silencing is causally linked to human cancers.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"E3 ubiquitin ligase for DOK1 not identified\", \"Nuclear role of DOK1 uncharacterized\", \"No human genetic evidence for DOK1 as a tumor suppressor in patients\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4, 9, 10, 11, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 6, 15, 16, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 7, 20, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6, 7, 9, 10, 15, 18, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 18, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 24]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [36, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RASA1\", \"NCK1\", \"SHIP1\", \"CSK\", \"SHP1\", \"SHP2\", \"GRB2\", \"YWHAZ\"],\n    \"other_free_text\": []\n  }\n}\n```"}