{"gene":"DOK2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1998,"finding":"DOK2 (p56dok-2) was purified from BCR-ABL-expressing CML cells as a 56-kDa tyrosine-phosphorylated protein. It encodes a 412-amino acid protein with an N-terminal pleckstrin homology (PH) domain, 13 potential tyrosine phosphorylation sites, six PXXP motifs, and directly binds to p120(RasGAP).","method":"Protein purification, cDNA cloning, domain analysis, RasGAP binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — original biochemical characterization with protein purification, cloning, and direct binding demonstration; foundational paper replicated by multiple subsequent studies","pmids":["9478921"],"is_preprint":false},{"year":2003,"finding":"In human platelets, DOK2 undergoes tyrosine phosphorylation upon stimulation by thrombin receptor activating peptide (TRAP), collagen receptor GPVI signaling, and outside-in signaling through integrin αIIbβ3.","method":"2D gel electrophoresis, LC-MS/MS proteomics, phosphotyrosine analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation identified by proteomics with multiple activation stimuli tested in a single study","pmids":["14645010"],"is_preprint":false},{"year":2004,"finding":"Dok-1 and Dok-2 double-knockout mice develop spontaneous CML-like myeloproliferative disease with enhanced Ras/MAPK (ERK) and Akt activation, demonstrating that both proteins are required for negative regulation of RAS/MAP kinase signaling downstream of tyrosine kinases in hematopoietic cells. Single knockouts show normal hematopoiesis.","method":"Single and double knockout mouse generation, hematopoietic analysis, Ras/MAPK activation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent replication in two concurrent KO studies (PMID:15611294 and 15611295) with consistent genetic epistasis and pathway-level readouts","pmids":["15611294","15611295"],"is_preprint":false},{"year":2005,"finding":"LPS rapidly induces tyrosine phosphorylation of Dok-1 and Dok-2 in macrophages downstream of TLR4. Knockout of either protein leads to elevated ERK (but not NF-κB or other MAP kinases) activation and hyperproduction of TNF-α, while forced expression of Dok-2 (but not a Tyr/Phe substitution mutant) inhibits LPS-induced ERK activation, establishing Dok-2 as a negative regulator of TLR4-dependent Ras-ERK signaling requiring its tyrosine phosphorylation.","method":"Dok-1/Dok-2 knockout macrophages, forced expression with Tyr/Phe mutant, ERK/NF-κB activity assays, cytokine measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function with phosphorylation-null mutant in same study; specific pathway (ERK not NF-κB) established","pmids":["15699069"],"is_preprint":false},{"year":2005,"finding":"The PTB domain of Dok-2 mediates phosphotyrosine-dependent homotypic (Dok-2/Dok-2) and heterotypic (Dok-1/Dok-2) oligomerization. Mutation of either the PTB domain or Tyr139 of Dok-2 abrogates CD2-induced Dok-2 phosphorylation and its ability to inhibit CD2-induced ERK1/2 and NFAT activation, indicating PTB-mediated oligomerization is required for Dok-2 phosphorylation and inhibitory function.","method":"Co-immunoprecipitation, PTB domain mutant and Tyr139Phe mutant overexpression, ERK and NFAT reporter assays in Jurkat cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus mutagenesis in a single lab; functional consequence linked to specific residues","pmids":["16177091"],"is_preprint":false},{"year":2006,"finding":"After TCR stimulation, Dok-2 (and Dok-1) form a multimolecular complex including SHIP-1 and Grb-2 that interacts with the membrane scaffold LAT. SHIP-1 favors recruitment of Dok-2 to LAT. Knockdown of Dok-2 (and Dok-1) reveals their negative regulation of Akt and Zap-70 activation, placing them in a LAT-dependent negative feedback loop that attenuates early TCR signaling.","method":"Co-immunoprecipitation, LAT/SHIP-1 siRNA knockdown, phospho-Akt and phospho-Zap-70 analysis in T cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing complex membership, knockdown of multiple components, multiple downstream readouts in one rigorous study","pmids":["17043143"],"is_preprint":false},{"year":2006,"finding":"In platelets, Dok-2 phosphorylation is downstream of GPVI and integrin αIIbβ3 (but Dok-1 is not); Dok-2 phosphorylation is inhibited by Src kinase inhibitors and intracellular calcium chelation; Dok-2 coimmunoprecipitates with integrin αIIbβ3, suggesting a physical and functional interaction in integrin outside-in signaling.","method":"Differential phosphorylation analysis, Src kinase inhibitors, calcium chelation, co-immunoprecipitation in mouse platelets","journal":"Journal of thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP and pharmacological inhibitors in platelet system, single lab but multiple approaches","pmids":["17092301"],"is_preprint":false},{"year":2007,"finding":"Dok-1 and Dok-2 negatively regulate ZAP-70 activation upon TCR stimulation. Mice lacking both proteins show elevated ZAP-70 activation, proliferation, and cytokine production in T cells. Importantly, forced expression of Dok-1 or Dok-2 in CD3+CD4+ T cells inhibited ZAP-70 activation, and this effect was independent of the C-terminal SH2 target motifs, indicating a novel mechanism distinct from the classical RasGAP-recruiting adaptor function.","method":"Dok-1/Dok-2 knockout mice, forced expression in T cell clones, phospho-ZAP-70 and proliferation assays, C-terminal deletion mutant analysis","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus gain-of-function with domain-deletion mutants in a single study; ZAP-70 as novel regulatory target established","pmids":["17329234"],"is_preprint":false},{"year":2009,"finding":"The CD200 receptor (CD200R) directly recruits Dok-2 via its phosphorylated NPLY (PTB domain-binding) motif with ~1 µM affinity (10-fold higher than Dok-1). Dok-2 is then phosphorylated and recruits RasGAP. siRNA knockdown of Dok-2 and RasGAP abolished CD200R-mediated inhibition of human myeloid cells, while Dok-1 and SHIP knockdown had no effect, establishing a Dok-2–RasGAP axis as essential for CD200R signaling.","method":"Phosphopeptide binding affinity measurement, co-immunoprecipitation, siRNA knockdown of Dok-2/Dok-1/RasGAP/SHIP in U937 cells, NPLY mutant receptor constructs","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative binding affinity, receptor mutants, siRNA knockdown of multiple components, human cell system with functional readout","pmids":["19786546"],"is_preprint":false},{"year":2009,"finding":"The PH domains of Dok-1 and Dok-2 bind phosphatidylinositol 5-phosphate (PtdIns5P) in vitro, and PtdIns5P production upon TCR triggering correlates with and is required for Dok tyrosine phosphorylation in vivo. PH domain deletion prevents tyrosine phosphorylation and negative signaling function, linking lipid-PH domain interaction to Dok-2 activation.","method":"In vitro lipid-binding assay (PH domain–PtdIns5P), PtdIns5P manipulation in T cells, PH domain deletion mutant analysis, phosphotyrosine detection","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding combined with in vivo PtdIns5P modulation and domain deletion, single lab","pmids":["19299694"],"is_preprint":false},{"year":2012,"finding":"Dok2 phosphorylation is required for the inhibitory effect of CD200R activation (via CD200Fc) on microglial activation and inflammatory cytokine (IL-1β, TNFα) production; siRNA knockdown of Dok2 abrogates the anti-inflammatory effects of CD200Fc in cultured glia.","method":"siRNA knockdown of Dok2 in glial cells, CD200Fc stimulation, cytokine measurement, microglial activation marker analysis","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with functional cytokine readout and activation markers, single lab","pmids":["22642833"],"is_preprint":false},{"year":2013,"finding":"DOK2 participates in a negative feedback loop downstream of mutant EGFR: mutated EGFR leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream RAS activation. Loss of Dok2 in mice accelerates EGFR-mutant (but not Kras-mutant) lung tumorigenesis.","method":"Co-immunoprecipitation of DOK2 with EGFR, RAS activation assays, genetically engineered mouse models with EGFR mutation and Dok2 knockout","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP with EGFR, RAS activation assay, mouse genetic model with oncogene specificity (EGFR not KRAS), multiple orthogonal approaches","pmids":["24255704"],"is_preprint":false},{"year":2013,"finding":"Loss of DOK2 decreases apoptosis in response to carboplatin treatment and reduces anoikis in ovarian cancer cells, linking DOK2 function to pro-apoptotic signaling downstream of platinum-induced damage.","method":"siRNA/shRNA knockdown of DOK2 in ovarian cancer cell lines, carboplatin resistance assay, apoptosis and anoikis measurement","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional knockdown with apoptosis readout, single lab","pmids":["23684582"],"is_preprint":false},{"year":2013,"finding":"TLR2 activation induces tyrosine phosphorylation of Dok-1 and Dok-2 in both astrocytes and microglia. In astrocytes, siRNA knockdown of both Dok1 and Dok2 elevates TLR2-induced ERK, NF-κB activation, and IL-6 production. In microglia, Dok1 knockdown (but not Dok2 knockdown) affects NF-κB activation and IL-6, revealing cell-type-specific differential roles.","method":"siRNA knockdown of Dok1 and Dok2 in primary glia, phosphotyrosine western blotting, ERK/NF-κB activation assays, IL-6 measurement","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown of both proteins with multiple pathway readouts in two cell types, single lab","pmids":["23659921"],"is_preprint":false},{"year":2014,"finding":"Dok-2 in platelets is primarily phosphorylated by Lyn kinase. Dok-2 deficiency leads to dysregulated integrin αIIbβ3-dependent cytosolic calcium flux and PI(3,4)P2 accumulation. Dok-2(-/-) platelets exhibit shear-dependent increases in integrin αIIbβ3 adhesive function affecting membrane tether regulation, resulting in enhanced platelet aggregate formation and accelerated thrombus growth in vivo.","method":"Dok-2 knockout mice, Lyn kinase identification, calcium flux assay, PI(3,4)P2 measurement, platelet adhesion under flow, in vivo thrombosis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple biochemical (kinase identification, lipid measurements, Ca2+ flux) and functional (in vivo thrombosis) readouts, single lab but multiple orthogonal methods","pmids":["24385425"],"is_preprint":false},{"year":2014,"finding":"Dok-1 and Dok-2 are tyrosine phosphorylated upon NK cell activation. Overexpression of Dok proteins in human NK cells reduces activation by NK-activating receptors. Dok1/Dok2 gene ablation in mice causes NK cell maturation defects and increased IFN-γ production, establishing their role in a negative feedback loop downstream of NK-activating receptors.","method":"Overexpression in human NK cells, Dok1/Dok2 knockout mice, NK cell maturation and IFN-γ production assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus gain-of-function in human cells with multiple functional readouts (maturation, cytokine) in mouse and human systems","pmids":["24963146"],"is_preprint":false},{"year":2014,"finding":"Dok2 protein localizes to the nucleus of erythroleukemia cells and binds directly to the promoter region of the Klf1 gene, repressing Klf1 transcription; Dok2 knockdown leads to increased Klf1 mRNA expression.","method":"Immunocytochemistry for nuclear localization, chromatin immunoprecipitation (ChIP) of Dok2 at Klf1 promoter, siRNA knockdown with RT-PCR","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ChIP and knockdown in a single cell line, no replication; nuclear localization is unexpected and not independently confirmed","pmids":["25075100"],"is_preprint":false},{"year":2017,"finding":"HSV-1 infection of T cells induces tyrosine phosphorylation of Dok-2 and its selective degradation. Dok-2 physically interacts with the viral tegument protein VP11/12, and this interaction requires the Src Family Kinase-binding motifs and SHC-binding motif of VP11/12. Both the phosphorylation and degradation of Dok-2 are dependent on VP11/12.","method":"Co-immunoprecipitation of Dok-2 with VP11/12, VP11/12 binding motif mutants, western blotting for phosphorylation and protein levels upon HSV-1 infection","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with viral protein plus binding-site mutants establishing requirement, single lab","pmids":["28841444"],"is_preprint":false},{"year":2018,"finding":"Compound heterozygous deletion of Dok2 and Dusp4 (co-deleted in ~50% of human lung adenocarcinomas) in mice causes lung tumorigenesis with short latency. Their co-deletion synergistically activates MAPK signaling and promotes cell proliferation; restoration of DOK2 and DUSP4 in lung cancer cells suppresses MAPK activation and cell proliferation.","method":"Compound heterozygous mouse model, MAPK activation assays, DOK2/DUSP4 restoration in cancer cell lines, cell proliferation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model plus in vitro rescue experiments with MAPK pathway readout, synergy established by compound model","pmids":["30475228"],"is_preprint":false},{"year":2004,"finding":"Dok-1 and Dok-2 are major tyrosine-phosphorylated proteins associated with the Tec tyrosine kinase in T cells. Dok-1 or Dok-2 expression provides negative feedback regulation of Tec by downregulating its tyrosine phosphorylation and downstream Ras pathway signaling.","method":"Co-immunoprecipitation of Dok-1/Dok-2 with Tec, Tec phosphorylation and Ras pathway activity assays upon Dok overexpression in T cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus functional signaling assays, single lab","pmids":["14647425"],"is_preprint":false}],"current_model":"DOK2 is a PH domain- and PTB domain-containing adaptor protein that, upon tyrosine phosphorylation downstream of receptor tyrosine kinases (EGFR, BCR-ABL, c-Kit, M-CSFR), Src family kinases (Lyn), and immune receptors (TCR, CD200R, TLR4, NK-activating receptors), recruits RasGAP to suppress RAS–ERK signaling and also inhibits PI3K–AKT activation; it functions as a negative-feedback regulator of proliferation and immune activation in hematopoietic cells, with its PH domain binding PtdIns5P to facilitate membrane recruitment and phosphorylation, its PTB domain mediating both pTyr-dependent oligomerization and direct receptor binding (e.g., phospho-NPLY of CD200R), and its activity being co-opted by the HSV-1 tegument protein VP11/12 which binds, phosphorylates, and degrades DOK2 as an immune evasion mechanism."},"narrative":{"mechanistic_narrative":"DOK2 is a tyrosine-phosphorylated adaptor protein that acts as a negative-feedback regulator of RAS–ERK and PI3K–AKT signaling downstream of receptor and non-receptor tyrosine kinases in hematopoietic and immune cells [PMID:9478921, PMID:15611294, PMID:15611295]. Originally purified from BCR-ABL-expressing CML cells as a 56-kDa protein that directly binds p120 RasGAP, it carries an N-terminal PH domain, a PTB domain, and multiple tyrosine-phosphorylation sites [PMID:9478921]. Combined loss of Dok-2 and its paralog Dok-1 in mice produces a CML-like myeloproliferative disease with hyperactivated ERK and Akt, establishing the pair as essential brakes on RAS/MAPK signaling [PMID:15611294, PMID:15611295]. DOK2 is recruited to and phosphorylated downstream of diverse activating inputs—TLR4 and TLR2 in macrophages and glia [PMID:15699069, PMID:23659921], the TCR via a LAT/SHIP-1/Grb-2 complex that also restrains Akt and ZAP-70 [PMID:17043143, PMID:17329234], NK-activating receptors [PMID:24963146], and the inhibitory CD200 receptor, whose phosphorylated NPLY motif binds the DOK2 PTB domain to nucleate a DOK2–RasGAP inhibitory axis [PMID:19786546]. Activation requires PH-domain binding to PtdIns5P for membrane recruitment and phosphorylation, and PTB-domain-mediated homo- and hetero-oligomerization with Dok-1 [PMID:16177091, PMID:19299694]. In platelets DOK2 is phosphorylated by Lyn downstream of GPVI and integrin αIIbβ3, where it limits integrin adhesive function and thrombus growth [PMID:17092301, PMID:24385425]. As a tumor suppressor, DOK2 forms a negative-feedback loop on mutant EGFR and, together with DUSP4, restrains MAPK-driven lung tumorigenesis [PMID:24255704, PMID:30475228]. The HSV-1 tegument protein VP11/12 binds, phosphorylates, and triggers degradation of DOK2 as an immune-evasion strategy [PMID:28841444].","teleology":[{"year":1998,"claim":"Identified the molecular identity of a prominent tyrosine-phosphorylated species in CML cells, establishing DOK2 as a multidomain adaptor that directly couples to the RAS regulator RasGAP.","evidence":"Protein purification, cDNA cloning, domain analysis, and RasGAP binding assay from BCR-ABL CML cells","pmids":["9478921"],"confidence":"High","gaps":["Did not establish a cellular phenotype for DOK2 loss","Tyrosine kinase(s) driving phosphorylation not defined","Functional consequence of RasGAP binding untested"]},{"year":2004,"claim":"Genetic epistasis showed DOK2 and DOK1 are jointly required to suppress RAS/MAPK and Akt signaling in hematopoietic cells, defining their tumor-suppressive negative-feedback role.","evidence":"Single and double knockout mice with hematopoietic and Ras/MAPK activation analysis","pmids":["15611294","15611295"],"confidence":"High","gaps":["Functional redundancy obscures Dok-2-specific roles","Direct molecular targets within the pathway not resolved here","Mechanism of ERK/Akt suppression not dissected"]},{"year":2004,"claim":"Linked DOK2 to a specific upstream kinase by showing it associates with and feedback-inhibits Tec in T cells, extending its negative regulation beyond receptor tyrosine kinases.","evidence":"Co-immunoprecipitation with Tec and Ras-pathway assays upon Dok overexpression in T cells","pmids":["14647425"],"confidence":"Medium","gaps":["Single lab, no genetic confirmation","Direct vs indirect Tec association not distinguished","Physiological setting where this loop dominates unclear"]},{"year":2005,"claim":"Established DOK2 as a phosphorylation-dependent negative regulator of TLR4-driven ERK signaling and TNF-α production in macrophages, extending its role into innate immunity.","evidence":"Dok-1/Dok-2 knockout macrophages with gain-of-function and a Tyr/Phe mutant, ERK/NF-κB and cytokine readouts","pmids":["15699069"],"confidence":"High","gaps":["Pathway selectivity for ERK over NF-κB mechanistically unexplained","Adaptor connecting DOK2 to TLR4 not identified","In vivo inflammatory consequence not tested here"]},{"year":2005,"claim":"Defined the PTB domain and Tyr139 as required for phosphotyrosine-dependent oligomerization, linking DOK2 self/cross-association to its phosphorylation and inhibitory function.","evidence":"Co-IP, PTB and Tyr139Phe mutants, ERK and NFAT reporter assays in Jurkat cells","pmids":["16177091"],"confidence":"Medium","gaps":["Structural basis of oligomerization not defined","Single-lab overexpression system","Whether oligomerization occurs at endogenous levels untested"]},{"year":2006,"claim":"Placed DOK2 within a LAT-anchored, SHIP-1-dependent complex that restrains early TCR signaling at the level of Akt and ZAP-70, defining a membrane-proximal negative feedback loop.","evidence":"Reciprocal co-IP, LAT/SHIP-1 siRNA, phospho-Akt and phospho-Zap-70 analysis in T cells","pmids":["17043143"],"confidence":"High","gaps":["Stoichiometry and order of complex assembly unresolved","Direct vs scaffolded LAT interaction unclear","How SHIP-1 favors DOK2 recruitment mechanistically undefined"]},{"year":2006,"claim":"Demonstrated DOK2-specific (Dok-1-independent) phosphorylation downstream of GPVI and integrin αIIbβ3 in platelets, with physical association to the integrin, implicating it in outside-in signaling.","evidence":"Differential phosphorylation, Src inhibitors, calcium chelation, and co-IP in mouse platelets","pmids":["17092301"],"confidence":"Medium","gaps":["Direct vs indirect integrin association not resolved","Functional consequence not yet established here","Responsible Src-family kinase not identified at this stage"]},{"year":2007,"claim":"Revealed a non-canonical inhibitory mechanism: DOK2 suppresses ZAP-70 activation independent of its C-terminal SH2-target (RasGAP-recruiting) motifs, distinguishing it from the classical adaptor function.","evidence":"Dok-1/Dok-2 knockout mice, forced expression with C-terminal deletion mutants, phospho-ZAP-70 and proliferation assays","pmids":["17329234"],"confidence":"High","gaps":["Domain mediating ZAP-70 inhibition not pinpointed","Direct vs indirect ZAP-70 regulation unresolved","Molecular intermediary not identified"]},{"year":2009,"claim":"Quantitatively defined CD200R as a direct DOK2 receptor through phospho-NPLY/PTB binding and showed the DOK2–RasGAP axis is essential and Dok-2-selective for CD200R-mediated inhibition of myeloid cells.","evidence":"Phosphopeptide affinity measurement, co-IP, siRNA of Dok-2/Dok-1/RasGAP/SHIP, and NPLY receptor mutants in U937 cells","pmids":["19786546"],"confidence":"High","gaps":["Structure of the CD200R–PTB complex not solved","Why Dok-2 outcompetes Dok-1 mechanistically unclear beyond affinity","Downstream effectors of RasGAP not enumerated"]},{"year":2009,"claim":"Connected lipid binding to activation by showing the PH domain binds PtdIns5P and that PtdIns5P is required for DOK2 tyrosine phosphorylation and inhibitory function in T cells.","evidence":"In vitro PH–PtdIns5P binding, in vivo PtdIns5P modulation, and PH-deletion mutant phosphotyrosine analysis","pmids":["19299694"],"confidence":"Medium","gaps":["In vivo membrane localization not directly imaged","Single lab","Enzymatic source of PtdIns5P pool not defined"]},{"year":2012,"claim":"Extended the CD200R–DOK2 inhibitory axis to the CNS, showing DOK2 phosphorylation is required for CD200R-mediated suppression of microglial inflammatory activation.","evidence":"siRNA knockdown of Dok2 in glia with CD200Fc stimulation and cytokine/activation-marker readouts","pmids":["22642833"],"confidence":"Medium","gaps":["Single-lab knockdown without genetic confirmation","Downstream signaling in microglia not mapped","In vivo neuroinflammatory relevance untested"]},{"year":2013,"claim":"Established DOK2 as a tumor suppressor in EGFR-mutant lung cancer through a negative-feedback loop on mutant EGFR, with oncogene specificity (EGFR but not KRAS).","evidence":"Co-IP of DOK2 with EGFR, RAS activation assays, and EGFR-mutant Dok2-knockout mouse models","pmids":["24255704"],"confidence":"High","gaps":["Direct vs adaptor-mediated EGFR binding unresolved","Why KRAS-mutant tumors are unaffected not explained","Human tumor data correlation not addressed here"]},{"year":2013,"claim":"Implicated DOK2 in chemotherapy response by showing its loss reduces carboplatin-induced apoptosis and anoikis in ovarian cancer cells.","evidence":"siRNA/shRNA knockdown in ovarian cancer lines with carboplatin resistance and apoptosis/anoikis assays","pmids":["23684582"],"confidence":"Medium","gaps":["Mechanism linking DOK2 to apoptosis not defined","Single-lab cell-line study","In vivo therapeutic relevance untested"]},{"year":2013,"claim":"Showed TLR2-induced DOK2 phosphorylation and revealed cell-type-specific division of labor between Dok-1 and Dok-2 in glial inflammatory signaling.","evidence":"siRNA knockdown of Dok1 and Dok2 in primary astrocytes and microglia with ERK/NF-κB and IL-6 readouts","pmids":["23659921"],"confidence":"Medium","gaps":["Basis of cell-type specificity unexplained","Direct TLR2 coupling not demonstrated","Single-lab knockdown without rescue"]},{"year":2014,"claim":"Identified Lyn as the DOK2 kinase in platelets and demonstrated that DOK2 loss enhances integrin αIIbβ3 adhesion and accelerates thrombus formation in vivo, establishing a hemostatic regulatory role.","evidence":"Dok-2 knockout mice, kinase identification, calcium and PI(3,4)P2 measurements, flow-adhesion and in vivo thrombosis assays","pmids":["24385425"],"confidence":"High","gaps":["Direct DOK2 substrates/effectors in platelets not defined","Link between PI(3,4)P2 accumulation and adhesion mechanistic detail incomplete","Single lab"]},{"year":2014,"claim":"Established DOK2 (with Dok-1) as a negative regulator of NK-cell activation and maturation downstream of activating receptors.","evidence":"Overexpression in human NK cells and Dok1/Dok2 knockout mice with maturation and IFN-γ readouts","pmids":["24963146"],"confidence":"High","gaps":["Specific activating receptors coupled to DOK2 not enumerated","Dok-2-specific vs redundant contributions not separated","Molecular target in NK cells unresolved"]},{"year":2014,"claim":"Reported an unexpected nuclear, transcriptional-repressor role: DOK2 binds the Klf1 promoter and represses its transcription in erythroleukemia cells.","evidence":"Immunocytochemistry, ChIP at the Klf1 promoter, and siRNA knockdown with RT-PCR in a single cell line","pmids":["25075100"],"confidence":"Low","gaps":["Nuclear localization unexpected and not independently confirmed","Single cell line without replication","No demonstrated DNA-binding domain or direct binding mechanism"]},{"year":2017,"claim":"Defined a viral immune-evasion mechanism in which HSV-1 VP11/12 binds, phosphorylates, and targets DOK2 for degradation, requiring VP11/12 SFK- and SHC-binding motifs.","evidence":"Co-IP of Dok-2 with VP11/12, VP11/12 binding-motif mutants, and phosphorylation/protein-level analysis upon HSV-1 infection","pmids":["28841444"],"confidence":"Medium","gaps":["Degradation machinery (e.g., proteasome/ubiquitin) not identified","Functional immune consequence of DOK2 loss in infection untested","Single lab"]},{"year":2018,"claim":"Demonstrated synergistic tumor suppression by showing co-deletion of DOK2 and DUSP4 drives MAPK activation and lung tumorigenesis, reversible by their restoration.","evidence":"Compound heterozygous mouse model, MAPK assays, and DOK2/DUSP4 restoration with proliferation assays in cancer cell lines","pmids":["30475228"],"confidence":"High","gaps":["Mechanistic interplay between DOK2 and DUSP4 nodes not fully resolved","Whether the two act on the same or parallel MAPK steps unclear","Direct binding partners in this context not mapped"]},{"year":null,"claim":"How DOK2 selectively inhibits ERK versus NF-κB, the structural basis of its PTB/PH-mediated receptor and lipid recognition, and the validity of its proposed nuclear transcriptional role remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PTB–phosphoreceptor or PH–PtdIns5P complexes","Nuclear/transcriptional function rests on a single low-confidence study","Pathway-selectivity mechanism (ERK-specific suppression) undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5,7,15]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[6,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,18]}],"complexes":["LAT signaling complex (with SHIP-1 and Grb-2)"],"partners":["RASA1","DOK1","INPP5D","GRB2","LAT","CD200R1","EGFR","ITGB3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60496","full_name":"Docking protein 2","aliases":["Downstream of tyrosine kinase 2","p56(dok-2)"],"length_aa":412,"mass_kda":45.4,"function":"DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK2 may modulate the cellular proliferation induced by IL-4, as well as IL-2 and IL-3. May be involved in modulating Bcr-Abl signaling. Attenuates EGF-stimulated MAP kinase activation (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O60496/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOK2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DOK2","total_profiled":1310},"omim":[{"mim_id":"611435","title":"DOCKING PROTEIN 3; DOK3","url":"https://www.omim.org/entry/611435"},{"mim_id":"604997","title":"DOCKING PROTEIN 2; DOK2","url":"https://www.omim.org/entry/604997"},{"mim_id":"604298","title":"SIGNAL TRANSDUCING ADAPTOR FAMILY MEMBER 1; STAP1","url":"https://www.omim.org/entry/604298"},{"mim_id":"603492","title":"SLAM FAMILY, MEMBER 1; SLAMF1","url":"https://www.omim.org/entry/603492"},{"mim_id":"602919","title":"DOCKING PROTEIN 1; DOK1","url":"https://www.omim.org/entry/602919"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":24.2},{"tissue":"lymphoid tissue","ntpm":44.0}],"url":"https://www.proteinatlas.org/search/DOK2"},"hgnc":{"alias_symbol":["p56dok-2","Dok-2"],"prev_symbol":[]},"alphafold":{"accession":"O60496","domains":[{"cath_id":"2.30.29.30","chopping":"6-114","consensus_level":"high","plddt":85.3693,"start":6,"end":114},{"cath_id":"2.30.29.30","chopping":"150-248","consensus_level":"high","plddt":93.2031,"start":150,"end":248}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60496","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60496-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60496-F1-predicted_aligned_error_v6.png","plddt_mean":69.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DOK2","jax_strain_url":"https://www.jax.org/strain/search?query=DOK2"},"sequence":{"accession":"O60496","fasta_url":"https://rest.uniprot.org/uniprotkb/O60496.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60496/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60496"}},"corpus_meta":[{"pmid":"14645010","id":"PMC_14645010","title":"Differential proteome analysis of TRAP-activated platelets: involvement of DOK-2 and phosphorylation of RGS proteins.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/14645010","citation_count":142,"is_preprint":false},{"pmid":"19786546","id":"PMC_19786546","title":"Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19786546","citation_count":125,"is_preprint":false},{"pmid":"9478921","id":"PMC_9478921","title":"Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9478921","citation_count":112,"is_preprint":false},{"pmid":"17043143","id":"PMC_17043143","title":"T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2.","date":"2006","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17043143","citation_count":92,"is_preprint":false},{"pmid":"15611294","id":"PMC_15611294","title":"Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15611294","citation_count":86,"is_preprint":false},{"pmid":"17329234","id":"PMC_17329234","title":"Dok-1 and Dok-2 are negative regulators of T cell receptor signaling.","date":"2007","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17329234","citation_count":76,"is_preprint":false},{"pmid":"15611295","id":"PMC_15611295","title":"Role of Dok-1 and Dok-2 in leukemia suppression.","date":"2004","source":"The Journal of experimental 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19299694","citation_count":52,"is_preprint":false},{"pmid":"22642833","id":"PMC_22642833","title":"Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia.","date":"2012","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/22642833","citation_count":46,"is_preprint":false},{"pmid":"23684582","id":"PMC_23684582","title":"Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis.","date":"2013","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23684582","citation_count":38,"is_preprint":false},{"pmid":"24963146","id":"PMC_24963146","title":"Dok1 and Dok2 proteins regulate natural killer cell development and function.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/24963146","citation_count":35,"is_preprint":false},{"pmid":"14647425","id":"PMC_14647425","title":"Functional interaction of RasGAP-binding proteins Dok-1 and Dok-2 with the Tec protein tyrosine kinase.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14647425","citation_count":31,"is_preprint":false},{"pmid":"23659921","id":"PMC_23659921","title":"Differential role of Dok1 and Dok2 in TLR2-induced inflammatory signaling in glia.","date":"2013","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/23659921","citation_count":28,"is_preprint":false},{"pmid":"30475228","id":"PMC_30475228","title":"Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30475228","citation_count":25,"is_preprint":false},{"pmid":"27183638","id":"PMC_27183638","title":"Dok1 and Dok2 Proteins Regulate Cell Cycle in Hematopoietic Stem and Progenitor Cells.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27183638","citation_count":17,"is_preprint":false},{"pmid":"16177091","id":"PMC_16177091","title":"Phosphotyrosine binding-mediated oligomerization of downstream of tyrosine kinase (Dok)-1 and Dok-2 is involved in CD2-induced Dok phosphorylation.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16177091","citation_count":17,"is_preprint":false},{"pmid":"30652956","id":"PMC_30652956","title":"Long noncoding RNA AK089579 inhibits epithelial-to-mesenchymal transition of peritoneal mesothelial cells by competitively binding to microRNA-296-3p via DOK2 in peritoneal fibrosis.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30652956","citation_count":17,"is_preprint":false},{"pmid":"17092301","id":"PMC_17092301","title":"Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin alphaIIbbeta3.","date":"2006","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/17092301","citation_count":16,"is_preprint":false},{"pmid":"34505522","id":"PMC_34505522","title":"Introduction to DOK2 and its potential role in cancer.","date":"2021","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/34505522","citation_count":14,"is_preprint":false},{"pmid":"29098030","id":"PMC_29098030","title":"Co-expression and significance of Dok2 and Ras p21 protein activator 1 in breast cancer.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29098030","citation_count":13,"is_preprint":false},{"pmid":"24255704","id":"PMC_24255704","title":"DOK2 inhibits EGFR-mutated lung adenocarcinoma.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24255704","citation_count":13,"is_preprint":false},{"pmid":"25435967","id":"PMC_25435967","title":"Expression and significance of DOK2 in colorectal cancer.","date":"2014","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25435967","citation_count":12,"is_preprint":false},{"pmid":"24385425","id":"PMC_24385425","title":"Dok-2 adaptor protein regulates the shear-dependent adhesive function of platelet integrin αIIbβ3 in mice.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24385425","citation_count":12,"is_preprint":false},{"pmid":"28490594","id":"PMC_28490594","title":"Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8+ T Cells in a Murine Model of Ocular Infection.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28490594","citation_count":9,"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":"21732353","id":"PMC_21732353","title":"Dok-1 and Dok-2 deficiency induces osteopenia via activation of osteoclasts.","date":"2011","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21732353","citation_count":8,"is_preprint":false},{"pmid":"28841444","id":"PMC_28841444","title":"Herpes simplex virus 1 infection of T cells causes VP11/12-dependent phosphorylation and degradation of the cellular protein Dok-2.","date":"2017","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/28841444","citation_count":8,"is_preprint":false},{"pmid":"39972407","id":"PMC_39972407","title":"Bioinformatics-based identification of CTSS, DOK2, and ENTPD1 as potential blood biomarkers of schizophrenia.","date":"2025","source":"BMC psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/39972407","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":"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":"40982233","id":"PMC_40982233","title":"Identification of anti-DOK2 antibodies in patients with autoimmune hepatitis via a human protein microarray.","date":"2025","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/40982233","citation_count":4,"is_preprint":false},{"pmid":"25075100","id":"PMC_25075100","title":"Dok2 likely down-regulates Klf1 in mouse erythroleukemia cells.","date":"2014","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25075100","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18681,"output_tokens":5337,"usd":0.068049,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13731,"output_tokens":6091,"usd":0.110465,"stage2_stop_reason":"end_turn"},"total_usd":0.178514,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"DOK2 (p56dok-2) was purified from BCR-ABL-expressing CML cells as a 56-kDa tyrosine-phosphorylated protein. It encodes a 412-amino acid protein with an N-terminal pleckstrin homology (PH) domain, 13 potential tyrosine phosphorylation sites, six PXXP motifs, and directly binds to p120(RasGAP).\",\n      \"method\": \"Protein purification, cDNA cloning, domain analysis, RasGAP binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — original biochemical characterization with protein purification, cloning, and direct binding demonstration; foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"9478921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In human platelets, DOK2 undergoes tyrosine phosphorylation upon stimulation by thrombin receptor activating peptide (TRAP), collagen receptor GPVI signaling, and outside-in signaling through integrin αIIbβ3.\",\n      \"method\": \"2D gel electrophoresis, LC-MS/MS proteomics, phosphotyrosine analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation identified by proteomics with multiple activation stimuli tested in a single study\",\n      \"pmids\": [\"14645010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Dok-1 and Dok-2 double-knockout mice develop spontaneous CML-like myeloproliferative disease with enhanced Ras/MAPK (ERK) and Akt activation, demonstrating that both proteins are required for negative regulation of RAS/MAP kinase signaling downstream of tyrosine kinases in hematopoietic cells. Single knockouts show normal hematopoiesis.\",\n      \"method\": \"Single and double knockout mouse generation, hematopoietic analysis, Ras/MAPK activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent replication in two concurrent KO studies (PMID:15611294 and 15611295) with consistent genetic epistasis and pathway-level readouts\",\n      \"pmids\": [\"15611294\", \"15611295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LPS rapidly induces tyrosine phosphorylation of Dok-1 and Dok-2 in macrophages downstream of TLR4. Knockout of either protein leads to elevated ERK (but not NF-κB or other MAP kinases) activation and hyperproduction of TNF-α, while forced expression of Dok-2 (but not a Tyr/Phe substitution mutant) inhibits LPS-induced ERK activation, establishing Dok-2 as a negative regulator of TLR4-dependent Ras-ERK signaling requiring its tyrosine phosphorylation.\",\n      \"method\": \"Dok-1/Dok-2 knockout macrophages, forced expression with Tyr/Phe mutant, ERK/NF-κB activity assays, cytokine measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function with phosphorylation-null mutant in same study; specific pathway (ERK not NF-κB) established\",\n      \"pmids\": [\"15699069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The PTB domain of Dok-2 mediates phosphotyrosine-dependent homotypic (Dok-2/Dok-2) and heterotypic (Dok-1/Dok-2) oligomerization. Mutation of either the PTB domain or Tyr139 of Dok-2 abrogates CD2-induced Dok-2 phosphorylation and its ability to inhibit CD2-induced ERK1/2 and NFAT activation, indicating PTB-mediated oligomerization is required for Dok-2 phosphorylation and inhibitory function.\",\n      \"method\": \"Co-immunoprecipitation, PTB domain mutant and Tyr139Phe mutant overexpression, ERK and NFAT reporter assays in Jurkat cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus mutagenesis in a single lab; functional consequence linked to specific residues\",\n      \"pmids\": [\"16177091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"After TCR stimulation, Dok-2 (and Dok-1) form a multimolecular complex including SHIP-1 and Grb-2 that interacts with the membrane scaffold LAT. SHIP-1 favors recruitment of Dok-2 to LAT. Knockdown of Dok-2 (and Dok-1) reveals their negative regulation of Akt and Zap-70 activation, placing them in a LAT-dependent negative feedback loop that attenuates early TCR signaling.\",\n      \"method\": \"Co-immunoprecipitation, LAT/SHIP-1 siRNA knockdown, phospho-Akt and phospho-Zap-70 analysis in T cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing complex membership, knockdown of multiple components, multiple downstream readouts in one rigorous study\",\n      \"pmids\": [\"17043143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In platelets, Dok-2 phosphorylation is downstream of GPVI and integrin αIIbβ3 (but Dok-1 is not); Dok-2 phosphorylation is inhibited by Src kinase inhibitors and intracellular calcium chelation; Dok-2 coimmunoprecipitates with integrin αIIbβ3, suggesting a physical and functional interaction in integrin outside-in signaling.\",\n      \"method\": \"Differential phosphorylation analysis, Src kinase inhibitors, calcium chelation, co-immunoprecipitation in mouse platelets\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP and pharmacological inhibitors in platelet system, single lab but multiple approaches\",\n      \"pmids\": [\"17092301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dok-1 and Dok-2 negatively regulate ZAP-70 activation upon TCR stimulation. Mice lacking both proteins show elevated ZAP-70 activation, proliferation, and cytokine production in T cells. Importantly, forced expression of Dok-1 or Dok-2 in CD3+CD4+ T cells inhibited ZAP-70 activation, and this effect was independent of the C-terminal SH2 target motifs, indicating a novel mechanism distinct from the classical RasGAP-recruiting adaptor function.\",\n      \"method\": \"Dok-1/Dok-2 knockout mice, forced expression in T cell clones, phospho-ZAP-70 and proliferation assays, C-terminal deletion mutant analysis\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus gain-of-function with domain-deletion mutants in a single study; ZAP-70 as novel regulatory target established\",\n      \"pmids\": [\"17329234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The CD200 receptor (CD200R) directly recruits Dok-2 via its phosphorylated NPLY (PTB domain-binding) motif with ~1 µM affinity (10-fold higher than Dok-1). Dok-2 is then phosphorylated and recruits RasGAP. siRNA knockdown of Dok-2 and RasGAP abolished CD200R-mediated inhibition of human myeloid cells, while Dok-1 and SHIP knockdown had no effect, establishing a Dok-2–RasGAP axis as essential for CD200R signaling.\",\n      \"method\": \"Phosphopeptide binding affinity measurement, co-immunoprecipitation, siRNA knockdown of Dok-2/Dok-1/RasGAP/SHIP in U937 cells, NPLY mutant receptor constructs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative binding affinity, receptor mutants, siRNA knockdown of multiple components, human cell system with functional readout\",\n      \"pmids\": [\"19786546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The PH domains of Dok-1 and Dok-2 bind phosphatidylinositol 5-phosphate (PtdIns5P) in vitro, and PtdIns5P production upon TCR triggering correlates with and is required for Dok tyrosine phosphorylation in vivo. PH domain deletion prevents tyrosine phosphorylation and negative signaling function, linking lipid-PH domain interaction to Dok-2 activation.\",\n      \"method\": \"In vitro lipid-binding assay (PH domain–PtdIns5P), PtdIns5P manipulation in T cells, PH domain deletion mutant analysis, phosphotyrosine detection\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding combined with in vivo PtdIns5P modulation and domain deletion, single lab\",\n      \"pmids\": [\"19299694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dok2 phosphorylation is required for the inhibitory effect of CD200R activation (via CD200Fc) on microglial activation and inflammatory cytokine (IL-1β, TNFα) production; siRNA knockdown of Dok2 abrogates the anti-inflammatory effects of CD200Fc in cultured glia.\",\n      \"method\": \"siRNA knockdown of Dok2 in glial cells, CD200Fc stimulation, cytokine measurement, microglial activation marker analysis\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with functional cytokine readout and activation markers, single lab\",\n      \"pmids\": [\"22642833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOK2 participates in a negative feedback loop downstream of mutant EGFR: mutated EGFR leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream RAS activation. Loss of Dok2 in mice accelerates EGFR-mutant (but not Kras-mutant) lung tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation of DOK2 with EGFR, RAS activation assays, genetically engineered mouse models with EGFR mutation and Dok2 knockout\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP with EGFR, RAS activation assay, mouse genetic model with oncogene specificity (EGFR not KRAS), multiple orthogonal approaches\",\n      \"pmids\": [\"24255704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of DOK2 decreases apoptosis in response to carboplatin treatment and reduces anoikis in ovarian cancer cells, linking DOK2 function to pro-apoptotic signaling downstream of platinum-induced damage.\",\n      \"method\": \"siRNA/shRNA knockdown of DOK2 in ovarian cancer cell lines, carboplatin resistance assay, apoptosis and anoikis measurement\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional knockdown with apoptosis readout, single lab\",\n      \"pmids\": [\"23684582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLR2 activation induces tyrosine phosphorylation of Dok-1 and Dok-2 in both astrocytes and microglia. In astrocytes, siRNA knockdown of both Dok1 and Dok2 elevates TLR2-induced ERK, NF-κB activation, and IL-6 production. In microglia, Dok1 knockdown (but not Dok2 knockdown) affects NF-κB activation and IL-6, revealing cell-type-specific differential roles.\",\n      \"method\": \"siRNA knockdown of Dok1 and Dok2 in primary glia, phosphotyrosine western blotting, ERK/NF-κB activation assays, IL-6 measurement\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown of both proteins with multiple pathway readouts in two cell types, single lab\",\n      \"pmids\": [\"23659921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dok-2 in platelets is primarily phosphorylated by Lyn kinase. Dok-2 deficiency leads to dysregulated integrin αIIbβ3-dependent cytosolic calcium flux and PI(3,4)P2 accumulation. Dok-2(-/-) platelets exhibit shear-dependent increases in integrin αIIbβ3 adhesive function affecting membrane tether regulation, resulting in enhanced platelet aggregate formation and accelerated thrombus growth in vivo.\",\n      \"method\": \"Dok-2 knockout mice, Lyn kinase identification, calcium flux assay, PI(3,4)P2 measurement, platelet adhesion under flow, in vivo thrombosis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple biochemical (kinase identification, lipid measurements, Ca2+ flux) and functional (in vivo thrombosis) readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24385425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dok-1 and Dok-2 are tyrosine phosphorylated upon NK cell activation. Overexpression of Dok proteins in human NK cells reduces activation by NK-activating receptors. Dok1/Dok2 gene ablation in mice causes NK cell maturation defects and increased IFN-γ production, establishing their role in a negative feedback loop downstream of NK-activating receptors.\",\n      \"method\": \"Overexpression in human NK cells, Dok1/Dok2 knockout mice, NK cell maturation and IFN-γ production assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus gain-of-function in human cells with multiple functional readouts (maturation, cytokine) in mouse and human systems\",\n      \"pmids\": [\"24963146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dok2 protein localizes to the nucleus of erythroleukemia cells and binds directly to the promoter region of the Klf1 gene, repressing Klf1 transcription; Dok2 knockdown leads to increased Klf1 mRNA expression.\",\n      \"method\": \"Immunocytochemistry for nuclear localization, chromatin immunoprecipitation (ChIP) of Dok2 at Klf1 promoter, siRNA knockdown with RT-PCR\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ChIP and knockdown in a single cell line, no replication; nuclear localization is unexpected and not independently confirmed\",\n      \"pmids\": [\"25075100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HSV-1 infection of T cells induces tyrosine phosphorylation of Dok-2 and its selective degradation. Dok-2 physically interacts with the viral tegument protein VP11/12, and this interaction requires the Src Family Kinase-binding motifs and SHC-binding motif of VP11/12. Both the phosphorylation and degradation of Dok-2 are dependent on VP11/12.\",\n      \"method\": \"Co-immunoprecipitation of Dok-2 with VP11/12, VP11/12 binding motif mutants, western blotting for phosphorylation and protein levels upon HSV-1 infection\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with viral protein plus binding-site mutants establishing requirement, single lab\",\n      \"pmids\": [\"28841444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Compound heterozygous deletion of Dok2 and Dusp4 (co-deleted in ~50% of human lung adenocarcinomas) in mice causes lung tumorigenesis with short latency. Their co-deletion synergistically activates MAPK signaling and promotes cell proliferation; restoration of DOK2 and DUSP4 in lung cancer cells suppresses MAPK activation and cell proliferation.\",\n      \"method\": \"Compound heterozygous mouse model, MAPK activation assays, DOK2/DUSP4 restoration in cancer cell lines, cell proliferation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model plus in vitro rescue experiments with MAPK pathway readout, synergy established by compound model\",\n      \"pmids\": [\"30475228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Dok-1 and Dok-2 are major tyrosine-phosphorylated proteins associated with the Tec tyrosine kinase in T cells. Dok-1 or Dok-2 expression provides negative feedback regulation of Tec by downregulating its tyrosine phosphorylation and downstream Ras pathway signaling.\",\n      \"method\": \"Co-immunoprecipitation of Dok-1/Dok-2 with Tec, Tec phosphorylation and Ras pathway activity assays upon Dok overexpression in T cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus functional signaling assays, single lab\",\n      \"pmids\": [\"14647425\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOK2 is a PH domain- and PTB domain-containing adaptor protein that, upon tyrosine phosphorylation downstream of receptor tyrosine kinases (EGFR, BCR-ABL, c-Kit, M-CSFR), Src family kinases (Lyn), and immune receptors (TCR, CD200R, TLR4, NK-activating receptors), recruits RasGAP to suppress RAS–ERK signaling and also inhibits PI3K–AKT activation; it functions as a negative-feedback regulator of proliferation and immune activation in hematopoietic cells, with its PH domain binding PtdIns5P to facilitate membrane recruitment and phosphorylation, its PTB domain mediating both pTyr-dependent oligomerization and direct receptor binding (e.g., phospho-NPLY of CD200R), and its activity being co-opted by the HSV-1 tegument protein VP11/12 which binds, phosphorylates, and degrades DOK2 as an immune evasion mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOK2 is a tyrosine-phosphorylated adaptor protein that acts as a negative-feedback regulator of RAS–ERK and PI3K–AKT signaling downstream of receptor and non-receptor tyrosine kinases in hematopoietic and immune cells [#0, #2]. Originally purified from BCR-ABL-expressing CML cells as a 56-kDa protein that directly binds p120 RasGAP, it carries an N-terminal PH domain, a PTB domain, and multiple tyrosine-phosphorylation sites [#0]. Combined loss of Dok-2 and its paralog Dok-1 in mice produces a CML-like myeloproliferative disease with hyperactivated ERK and Akt, establishing the pair as essential brakes on RAS/MAPK signaling [#2]. DOK2 is recruited to and phosphorylated downstream of diverse activating inputs—TLR4 and TLR2 in macrophages and glia [#3, #13], the TCR via a LAT/SHIP-1/Grb-2 complex that also restrains Akt and ZAP-70 [#5, #7], NK-activating receptors [#15], and the inhibitory CD200 receptor, whose phosphorylated NPLY motif binds the DOK2 PTB domain to nucleate a DOK2–RasGAP inhibitory axis [#8]. Activation requires PH-domain binding to PtdIns5P for membrane recruitment and phosphorylation, and PTB-domain-mediated homo- and hetero-oligomerization with Dok-1 [#4, #9]. In platelets DOK2 is phosphorylated by Lyn downstream of GPVI and integrin αIIbβ3, where it limits integrin adhesive function and thrombus growth [#6, #14]. As a tumor suppressor, DOK2 forms a negative-feedback loop on mutant EGFR and, together with DUSP4, restrains MAPK-driven lung tumorigenesis [#11, #18]. The HSV-1 tegument protein VP11/12 binds, phosphorylates, and triggers degradation of DOK2 as an immune-evasion strategy [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified the molecular identity of a prominent tyrosine-phosphorylated species in CML cells, establishing DOK2 as a multidomain adaptor that directly couples to the RAS regulator RasGAP.\",\n      \"evidence\": \"Protein purification, cDNA cloning, domain analysis, and RasGAP binding assay from BCR-ABL CML cells\",\n      \"pmids\": [\"9478921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a cellular phenotype for DOK2 loss\", \"Tyrosine kinase(s) driving phosphorylation not defined\", \"Functional consequence of RasGAP binding untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic epistasis showed DOK2 and DOK1 are jointly required to suppress RAS/MAPK and Akt signaling in hematopoietic cells, defining their tumor-suppressive negative-feedback role.\",\n      \"evidence\": \"Single and double knockout mice with hematopoietic and Ras/MAPK activation analysis\",\n      \"pmids\": [\"15611294\", \"15611295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy obscures Dok-2-specific roles\", \"Direct molecular targets within the pathway not resolved here\", \"Mechanism of ERK/Akt suppression not dissected\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked DOK2 to a specific upstream kinase by showing it associates with and feedback-inhibits Tec in T cells, extending its negative regulation beyond receptor tyrosine kinases.\",\n      \"evidence\": \"Co-immunoprecipitation with Tec and Ras-pathway assays upon Dok overexpression in T cells\",\n      \"pmids\": [\"14647425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no genetic confirmation\", \"Direct vs indirect Tec association not distinguished\", \"Physiological setting where this loop dominates unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established DOK2 as a phosphorylation-dependent negative regulator of TLR4-driven ERK signaling and TNF-α production in macrophages, extending its role into innate immunity.\",\n      \"evidence\": \"Dok-1/Dok-2 knockout macrophages with gain-of-function and a Tyr/Phe mutant, ERK/NF-κB and cytokine readouts\",\n      \"pmids\": [\"15699069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pathway selectivity for ERK over NF-κB mechanistically unexplained\", \"Adaptor connecting DOK2 to TLR4 not identified\", \"In vivo inflammatory consequence not tested here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the PTB domain and Tyr139 as required for phosphotyrosine-dependent oligomerization, linking DOK2 self/cross-association to its phosphorylation and inhibitory function.\",\n      \"evidence\": \"Co-IP, PTB and Tyr139Phe mutants, ERK and NFAT reporter assays in Jurkat cells\",\n      \"pmids\": [\"16177091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of oligomerization not defined\", \"Single-lab overexpression system\", \"Whether oligomerization occurs at endogenous levels untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed DOK2 within a LAT-anchored, SHIP-1-dependent complex that restrains early TCR signaling at the level of Akt and ZAP-70, defining a membrane-proximal negative feedback loop.\",\n      \"evidence\": \"Reciprocal co-IP, LAT/SHIP-1 siRNA, phospho-Akt and phospho-Zap-70 analysis in T cells\",\n      \"pmids\": [\"17043143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and order of complex assembly unresolved\", \"Direct vs scaffolded LAT interaction unclear\", \"How SHIP-1 favors DOK2 recruitment mechanistically undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated DOK2-specific (Dok-1-independent) phosphorylation downstream of GPVI and integrin αIIbβ3 in platelets, with physical association to the integrin, implicating it in outside-in signaling.\",\n      \"evidence\": \"Differential phosphorylation, Src inhibitors, calcium chelation, and co-IP in mouse platelets\",\n      \"pmids\": [\"17092301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect integrin association not resolved\", \"Functional consequence not yet established here\", \"Responsible Src-family kinase not identified at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a non-canonical inhibitory mechanism: DOK2 suppresses ZAP-70 activation independent of its C-terminal SH2-target (RasGAP-recruiting) motifs, distinguishing it from the classical adaptor function.\",\n      \"evidence\": \"Dok-1/Dok-2 knockout mice, forced expression with C-terminal deletion mutants, phospho-ZAP-70 and proliferation assays\",\n      \"pmids\": [\"17329234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain mediating ZAP-70 inhibition not pinpointed\", \"Direct vs indirect ZAP-70 regulation unresolved\", \"Molecular intermediary not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Quantitatively defined CD200R as a direct DOK2 receptor through phospho-NPLY/PTB binding and showed the DOK2–RasGAP axis is essential and Dok-2-selective for CD200R-mediated inhibition of myeloid cells.\",\n      \"evidence\": \"Phosphopeptide affinity measurement, co-IP, siRNA of Dok-2/Dok-1/RasGAP/SHIP, and NPLY receptor mutants in U937 cells\",\n      \"pmids\": [\"19786546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the CD200R–PTB complex not solved\", \"Why Dok-2 outcompetes Dok-1 mechanistically unclear beyond affinity\", \"Downstream effectors of RasGAP not enumerated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected lipid binding to activation by showing the PH domain binds PtdIns5P and that PtdIns5P is required for DOK2 tyrosine phosphorylation and inhibitory function in T cells.\",\n      \"evidence\": \"In vitro PH–PtdIns5P binding, in vivo PtdIns5P modulation, and PH-deletion mutant phosphotyrosine analysis\",\n      \"pmids\": [\"19299694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo membrane localization not directly imaged\", \"Single lab\", \"Enzymatic source of PtdIns5P pool not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the CD200R–DOK2 inhibitory axis to the CNS, showing DOK2 phosphorylation is required for CD200R-mediated suppression of microglial inflammatory activation.\",\n      \"evidence\": \"siRNA knockdown of Dok2 in glia with CD200Fc stimulation and cytokine/activation-marker readouts\",\n      \"pmids\": [\"22642833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab knockdown without genetic confirmation\", \"Downstream signaling in microglia not mapped\", \"In vivo neuroinflammatory relevance untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established DOK2 as a tumor suppressor in EGFR-mutant lung cancer through a negative-feedback loop on mutant EGFR, with oncogene specificity (EGFR but not KRAS).\",\n      \"evidence\": \"Co-IP of DOK2 with EGFR, RAS activation assays, and EGFR-mutant Dok2-knockout mouse models\",\n      \"pmids\": [\"24255704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs adaptor-mediated EGFR binding unresolved\", \"Why KRAS-mutant tumors are unaffected not explained\", \"Human tumor data correlation not addressed here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated DOK2 in chemotherapy response by showing its loss reduces carboplatin-induced apoptosis and anoikis in ovarian cancer cells.\",\n      \"evidence\": \"siRNA/shRNA knockdown in ovarian cancer lines with carboplatin resistance and apoptosis/anoikis assays\",\n      \"pmids\": [\"23684582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking DOK2 to apoptosis not defined\", \"Single-lab cell-line study\", \"In vivo therapeutic relevance untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed TLR2-induced DOK2 phosphorylation and revealed cell-type-specific division of labor between Dok-1 and Dok-2 in glial inflammatory signaling.\",\n      \"evidence\": \"siRNA knockdown of Dok1 and Dok2 in primary astrocytes and microglia with ERK/NF-κB and IL-6 readouts\",\n      \"pmids\": [\"23659921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of cell-type specificity unexplained\", \"Direct TLR2 coupling not demonstrated\", \"Single-lab knockdown without rescue\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Lyn as the DOK2 kinase in platelets and demonstrated that DOK2 loss enhances integrin αIIbβ3 adhesion and accelerates thrombus formation in vivo, establishing a hemostatic regulatory role.\",\n      \"evidence\": \"Dok-2 knockout mice, kinase identification, calcium and PI(3,4)P2 measurements, flow-adhesion and in vivo thrombosis assays\",\n      \"pmids\": [\"24385425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DOK2 substrates/effectors in platelets not defined\", \"Link between PI(3,4)P2 accumulation and adhesion mechanistic detail incomplete\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established DOK2 (with Dok-1) as a negative regulator of NK-cell activation and maturation downstream of activating receptors.\",\n      \"evidence\": \"Overexpression in human NK cells and Dok1/Dok2 knockout mice with maturation and IFN-γ readouts\",\n      \"pmids\": [\"24963146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific activating receptors coupled to DOK2 not enumerated\", \"Dok-2-specific vs redundant contributions not separated\", \"Molecular target in NK cells unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reported an unexpected nuclear, transcriptional-repressor role: DOK2 binds the Klf1 promoter and represses its transcription in erythroleukemia cells.\",\n      \"evidence\": \"Immunocytochemistry, ChIP at the Klf1 promoter, and siRNA knockdown with RT-PCR in a single cell line\",\n      \"pmids\": [\"25075100\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Nuclear localization unexpected and not independently confirmed\", \"Single cell line without replication\", \"No demonstrated DNA-binding domain or direct binding mechanism\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a viral immune-evasion mechanism in which HSV-1 VP11/12 binds, phosphorylates, and targets DOK2 for degradation, requiring VP11/12 SFK- and SHC-binding motifs.\",\n      \"evidence\": \"Co-IP of Dok-2 with VP11/12, VP11/12 binding-motif mutants, and phosphorylation/protein-level analysis upon HSV-1 infection\",\n      \"pmids\": [\"28841444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation machinery (e.g., proteasome/ubiquitin) not identified\", \"Functional immune consequence of DOK2 loss in infection untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated synergistic tumor suppression by showing co-deletion of DOK2 and DUSP4 drives MAPK activation and lung tumorigenesis, reversible by their restoration.\",\n      \"evidence\": \"Compound heterozygous mouse model, MAPK assays, and DOK2/DUSP4 restoration with proliferation assays in cancer cell lines\",\n      \"pmids\": [\"30475228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic interplay between DOK2 and DUSP4 nodes not fully resolved\", \"Whether the two act on the same or parallel MAPK steps unclear\", \"Direct binding partners in this context not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DOK2 selectively inhibits ERK versus NF-κB, the structural basis of its PTB/PH-mediated receptor and lipid recognition, and the validity of its proposed nuclear transcriptional role remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PTB–phosphoreceptor or PH–PtdIns5P complexes\", \"Nuclear/transcriptional function rests on a single low-confidence study\", \"Pathway-selectivity mechanism (ERK-specific suppression) undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5, 7, 15]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 18]}\n    ],\n    \"complexes\": [\"LAT signaling complex (with SHIP-1 and Grb-2)\"],\n    \"partners\": [\"RASA1\", \"DOK1\", \"INPP5D\", \"GRB2\", \"LAT\", \"CD200R1\", \"EGFR\", \"ITGB3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}