{"gene":"DOK2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1998,"finding":"DOK2 (p56dok-2) was identified as a 412-amino acid protein containing an N-terminal pleckstrin homology (PH) domain, 13 potential tyrosine phosphorylation sites, six PXXP motifs, and the ability to bind to p120RasGAP. It is phosphorylated by p210bcr-abl tyrosine kinase in CML cells.","method":"Protein purification, cDNA cloning, co-immunoprecipitation, sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — original cloning with direct binding assay and multiple domain characterization, foundational paper","pmids":["9478921"],"is_preprint":false},{"year":2003,"finding":"DOK2 is expressed in human platelets and undergoes tyrosine phosphorylation upon stimulation by TRAP (thrombin receptor activating peptide), collagen receptor GPVI signaling, and outside-in signaling through integrin αIIbβ3.","method":"2D gel electrophoresis, LC-MS/MS mass spectrometry, proteomics","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — MS-based identification with phosphorylation mapping in activated platelets, replicated in subsequent studies","pmids":["14645010"],"is_preprint":false},{"year":2004,"finding":"Dok-1 and Dok-2 associate with RasGAP upon phosphorylation by p210bcr-abl and other tyrosine kinases. Double knockout of Dok-1 and Dok-2 in mice causes myeloproliferative disease with aberrant Ras/MAP kinase activation, establishing their role as negative regulators of Ras-ERK signaling downstream of tyrosine kinases.","method":"Genetic knockout mice, co-immunoprecipitation, signaling assays (ERK/Akt activation)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — two independent labs generated Dok-1/Dok-2 double KO mice with consistent phenotypes (PMIDs 15611294 and 15611295)","pmids":["15611294","15611295"],"is_preprint":false},{"year":2004,"finding":"Dok-1 and Dok-2 are the major tyrosine-phosphorylated proteins associated with the Tec protein tyrosine kinase in T cells, and they negatively regulate Tec-mediated signaling including the Ras pathway by downregulating Tec tyrosine phosphorylation.","method":"Co-immunoprecipitation, overexpression in T cells, signaling assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal co-IP with functional follow-up, single lab","pmids":["14647425"],"is_preprint":false},{"year":2005,"finding":"Dok-1 and Dok-2 are essential negative regulators downstream of TLR4. LPS stimulation induces tyrosine phosphorylation of Dok-1 and Dok-2 in macrophages; loss of either protein elevates ERK activation and hyperproduction of TNF-α and nitric oxide. A Tyr/Phe substitution mutant abolished the inhibitory function, confirming tyrosine phosphorylation is required.","method":"Knockout mice, macrophage stimulation assays, forced expression with phosphorylation mutants, cytokine measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — KO phenotype combined with phosphorylation-dead mutant rescue experiment, strong mechanistic evidence","pmids":["15699069"],"is_preprint":false},{"year":2005,"finding":"The PTB domain of Dok-1 and Dok-2 mediates phosphotyrosine-dependent homotypic and heterotypic oligomerization. PTB-mediated oligomerization (requiring Tyr146 of Dok-1 and Tyr139 of Dok-2) is essential for CD2-induced Dok phosphorylation and subsequent inhibition of ERK1/2 and NFAT activation.","method":"Site-directed mutagenesis, co-immunoprecipitation in Jurkat cells, overexpression of PTB and tyrosine mutants","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with multiple functional readouts in the same study","pmids":["16177091"],"is_preprint":false},{"year":2006,"finding":"After TCR stimulation, Dok-2 and Dok-1 form a multimolecular complex with SHIP-1 and Grb-2 that associates with LAT. SHIP-1 promotes recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed negative control on Akt and ZAP-70 activation.","method":"Co-immunoprecipitation, siRNA knockdown, signaling assays in T cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus siRNA knockdown with multiple signaling readouts","pmids":["17043143"],"is_preprint":false},{"year":2006,"finding":"In platelets, Dok2 (but not Dok1) phosphorylation requires Src kinase activity and intracellular calcium, and Dok2 co-immunoprecipitates with integrin αIIbβ3, suggesting a physical and functional interaction with this integrin in outside-in signaling. Dok1 and Dok2 showed differential regulation: Dok1 phosphorylation is transient and downstream of thrombin only, while Dok2 phosphorylation is delayed, sustained, and downstream of multiple receptors.","method":"Co-immunoprecipitation, pharmacological inhibitors (Src kinase inhibitors, calcium chelation), platelet stimulation assays","journal":"Journal of thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and inhibitor studies, single lab","pmids":["17092301"],"is_preprint":false},{"year":2007,"finding":"Forced expression of Dok-1 or Dok-2 in CD3+CD4+ T cell clone inhibited ZAP-70 activation upon TCR stimulation; mice lacking Dok-1 and Dok-2 showed elevated ZAP-70 activation and augmented T cell responses. The C-terminal moieties bearing SH2-target motifs were dispensable for this negative regulation.","method":"Forced expression, knockout mice, TCR stimulation assays, ZAP-70 activation measurement","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — combination of KO mice and forced expression with domain deletion analysis","pmids":["17329234"],"is_preprint":false},{"year":2009,"finding":"DOK2 binds directly to the phosphorylated NPLY motif of CD200 receptor with ~10-fold higher affinity than Dok-1 (Kd ~1 μM at 37°C). Upon CD200R engagement, Dok2 is phosphorylated and recruits RasGAP. siRNA knockdown of Dok2 and RasGAP abolished CD200R-mediated inhibition of human myeloid cells, while Dok1 knockdown had no effect.","method":"Direct binding assay with affinity measurement, siRNA knockdown, phosphorylation assays, signaling readouts in U937 cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding with quantitative affinity measurement plus siRNA knockdown with functional readout, multiple orthogonal methods","pmids":["19786546"],"is_preprint":false},{"year":2009,"finding":"The PH domain of Dok-1 and Dok-2 binds in vitro to phosphatidylinositol 5-phosphate (PtdIns5P), a rare phosphoinositide. PtdIns5P production in T cells upon TCR triggering correlates with and regulates Dok tyrosine phosphorylation in vivo; the PH domain is required for Dok tyrosine phosphorylation and negative function in T cells.","method":"In vitro lipid binding assay, T cell PtdIns5P modulation, tyrosine phosphorylation measurement, domain deletion analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro binding plus in vivo correlation with functional domain requirement, single lab","pmids":["19299694"],"is_preprint":false},{"year":2012,"finding":"Dok2 phosphorylation mediates the anti-inflammatory effects of CD200Fc (CD200 receptor activation) in microglia; siRNA knockdown of Dok2 abolished CD200Fc-mediated inhibition of Aβ-induced IL-1β, TNFα, CD68, and CD40 increases, and prevented attenuation of Aβ-induced LTP impairment.","method":"siRNA knockdown, cytokine measurement, LTP electrophysiology, microglial activation markers","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2-3 — siRNA knockdown with multiple functional readouts, single lab","pmids":["22642833"],"is_preprint":false},{"year":2013,"finding":"DOK2 participates in a negative feedback loop opposing mutated EGFR in lung adenocarcinoma: EGFR mutation leads to recruitment of DOK2 to EGFR, and DOK2 mediates inhibition of downstream RAS activation. Loss of Dok2 accelerates EGFR-mutant but not Kras-mutant lung tumorigenesis in mouse models.","method":"Genetically engineered mouse models, co-immunoprecipitation (DOK2 with EGFR), RAS activation assays, epistasis analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — co-IP establishing physical interaction plus genetic epistasis in two distinct mouse models","pmids":["24255704"],"is_preprint":false},{"year":2013,"finding":"Dok-1 and Dok-2 negatively regulate TLR2-induced ERK signaling in both astrocytes and microglia; TLR2 stimulation with Pam3CSK4 induces tyrosine phosphorylation of Dok1 and Dok2. In astrocytes, both Dok1 and Dok2 knockdown elevated TLR2-induced NF-κB activation and IL-6 production, whereas in microglia only Dok1 (not Dok2) knockdown affected NF-κB and IL-6.","method":"siRNA knockdown, TLR2 stimulation, ERK/NF-κB activation assays, cytokine measurement","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — siRNA knockdown with multiple readouts revealing cell-type-specific roles, single lab","pmids":["23659921"],"is_preprint":false},{"year":2014,"finding":"In platelets, Dok-2 is primarily phosphorylated by Lyn kinase. Deficiency of Dok-2 leads to dysregulated integrin αIIbβ3-dependent cytosolic calcium flux and phosphatidylinositol(3,4)P2 accumulation, and causes shear-dependent increase in integrin αIIbβ3 adhesive function and enhanced platelet aggregate formation in vivo.","method":"Dok-2 knockout mice, Lyn kinase inhibition/deficiency studies, calcium flux measurement, PI(3,4)P2 measurement, flow-based adhesion assays, in vivo thrombosis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — KO mouse with multiple orthogonal biochemical and functional assays, identifies Lyn as upstream kinase","pmids":["24385425"],"is_preprint":false},{"year":2014,"finding":"Dok2 protein localizes to the nucleus in mouse erythroleukemia cells and binds to the promoter region of the Klf1 gene, negatively regulating Klf1 transcription; Dok2 knockdown increased Klf1 mRNA ~1.94-fold.","method":"siRNA knockdown, immunocytochemistry, chromatin immunoprecipitation (ChIP)","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single ChIP experiment without rescue or mutagenesis validation","pmids":["25075100"],"is_preprint":false},{"year":2017,"finding":"HSV-1 infection causes VP11/12-dependent tyrosine phosphorylation and selective degradation of Dok-2 in T cells. Dok-2 physically interacts with VP11/12; inactivation of Src Family Kinase binding motifs or the SHC binding motif of VP11/12 eliminates Dok-2 interaction, phosphorylation, and degradation.","method":"Co-immunoprecipitation, VP11/12 binding site mutagenesis, HSV-1 infection assays, western blotting for Dok-2 levels","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus mutagenesis of viral protein binding motifs, single lab","pmids":["28841444"],"is_preprint":false},{"year":2018,"finding":"Compound haploinsufficiency of Dok2 and Dusp4 (co-deleted in ~50% of human lung adenocarcinomas) synergistically activates MAPK signaling and promotes cell proliferation; restoration of DOK2 in lung cancer cells suppresses MAPK activation and cell proliferation, establishing DOK2 as a negative regulator of MAPK signaling in lung tumorigenesis.","method":"Compound heterozygous mouse models, MAPK signaling assays, DOK2 restoration in cancer cell lines, cell proliferation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo mouse model combined with cell-line restoration experiments and MAPK mechanistic readouts","pmids":["30475228"],"is_preprint":false},{"year":2025,"finding":"DOK2 interacts with the SH2 domain of TSAd (T cell specific adapter protein) in T cells; the specific phosphotyrosines on DOK2 responsible for TSAd SH2 domain-dependent binding were identified. CRISPR/Cas9 ablation of TSAd and DOK2 in Jurkat T cells resulted in altered tyrosine phosphorylation patterns.","method":"Affinity-purification mass spectrometry (AP-MS), CRISPR/Cas9 knockout, phosphotyrosine mapping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — AP-MS with CRISPR validation and phosphotyrosine identification, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.02.11.636929"],"is_preprint":true}],"current_model":"DOK2 is a scaffold/adaptor protein that, upon tyrosine phosphorylation by upstream kinases (including Bcr-Abl, Src-family kinases such as Lyn, Tec, and receptor tyrosine kinases including EGFR), recruits RasGAP through its C-terminal region to negatively regulate Ras-ERK and PI3K-Akt signaling; it also forms oligomers via its PTB domain, is recruited to activated immune receptors (TCR/LAT, CD200R, TLR4, integrin αIIbβ3) where it assembles inhibitory complexes with SHIP-1, Grb-2, and RasGAP, and thereby functions as a broadly expressed negative feedback regulator of cytokine, immune receptor, and oncogenic tyrosine kinase signaling in hematopoietic cells, with tumor suppressor activity particularly in myeloid and lung cancer contexts."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of DOK2 as a multi-domain adaptor protein with RasGAP-binding capacity established that a second Dok-family member exists and is a substrate of Bcr-Abl, opening questions about its role in CML and Ras regulation.","evidence":"Protein purification, cDNA cloning, and co-immunoprecipitation in CML cells","pmids":["9478921"],"confidence":"High","gaps":["No in vivo loss-of-function data","Physiological upstream activators beyond Bcr-Abl unknown","Functional consequence of RasGAP binding not tested"]},{"year":2004,"claim":"Genetic ablation of Dok-1 and Dok-2 in mice demonstrated that these adaptors are non-redundant negative regulators of Ras-ERK signaling downstream of tyrosine kinases, with loss causing myeloproliferative disease—resolving whether RasGAP recruitment had physiological consequences.","evidence":"Dok-1/Dok-2 double knockout mice with myeloproliferative phenotype and elevated ERK/Akt activation, reproduced by two independent labs","pmids":["15611294","15611295"],"confidence":"High","gaps":["Individual contributions of Dok-1 vs Dok-2 to the phenotype unresolved","Downstream effectors beyond ERK/Akt not mapped","No structural model of RasGAP recruitment"]},{"year":2005,"claim":"Discovery that DOK2 is phosphorylated and inhibits ERK and TNF-α production downstream of TLR4, and that PTB-domain-mediated oligomerization is required for DOK2 function, revealed that DOK2 operates in innate immunity and that its self-assembly is mechanistically essential.","evidence":"Dok-2 KO macrophages with elevated TLR4 responses plus phosphorylation-dead mutant rescue; PTB domain mutagenesis in Jurkat T cells with ERK and NFAT readouts","pmids":["15699069","16177091"],"confidence":"High","gaps":["Kinase responsible for DOK2 phosphorylation at TLR4 not identified","Oligomerization stoichiometry and structure undefined","Relative contribution of Dok-1 vs Dok-2 in macrophages unclear"]},{"year":2006,"claim":"Identification of a DOK2–SHIP-1–Grb-2 complex at LAT after TCR stimulation, and DOK2's role in restraining ZAP-70 and Akt activation, established the adaptor as a core component of TCR negative signaling architecture.","evidence":"Co-immunoprecipitation and siRNA knockdown in primary T cells with Akt and ZAP-70 readouts; forced expression and KO mice confirming ZAP-70 regulation","pmids":["17043143","17329234"],"confidence":"High","gaps":["How SHIP-1 promotes DOK2 recruitment to LAT mechanistically unresolved","C-terminal SH2-target motifs dispensable for ZAP-70 inhibition—alternative mechanism unknown","Whether DOK2 acts identically in CD4+ and CD8+ T cells untested"]},{"year":2009,"claim":"Quantitative binding studies showed DOK2 is the preferred adaptor for CD200R's NPXY motif and is essential for CD200R-mediated myeloid inhibition via RasGAP recruitment, providing a receptor-specific non-redundant role distinct from Dok-1.","evidence":"Direct binding assay with Kd measurement, siRNA knockdown of Dok-2 vs Dok-1 in U937 cells with functional readouts","pmids":["19786546"],"confidence":"High","gaps":["Whether DOK2 similarly dominates at other ITIM/NPXY-containing receptors unknown","No structural basis for the 10-fold affinity difference over Dok-1"]},{"year":2009,"claim":"Demonstration that the PH domain binds PtdIns5P and that this lipid interaction regulates DOK2 tyrosine phosphorylation in T cells introduced a lipid-sensing step upstream of DOK2 activation.","evidence":"In vitro lipid binding assay and PH domain deletion with phosphorylation readouts in T cells","pmids":["19299694"],"confidence":"Medium","gaps":["In vivo PtdIns5P–DOK2 interaction not confirmed by structural or live-cell methods","Whether PtdIns5P regulation applies in non-T cell contexts untested","Source kinase for PtdIns5P-dependent DOK2 phosphorylation not identified"]},{"year":2013,"claim":"Identification of DOK2 as a negative feedback element opposing mutant EGFR in lung adenocarcinoma, where its loss accelerates EGFR-driven but not KRAS-driven tumorigenesis, positioned DOK2 as an EGFR-specific tumor suppressor.","evidence":"Genetically engineered mouse models with co-immunoprecipitation of DOK2–EGFR and RAS activation assays; epistasis with KRAS-mutant model","pmids":["24255704"],"confidence":"High","gaps":["Whether DOK2 loss alone (without cooperating hits) suffices for tumorigenesis unknown","Mechanism of DOK2 silencing in human tumors (epigenetic vs genomic) not resolved"]},{"year":2014,"claim":"Lyn was identified as the primary kinase phosphorylating DOK2 in platelets, and Dok-2 deficiency caused dysregulated integrin αIIbβ3-dependent calcium flux and enhanced thrombus formation, establishing DOK2 as a negative regulator of platelet activation and thrombosis.","evidence":"Dok-2 KO mice, Lyn inhibition/deficiency, calcium flux and PI(3,4)P2 measurement, in vivo thrombosis model","pmids":["24385425"],"confidence":"High","gaps":["Direct substrates or downstream effectors of DOK2 in the integrin pathway not fully mapped","Whether Lyn→DOK2 axis operates in non-platelet hematopoietic cells not tested"]},{"year":2018,"claim":"Compound haploinsufficiency of DOK2 and DUSP4—frequently co-deleted in human lung adenocarcinoma—synergistically activates MAPK signaling, demonstrating that DOK2's tumor-suppressive function is dosage-sensitive and cooperates with parallel phosphatase-mediated MAPK control.","evidence":"Compound heterozygous mouse models, DOK2 restoration in lung cancer cell lines, MAPK and proliferation assays","pmids":["30475228"],"confidence":"High","gaps":["Whether restoration of DOK2 alone is sufficient for tumor regression in vivo unknown","Epigenetic regulation of DOK2 expression in human tumors not characterized"]},{"year":null,"claim":"Key unresolved questions include the structural basis for DOK2 oligomerization and receptor engagement, whether DOK2 has bona fide nuclear functions, and the full spectrum of cancers in which DOK2 loss is functionally consequential.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of DOK2 or its complexes","Nuclear localization and Klf1 ChIP finding from a single low-confidence study awaits independent replication","Mechanism by which HSV-1 VP11/12 targets DOK2 for degradation and its immunological consequence remain unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,6,9,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7,10,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4,6,9,12,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,8,9,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,12,17]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,7,14]}],"complexes":["DOK2–RasGAP inhibitory complex","DOK2–SHIP-1–Grb-2 complex at LAT"],"partners":["RASA1","INPP5D","GRB2","LYN","TEC","EGFR","CD200R1","LAT"],"other_free_text":[]},"mechanistic_narrative":"DOK2 is a broadly expressed adaptor protein that functions as a negative feedback regulator of Ras-ERK, PI3K-Akt, and NF-κB signaling downstream of diverse receptor and non-receptor tyrosine kinases in hematopoietic and epithelial cells. Upon tyrosine phosphorylation by upstream kinases such as Lyn, Tec, Bcr-Abl, and EGFR, DOK2 recruits RasGAP through its C-terminal phosphotyrosine motifs and assembles inhibitory complexes with SHIP-1 and Grb-2 at activated receptors including TCR/LAT, CD200R, TLR4, TLR2, and integrin αIIbβ3, thereby attenuating downstream MAPK activation, cytokine production, and cellular proliferation [PMID:15611294, PMID:15699069, PMID:17043143, PMID:19786546, PMID:24385425]. PTB domain-mediated oligomerization (requiring Tyr139) and PH domain binding to phosphatidylinositol 5-phosphate are essential for DOK2 membrane recruitment and tyrosine phosphorylation in T cells [PMID:16177091, PMID:19299694]. DOK2 acts as a tumor suppressor in lung adenocarcinoma, where it opposes EGFR-mutant-driven RAS activation, and its co-deletion with DUSP4 synergistically activates MAPK signaling to promote tumorigenesis [PMID:24255704, PMID:30475228]."},"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":123,"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 medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15611295","citation_count":74,"is_preprint":false},{"pmid":"15699069","id":"PMC_15699069","title":"Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.","date":"2005","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15699069","citation_count":74,"is_preprint":false},{"pmid":"11013214","id":"PMC_11013214","title":"p56(dok-2) as a cytokine-inducible inhibitor of cell proliferation and signal transduction.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11013214","citation_count":62,"is_preprint":false},{"pmid":"19299694","id":"PMC_19299694","title":"Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19299694","citation_count":51,"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":24,"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":"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":"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":13,"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":3,"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},{"pmid":null,"id":"bio_10.1101_2025.02.11.636929","title":"Identification of DOK2 and PTPN11 as novel interactors of T cell specific adapter protein TSAd","date":"2025-02-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.11.636929","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18462,"output_tokens":4614,"usd":0.062298},"stage2":{"model":"claude-opus-4-6","input_tokens":8147,"output_tokens":2924,"usd":0.170753},"total_usd":0.233051,"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\": 1998,\n      \"finding\": \"DOK2 (p56dok-2) was identified as a 412-amino acid protein containing an N-terminal pleckstrin homology (PH) domain, 13 potential tyrosine phosphorylation sites, six PXXP motifs, and the ability to bind to p120RasGAP. It is phosphorylated by p210bcr-abl tyrosine kinase in CML cells.\",\n      \"method\": \"Protein purification, cDNA cloning, co-immunoprecipitation, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original cloning with direct binding assay and multiple domain characterization, foundational paper\",\n      \"pmids\": [\"9478921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DOK2 is expressed in human platelets and undergoes tyrosine phosphorylation upon stimulation by TRAP (thrombin receptor activating peptide), collagen receptor GPVI signaling, and outside-in signaling through integrin αIIbβ3.\",\n      \"method\": \"2D gel electrophoresis, LC-MS/MS mass spectrometry, proteomics\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS-based identification with phosphorylation mapping in activated platelets, replicated in subsequent studies\",\n      \"pmids\": [\"14645010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Dok-1 and Dok-2 associate with RasGAP upon phosphorylation by p210bcr-abl and other tyrosine kinases. Double knockout of Dok-1 and Dok-2 in mice causes myeloproliferative disease with aberrant Ras/MAP kinase activation, establishing their role as negative regulators of Ras-ERK signaling downstream of tyrosine kinases.\",\n      \"method\": \"Genetic knockout mice, co-immunoprecipitation, signaling assays (ERK/Akt activation)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent labs generated Dok-1/Dok-2 double KO mice with consistent phenotypes (PMIDs 15611294 and 15611295)\",\n      \"pmids\": [\"15611294\", \"15611295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Dok-1 and Dok-2 are the major tyrosine-phosphorylated proteins associated with the Tec protein tyrosine kinase in T cells, and they negatively regulate Tec-mediated signaling including the Ras pathway by downregulating Tec tyrosine phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in T cells, signaling assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal co-IP with functional follow-up, single lab\",\n      \"pmids\": [\"14647425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Dok-1 and Dok-2 are essential negative regulators downstream of TLR4. LPS stimulation induces tyrosine phosphorylation of Dok-1 and Dok-2 in macrophages; loss of either protein elevates ERK activation and hyperproduction of TNF-α and nitric oxide. A Tyr/Phe substitution mutant abolished the inhibitory function, confirming tyrosine phosphorylation is required.\",\n      \"method\": \"Knockout mice, macrophage stimulation assays, forced expression with phosphorylation mutants, cytokine measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO phenotype combined with phosphorylation-dead mutant rescue experiment, strong mechanistic evidence\",\n      \"pmids\": [\"15699069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The PTB domain of Dok-1 and Dok-2 mediates phosphotyrosine-dependent homotypic and heterotypic oligomerization. PTB-mediated oligomerization (requiring Tyr146 of Dok-1 and Tyr139 of Dok-2) is essential for CD2-induced Dok phosphorylation and subsequent inhibition of ERK1/2 and NFAT activation.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation in Jurkat cells, overexpression of PTB and tyrosine mutants\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with multiple functional readouts in the same study\",\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 with SHIP-1 and Grb-2 that associates with LAT. SHIP-1 promotes recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed negative control on Akt and ZAP-70 activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, signaling assays in T cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus siRNA knockdown with multiple signaling readouts\",\n      \"pmids\": [\"17043143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In platelets, Dok2 (but not Dok1) phosphorylation requires Src kinase activity and intracellular calcium, and Dok2 co-immunoprecipitates with integrin αIIbβ3, suggesting a physical and functional interaction with this integrin in outside-in signaling. Dok1 and Dok2 showed differential regulation: Dok1 phosphorylation is transient and downstream of thrombin only, while Dok2 phosphorylation is delayed, sustained, and downstream of multiple receptors.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological inhibitors (Src kinase inhibitors, calcium chelation), platelet stimulation assays\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and inhibitor studies, single lab\",\n      \"pmids\": [\"17092301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Forced expression of Dok-1 or Dok-2 in CD3+CD4+ T cell clone inhibited ZAP-70 activation upon TCR stimulation; mice lacking Dok-1 and Dok-2 showed elevated ZAP-70 activation and augmented T cell responses. The C-terminal moieties bearing SH2-target motifs were dispensable for this negative regulation.\",\n      \"method\": \"Forced expression, knockout mice, TCR stimulation assays, ZAP-70 activation measurement\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — combination of KO mice and forced expression with domain deletion analysis\",\n      \"pmids\": [\"17329234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DOK2 binds directly to the phosphorylated NPLY motif of CD200 receptor with ~10-fold higher affinity than Dok-1 (Kd ~1 μM at 37°C). Upon CD200R engagement, Dok2 is phosphorylated and recruits RasGAP. siRNA knockdown of Dok2 and RasGAP abolished CD200R-mediated inhibition of human myeloid cells, while Dok1 knockdown had no effect.\",\n      \"method\": \"Direct binding assay with affinity measurement, siRNA knockdown, phosphorylation assays, signaling readouts in U937 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding with quantitative affinity measurement plus siRNA knockdown with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"19786546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The PH domain of Dok-1 and Dok-2 binds in vitro to phosphatidylinositol 5-phosphate (PtdIns5P), a rare phosphoinositide. PtdIns5P production in T cells upon TCR triggering correlates with and regulates Dok tyrosine phosphorylation in vivo; the PH domain is required for Dok tyrosine phosphorylation and negative function in T cells.\",\n      \"method\": \"In vitro lipid binding assay, T cell PtdIns5P modulation, tyrosine phosphorylation measurement, domain deletion analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding plus in vivo correlation with functional domain requirement, single lab\",\n      \"pmids\": [\"19299694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dok2 phosphorylation mediates the anti-inflammatory effects of CD200Fc (CD200 receptor activation) in microglia; siRNA knockdown of Dok2 abolished CD200Fc-mediated inhibition of Aβ-induced IL-1β, TNFα, CD68, and CD40 increases, and prevented attenuation of Aβ-induced LTP impairment.\",\n      \"method\": \"siRNA knockdown, cytokine measurement, LTP electrophysiology, microglial activation markers\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — siRNA knockdown with multiple functional readouts, single lab\",\n      \"pmids\": [\"22642833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOK2 participates in a negative feedback loop opposing mutated EGFR in lung adenocarcinoma: EGFR mutation leads to recruitment of DOK2 to EGFR, and DOK2 mediates inhibition of downstream RAS activation. Loss of Dok2 accelerates EGFR-mutant but not Kras-mutant lung tumorigenesis in mouse models.\",\n      \"method\": \"Genetically engineered mouse models, co-immunoprecipitation (DOK2 with EGFR), RAS activation assays, epistasis analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — co-IP establishing physical interaction plus genetic epistasis in two distinct mouse models\",\n      \"pmids\": [\"24255704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dok-1 and Dok-2 negatively regulate TLR2-induced ERK signaling in both astrocytes and microglia; TLR2 stimulation with Pam3CSK4 induces tyrosine phosphorylation of Dok1 and Dok2. In astrocytes, both Dok1 and Dok2 knockdown elevated TLR2-induced NF-κB activation and IL-6 production, whereas in microglia only Dok1 (not Dok2) knockdown affected NF-κB and IL-6.\",\n      \"method\": \"siRNA knockdown, TLR2 stimulation, ERK/NF-κB activation assays, cytokine measurement\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — siRNA knockdown with multiple readouts revealing cell-type-specific roles, single lab\",\n      \"pmids\": [\"23659921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In platelets, Dok-2 is primarily phosphorylated by Lyn kinase. Deficiency of Dok-2 leads to dysregulated integrin αIIbβ3-dependent cytosolic calcium flux and phosphatidylinositol(3,4)P2 accumulation, and causes shear-dependent increase in integrin αIIbβ3 adhesive function and enhanced platelet aggregate formation in vivo.\",\n      \"method\": \"Dok-2 knockout mice, Lyn kinase inhibition/deficiency studies, calcium flux measurement, PI(3,4)P2 measurement, flow-based adhesion assays, in vivo thrombosis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO mouse with multiple orthogonal biochemical and functional assays, identifies Lyn as upstream kinase\",\n      \"pmids\": [\"24385425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dok2 protein localizes to the nucleus in mouse erythroleukemia cells and binds to the promoter region of the Klf1 gene, negatively regulating Klf1 transcription; Dok2 knockdown increased Klf1 mRNA ~1.94-fold.\",\n      \"method\": \"siRNA knockdown, immunocytochemistry, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single ChIP experiment without rescue or mutagenesis validation\",\n      \"pmids\": [\"25075100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HSV-1 infection causes VP11/12-dependent tyrosine phosphorylation and selective degradation of Dok-2 in T cells. Dok-2 physically interacts with VP11/12; inactivation of Src Family Kinase binding motifs or the SHC binding motif of VP11/12 eliminates Dok-2 interaction, phosphorylation, and degradation.\",\n      \"method\": \"Co-immunoprecipitation, VP11/12 binding site mutagenesis, HSV-1 infection assays, western blotting for Dok-2 levels\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus mutagenesis of viral protein binding motifs, single lab\",\n      \"pmids\": [\"28841444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Compound haploinsufficiency of Dok2 and Dusp4 (co-deleted in ~50% of human lung adenocarcinomas) synergistically activates MAPK signaling and promotes cell proliferation; restoration of DOK2 in lung cancer cells suppresses MAPK activation and cell proliferation, establishing DOK2 as a negative regulator of MAPK signaling in lung tumorigenesis.\",\n      \"method\": \"Compound heterozygous mouse models, MAPK signaling assays, DOK2 restoration in cancer cell lines, cell proliferation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo mouse model combined with cell-line restoration experiments and MAPK mechanistic readouts\",\n      \"pmids\": [\"30475228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DOK2 interacts with the SH2 domain of TSAd (T cell specific adapter protein) in T cells; the specific phosphotyrosines on DOK2 responsible for TSAd SH2 domain-dependent binding were identified. CRISPR/Cas9 ablation of TSAd and DOK2 in Jurkat T cells resulted in altered tyrosine phosphorylation patterns.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS), CRISPR/Cas9 knockout, phosphotyrosine mapping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS with CRISPR validation and phosphotyrosine identification, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.11.636929\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DOK2 is a scaffold/adaptor protein that, upon tyrosine phosphorylation by upstream kinases (including Bcr-Abl, Src-family kinases such as Lyn, Tec, and receptor tyrosine kinases including EGFR), recruits RasGAP through its C-terminal region to negatively regulate Ras-ERK and PI3K-Akt signaling; it also forms oligomers via its PTB domain, is recruited to activated immune receptors (TCR/LAT, CD200R, TLR4, integrin αIIbβ3) where it assembles inhibitory complexes with SHIP-1, Grb-2, and RasGAP, and thereby functions as a broadly expressed negative feedback regulator of cytokine, immune receptor, and oncogenic tyrosine kinase signaling in hematopoietic cells, with tumor suppressor activity particularly in myeloid and lung cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DOK2 is a broadly expressed adaptor protein that functions as a negative feedback regulator of Ras-ERK, PI3K-Akt, and NF-κB signaling downstream of diverse receptor and non-receptor tyrosine kinases in hematopoietic and epithelial cells. Upon tyrosine phosphorylation by upstream kinases such as Lyn, Tec, Bcr-Abl, and EGFR, DOK2 recruits RasGAP through its C-terminal phosphotyrosine motifs and assembles inhibitory complexes with SHIP-1 and Grb-2 at activated receptors including TCR/LAT, CD200R, TLR4, TLR2, and integrin αIIbβ3, thereby attenuating downstream MAPK activation, cytokine production, and cellular proliferation [PMID:15611294, PMID:15699069, PMID:17043143, PMID:19786546, PMID:24385425]. PTB domain-mediated oligomerization (requiring Tyr139) and PH domain binding to phosphatidylinositol 5-phosphate are essential for DOK2 membrane recruitment and tyrosine phosphorylation in T cells [PMID:16177091, PMID:19299694]. DOK2 acts as a tumor suppressor in lung adenocarcinoma, where it opposes EGFR-mutant-driven RAS activation, and its co-deletion with DUSP4 synergistically activates MAPK signaling to promote tumorigenesis [PMID:24255704, PMID:30475228].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of DOK2 as a multi-domain adaptor protein with RasGAP-binding capacity established that a second Dok-family member exists and is a substrate of Bcr-Abl, opening questions about its role in CML and Ras regulation.\",\n      \"evidence\": \"Protein purification, cDNA cloning, and co-immunoprecipitation in CML cells\",\n      \"pmids\": [\"9478921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo loss-of-function data\", \"Physiological upstream activators beyond Bcr-Abl unknown\", \"Functional consequence of RasGAP binding not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic ablation of Dok-1 and Dok-2 in mice demonstrated that these adaptors are non-redundant negative regulators of Ras-ERK signaling downstream of tyrosine kinases, with loss causing myeloproliferative disease—resolving whether RasGAP recruitment had physiological consequences.\",\n      \"evidence\": \"Dok-1/Dok-2 double knockout mice with myeloproliferative phenotype and elevated ERK/Akt activation, reproduced by two independent labs\",\n      \"pmids\": [\"15611294\", \"15611295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contributions of Dok-1 vs Dok-2 to the phenotype unresolved\", \"Downstream effectors beyond ERK/Akt not mapped\", \"No structural model of RasGAP recruitment\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that DOK2 is phosphorylated and inhibits ERK and TNF-α production downstream of TLR4, and that PTB-domain-mediated oligomerization is required for DOK2 function, revealed that DOK2 operates in innate immunity and that its self-assembly is mechanistically essential.\",\n      \"evidence\": \"Dok-2 KO macrophages with elevated TLR4 responses plus phosphorylation-dead mutant rescue; PTB domain mutagenesis in Jurkat T cells with ERK and NFAT readouts\",\n      \"pmids\": [\"15699069\", \"16177091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for DOK2 phosphorylation at TLR4 not identified\", \"Oligomerization stoichiometry and structure undefined\", \"Relative contribution of Dok-1 vs Dok-2 in macrophages unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of a DOK2–SHIP-1–Grb-2 complex at LAT after TCR stimulation, and DOK2's role in restraining ZAP-70 and Akt activation, established the adaptor as a core component of TCR negative signaling architecture.\",\n      \"evidence\": \"Co-immunoprecipitation and siRNA knockdown in primary T cells with Akt and ZAP-70 readouts; forced expression and KO mice confirming ZAP-70 regulation\",\n      \"pmids\": [\"17043143\", \"17329234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SHIP-1 promotes DOK2 recruitment to LAT mechanistically unresolved\", \"C-terminal SH2-target motifs dispensable for ZAP-70 inhibition—alternative mechanism unknown\", \"Whether DOK2 acts identically in CD4+ and CD8+ T cells untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Quantitative binding studies showed DOK2 is the preferred adaptor for CD200R's NPXY motif and is essential for CD200R-mediated myeloid inhibition via RasGAP recruitment, providing a receptor-specific non-redundant role distinct from Dok-1.\",\n      \"evidence\": \"Direct binding assay with Kd measurement, siRNA knockdown of Dok-2 vs Dok-1 in U937 cells with functional readouts\",\n      \"pmids\": [\"19786546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOK2 similarly dominates at other ITIM/NPXY-containing receptors unknown\", \"No structural basis for the 10-fold affinity difference over Dok-1\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that the PH domain binds PtdIns5P and that this lipid interaction regulates DOK2 tyrosine phosphorylation in T cells introduced a lipid-sensing step upstream of DOK2 activation.\",\n      \"evidence\": \"In vitro lipid binding assay and PH domain deletion with phosphorylation readouts in T cells\",\n      \"pmids\": [\"19299694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo PtdIns5P–DOK2 interaction not confirmed by structural or live-cell methods\", \"Whether PtdIns5P regulation applies in non-T cell contexts untested\", \"Source kinase for PtdIns5P-dependent DOK2 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of DOK2 as a negative feedback element opposing mutant EGFR in lung adenocarcinoma, where its loss accelerates EGFR-driven but not KRAS-driven tumorigenesis, positioned DOK2 as an EGFR-specific tumor suppressor.\",\n      \"evidence\": \"Genetically engineered mouse models with co-immunoprecipitation of DOK2–EGFR and RAS activation assays; epistasis with KRAS-mutant model\",\n      \"pmids\": [\"24255704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOK2 loss alone (without cooperating hits) suffices for tumorigenesis unknown\", \"Mechanism of DOK2 silencing in human tumors (epigenetic vs genomic) not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Lyn was identified as the primary kinase phosphorylating DOK2 in platelets, and Dok-2 deficiency caused dysregulated integrin αIIbβ3-dependent calcium flux and enhanced thrombus formation, establishing DOK2 as a negative regulator of platelet activation and thrombosis.\",\n      \"evidence\": \"Dok-2 KO mice, Lyn inhibition/deficiency, calcium flux and PI(3,4)P2 measurement, in vivo thrombosis model\",\n      \"pmids\": [\"24385425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates or downstream effectors of DOK2 in the integrin pathway not fully mapped\", \"Whether Lyn→DOK2 axis operates in non-platelet hematopoietic cells not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Compound haploinsufficiency of DOK2 and DUSP4—frequently co-deleted in human lung adenocarcinoma—synergistically activates MAPK signaling, demonstrating that DOK2's tumor-suppressive function is dosage-sensitive and cooperates with parallel phosphatase-mediated MAPK control.\",\n      \"evidence\": \"Compound heterozygous mouse models, DOK2 restoration in lung cancer cell lines, MAPK and proliferation assays\",\n      \"pmids\": [\"30475228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether restoration of DOK2 alone is sufficient for tumor regression in vivo unknown\", \"Epigenetic regulation of DOK2 expression in human tumors not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for DOK2 oligomerization and receptor engagement, whether DOK2 has bona fide nuclear functions, and the full spectrum of cancers in which DOK2 loss is functionally consequential.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of DOK2 or its complexes\", \"Nuclear localization and Klf1 ChIP finding from a single low-confidence study awaits independent replication\", \"Mechanism by which HSV-1 VP11/12 targets DOK2 for degradation and its immunological consequence remain unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 6, 9, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7, 10, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 6, 9, 12, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 8, 9, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 12, 17]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 7, 14]}\n    ],\n    \"complexes\": [\n      \"DOK2–RasGAP inhibitory complex\",\n      \"DOK2–SHIP-1–Grb-2 complex at LAT\"\n    ],\n    \"partners\": [\n      \"RASA1\",\n      \"INPP5D\",\n      \"GRB2\",\n      \"LYN\",\n      \"TEC\",\n      \"EGFR\",\n      \"CD200R1\",\n      \"LAT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}