{"gene":"DOK3","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2000,"finding":"DOK3 undergoes tyrosine phosphorylation by Src family kinases upon immunoreceptor activation, which recruits the inhibitory molecules SHIP and Csk, thereby inhibiting NFAT activation and cytokine release in B cells. A DOK3 mutant with impaired SHIP/Csk binding enhanced B-cell responsiveness.","method":"Tyrosine phosphorylation assays, co-immunoprecipitation, overexpression of wild-type and mutant DOK3 in B-cell line with NFAT reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, mutagenesis, functional readout; highly cited foundational paper","pmids":["10733577"],"is_preprint":false},{"year":2004,"finding":"DOK3 suppresses BCR-evoked JNK activation selectively through its interaction with SHIP-1, not Csk. The DOK3-SHIP-1 complex inhibits JNK without affecting overall protein tyrosine phosphorylation or Btk/Akt activation. SHIP-1-deficient B cells show enhanced JNK activation, confirming physiological relevance.","method":"Biochemical co-immunoprecipitation, loss-of-function studies in SHIP-1-deficient mouse B cells, kinase activation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — epistasis via SHIP-1 KO mice, multiple orthogonal methods, replicated functional readouts","pmids":["14993273"],"is_preprint":false},{"year":2006,"finding":"DOK3 binds Grb2 via its SH2 domain upon tyrosine phosphorylation, sequesters the Grb2-Sos complex away from Shc, and thereby inhibits Ras-ERK activation downstream of Src-family PTKs. A Tyr/Phe mutant (Dok-3-FF) that cannot bind Grb2 fails to inhibit Ras and Erk.","method":"Co-immunoprecipitation, site-directed mutagenesis (Dok-3-FF), Ras/ERK activation assays, Grb2-Sos-Shc recruitment assay","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis combined with multiple biochemical assays demonstrating mechanism","pmids":["16436051"],"is_preprint":false},{"year":2007,"finding":"DOK3 localizes at the inner leaflet of the plasma membrane and is a major substrate of Lyn. Phosphorylated DOK3 recruits cytosolic Grb2 to the membrane, where Grb2 negatively regulates Btk, reducing PLCγ2 activation and inositol trisphosphate production, thereby inhibiting Ca2+ elevation in B cells.","method":"Subcellular fractionation, live-cell imaging, co-immunoprecipitation, PLCγ2 and IP3 activity assays, Dok-3-deficient B cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence, multiple orthogonal biochemical readouts","pmids":["17290227"],"is_preprint":false},{"year":2007,"finding":"Dok-3-deficient mice exhibit hyperproliferation, elevated Ca2+ signaling, and enhanced NF-κB, JNK, and p38MAPK activation in B cells upon BCR engagement. DOK3 loss compromises SHIP-1 phosphorylation (but not membrane localization), suggesting DOK3 facilitates SHIP-1 activation.","method":"Dok-3-/- mouse generation, B-cell proliferation assay, Ca2+ flux measurement, kinase activation assays, SHIP-1 phosphorylation/localization analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined cellular phenotypes and multiple signaling readouts","pmids":["17363732"],"is_preprint":false},{"year":2009,"finding":"DOK3 is tyrosine-phosphorylated downstream of integrin αIIbβ3 (outside-in signaling) in platelets in a Src kinase-independent manner, and downstream of GPVI in a Src kinase-dependent manner, leading to interaction with Grb2 and SHIP-1.","method":"Proteomic/phosphoproteomic analysis, co-immunoprecipitation, Src kinase inhibitor experiments in human platelets","journal":"Journal of thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus co-IP, single study","pmids":["19682241"],"is_preprint":false},{"year":2011,"finding":"DOK3, together with Grb2 and ubiquitin ligase Cbl, mediates association of BCR signaling microclusters with the microtubule motor dynein to drive directed microcluster movement and antigen accumulation. Loss of DOK3 abolishes directed movement and antigen gathering without affecting microcluster formation or actin-dependent spreading.","method":"High-resolution live imaging, quantitative mass spectrometry, Dok-3-deficient B cells, microtubule network disruption, co-immunoprecipitation","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — genetics, imaging, and MS combined; highly cited","pmids":["21703542"],"is_preprint":false},{"year":2012,"finding":"DOK3 negatively regulates TLR4 (LPS) signaling by limiting ERK activation and cytokine production. LPS induces ubiquitin-mediated degradation of DOK3, leading to SOS1 degradation and inhibition of ERK. DOK3 also stabilizes SHIP1, IRAK-M, SOCS1, and SOS1 during endotoxin tolerance.","method":"Dok-3-/- macrophages and mice, ERK activation assays, ubiquitination assays, protein stability experiments, cytokine ELISA","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — KO mice with multiple mechanistic readouts, in vivo and in vitro","pmids":["22761938"],"is_preprint":false},{"year":2013,"finding":"DOK3 physically associates with the ITAM of DAP12 through its phosphotyrosine-binding (PTB) domain. In response to LPS, DOK3 is phosphorylated in a DAP12- and Src-dependent manner and translocates to the plasma membrane, where it inhibits ERK activation and proinflammatory cytokine production.","method":"Co-immunoprecipitation, DOK3-deficient macrophages and mice, phosphorylation assays, domain mapping (PTB domain), subcellular fractionation","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — domain-level binding mapping, phosphorylation assay, KO mice with in vivo LPS challenge","pmids":["23962980"],"is_preprint":false},{"year":2014,"finding":"DOK3 is required for IFN-β production: it binds both TBK1 and TRAF3 via its tyrosine-rich C-terminal domain, enabling TRAF3/TBK1 complex formation, TBK1 activation, IRF3 phosphorylation and nuclear translocation, and IFN-β expression. DOK3 is phosphorylated by Bruton's tyrosine kinase (Btk).","method":"dok3-/- macrophages, IFN-β promoter reporter assay, co-immunoprecipitation, IRF3 phosphorylation and localization assays, overexpression studies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — KO macrophages, multiple co-IP interactions, reporter assay, defined C-terminal domain mapping","pmids":["24929003"],"is_preprint":false},{"year":2014,"finding":"DOK3 promotes plasma cell differentiation by sustaining PDL1 expression and upregulating PDL2 in B cells through attenuation of calcium signaling. Calcium signaling suppresses PD-1 ligand transcription; DOK3 restrains Ca2+ signaling to maintain PDL1/PDL2 levels required for PC differentiation.","method":"Dok3-/- mice, bone marrow reconstitution, PDL1/PDL2 overexpression rescue, calcineurin inhibitor (cyclosporine A) treatment, BTK- and PLCγ2-deficient B cells","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via multiple KO models, rescue experiment, bone marrow reconstitution","pmids":["25053811"],"is_preprint":false},{"year":2015,"finding":"TRAF6 mediates Lys48-linked polyubiquitination and degradation of DOK3 at lysine-27 during CpG/TLR9 stimulation. DOK3(K27R) mutant resists degradation and suppresses IL-6 and TNFα production in macrophages, demonstrating that TRAF6-driven DOK3 degradation is required for full TLR9-induced cytokine production.","method":"Ubiquitination assays, site-directed mutagenesis (K27R), co-immunoprecipitation with TRAF6, lentiviral reconstitution, cytokine ELISA in DOK3-deficient macrophages","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis identifying specific ubiquitination site, reconstitution in KO cells, biochemical interaction mapping","pmids":["26548852"],"is_preprint":false},{"year":2017,"finding":"DOK3 limits osteoclastogenesis by inhibiting Syk and ERK activation downstream of RANKL and M-CSF. DOK3 is phosphorylated in a DAP12-dependent manner and associates with Grb2 and Cbl in osteoclast precursors. In double KO (DOK3/DAP12) mice, bone mass normalizes compared to DAP12-/- alone, indicating DOK3 also limits DAP12-independent osteoclastogenesis.","method":"DOK3-/- and DKO mice, in vitro osteoclastogenesis assay, Syk/ERK phosphorylation assays, co-immunoprecipitation, bone histomorphometry","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — KO mice with genetic epistasis (DKO), biochemical signaling assays, in vivo bone histology","pmids":["28650106"],"is_preprint":false},{"year":2019,"finding":"DOK3 recruits protein phosphatase 1 (PP1) to dephosphorylate Card9, dampening downstream NF-κB and JNK activation and antifungal immune responses in neutrophils. DOK3-deficient neutrophils show increased phagocytosis, cytokine production, and NETosis.","method":"Co-immunoprecipitation (Dok3-PP1-Card9 complex), Dok3-/- mice with Candida albicans challenge, Card9 phosphorylation assay, NF-κB/JNK activation assays","journal":"Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — biochemical complex identification, KO mice with in vivo infection model, multiple signaling readouts","pmids":["31180338"],"is_preprint":false},{"year":2021,"finding":"ULK1 suppresses osteoclast differentiation through DOK3: knockdown of DOK3 offsets ULK1's inhibitory effect and induces phosphorylation of JNK and Syk, defining a ULK1/DOK3/Syk signaling axis in osteoclastogenesis.","method":"siRNA knockdown of DOK3 and ULK1, osteoclast differentiation assays, JNK/Syk phosphorylation assays, OVX mouse model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via co-knockdown, multiple signaling readouts; single study","pmids":["34820053"],"is_preprint":false},{"year":2021,"finding":"DOK3 suppresses JAK2/STAT3 signaling in colonic neutrophils to limit S100a8/9 (calprotectin) production, thereby maintaining gut microbial ecology and intestinal homeostasis. DOK3-/- mice show gut microbial dysbiosis and enhanced colitis susceptibility reversible by microbiota transfer.","method":"Dok3-/- mice, DSS-induced colitis model, JAK2/STAT3 phosphorylation assays, microbiota transfer experiments, S100a8/9 production assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — KO mice, defined mechanistic pathway (JAK2/STAT3), functional rescue by microbiota transfer","pmids":["34743196"],"is_preprint":false},{"year":2022,"finding":"DOK3 recruits SHP-2 to mediate dephosphorylation of MyD88 at Y257, attenuating downstream JAK2-STAT3 signaling and calprotectin (S100a8/9) production in neutrophils responding to SARS-CoV-2 spike protein via TLR4.","method":"Co-immunoprecipitation, MyD88 Y257 phosphorylation assay, DOK3-/- neutrophils, TLR4/JAK2/STAT3 inhibitor experiments","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical mechanism with KO cells; single study but multiple readouts","pmids":["36172386"],"is_preprint":false},{"year":2023,"finding":"DOK3 interacts with CARD11 in T cells and recruits the catalytic subunit of protein phosphatase 4 (PP4C) to decrease CARD11 phosphorylation, dampening downstream TCR signaling and skewing helper T cell differentiation. Hypomorphic CARD11 variants found in atopic dermatitis patients bind DOK3 more strongly than wild-type CARD11.","method":"Co-immunoprecipitation, CARD11 phosphorylation assay, Dok3-/- mice, experimental atopic dermatitis model, T cell cytokine assay, domain binding analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — biochemical complex identification with phosphatase recruitment, KO mice, patient variant binding analysis","pmids":["37906628"],"is_preprint":false},{"year":2025,"finding":"PRDX1 physically interacts with DOK3 and promotes its degradation via the autophagy-lysosome pathway, inhibiting plasma cell differentiation. The small molecule Salvianolic acid B acts as a molecular glue to enhance PRDX1-DOK3 interaction, impeding plasma cell differentiation and collagen-induced arthritis progression.","method":"Co-immunoprecipitation, autophagy-lysosome pathway inhibition experiments, collagen-induced arthritis mouse model, small molecule treatment","journal":"Acta pharmaceutica Sinica B","confidence":"Medium","confidence_rationale":"Tier 2 — protein interaction with defined degradation mechanism, in vivo model; single recent study","pmids":["40893682"],"is_preprint":false},{"year":2026,"finding":"IGF2BP2, an m6A reader protein, binds and stabilizes DOK3 mRNA via m6A modifications at nucleotides 1056 and 1101, maintaining DOK3 protein levels to limit NF-κB signaling and inflammatory cytokine production. Restoration of DOK3 in IGF2BP2-deficient cells rescues the hyper-inflammatory phenotype.","method":"m6A site mapping, RNA immunoprecipitation, IGF2BP2 knockdown/overexpression, DOK3 reconstitution in KO cells, NF-κB activation and cytokine assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — m6A mapping with functional rescue; single study","pmids":["41999269"],"is_preprint":false}],"current_model":"DOK3 is a hematopoietic adaptor protein that, upon tyrosine phosphorylation by Src-family kinases (and Btk), assembles inhibitory signaling complexes at the plasma membrane: it recruits SHIP-1 to suppress JNK, sequesters Grb2 away from the Sos/Shc complex to inhibit Ras-ERK, recruits PP1 to dephosphorylate Card9 dampening antifungal NF-κB/JNK responses, recruits PP4C to dephosphorylate CARD11 dampening TCR signaling, recruits SHP-2 to dephosphorylate MyD88-Y257 suppressing JAK2-STAT3 in neutrophils, and enables TRAF3/TBK1 complex formation for IRF3-driven IFN-β production; its levels are regulated by TRAF6-mediated Lys48 polyubiquitination at K27 and by PRDX1-dependent autophagy-lysosomal degradation, while its mRNA is stabilized by IGF2BP2-dependent m6A recognition."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing DOK3 as an inhibitory adaptor: the first study showed that Src-family-kinase-dependent tyrosine phosphorylation of DOK3 recruits SHIP and Csk to suppress NFAT activation and cytokine release in B cells, defining it as a negative regulator of immunoreceptor signaling.","evidence":"Co-immunoprecipitation, mutagenesis, and NFAT reporter assays in B-cell lines","pmids":["10733577"],"confidence":"High","gaps":["Relative contributions of SHIP vs. Csk to inhibition were unclear","In vivo role not yet tested"]},{"year":2004,"claim":"Resolving which effector mediates JNK suppression: SHIP-1, not Csk, was identified as the DOK3 partner responsible for selectively inhibiting BCR-evoked JNK, with SHIP-1-deficient B cells phenocopying DOK3 loss for this pathway.","evidence":"Co-immunoprecipitation and kinase assays in SHIP-1 knockout mouse B cells","pmids":["14993273"],"confidence":"High","gaps":["How DOK3 activates SHIP-1 catalytic activity was not resolved"]},{"year":2006,"claim":"Identifying the Grb2-sequestration mechanism for Ras-ERK inhibition: DOK3 was shown to bind Grb2 via phosphotyrosine-SH2 interaction, sequestering Grb2-Sos away from Shc and thereby blocking Ras-ERK, establishing a second distinct inhibitory pathway through the same adaptor.","evidence":"Site-directed mutagenesis (Dok-3-FF) with Ras/ERK activation and Grb2-Sos-Shc recruitment assays","pmids":["16436051"],"confidence":"High","gaps":["Whether Grb2-sequestration and SHIP-1 recruitment operate simultaneously or in distinct contexts was unknown"]},{"year":2007,"claim":"Defining the membrane-proximal spatial mechanism and in vivo requirement: DOK3 was localized to the plasma membrane inner leaflet as a major Lyn substrate, where phosphorylated DOK3 recruits Grb2 to inhibit Btk-PLCγ2-Ca²⁺ signaling; Dok3-knockout mice confirmed hyperproliferation and hyperactivation of NF-κB, JNK, and p38 in B cells.","evidence":"Subcellular fractionation, live-cell imaging, Dok-3⁻/⁻ mice with Ca²⁺ flux, proliferation, and kinase assays","pmids":["17290227","17363732"],"confidence":"High","gaps":["Which PH/PTB domain determinants drive membrane association was not fully mapped","Redundancy with DOK1/DOK2 in vivo was not assessed"]},{"year":2011,"claim":"Revealing a non-inhibitory scaffolding function: DOK3, together with Grb2 and Cbl, was found to couple BCR microclusters to dynein-dependent directed movement on microtubules, showing DOK3 also organizes spatial signaling architecture beyond simple inhibition.","evidence":"High-resolution live imaging, quantitative MS, and Dok-3-deficient B cells","pmids":["21703542"],"confidence":"High","gaps":["Direct DOK3-dynein interaction not demonstrated","Whether this function operates in non-B hematopoietic cells was unknown"]},{"year":2012,"claim":"Extending DOK3 function to innate immunity: DOK3 was shown to negatively regulate TLR4/LPS-induced ERK and cytokine production in macrophages and to stabilize negative regulators (SHIP1, IRAK-M, SOCS1) during endotoxin tolerance.","evidence":"Dok3⁻/⁻ macrophages and mice, ERK/ubiquitination assays, cytokine ELISA","pmids":["22761938"],"confidence":"High","gaps":["Mechanism by which DOK3 stabilizes IRAK-M and SOCS1 was not defined"]},{"year":2013,"claim":"Identifying the DAP12 ITAM–PTB domain interaction: DOK3 was shown to bind the DAP12 ITAM through its PTB domain, providing the molecular basis for its recruitment and Src-dependent phosphorylation at the membrane during TLR4 signaling in macrophages.","evidence":"Co-immunoprecipitation, domain mapping, Dok3⁻/⁻ macrophages with in vivo LPS challenge","pmids":["23962980"],"confidence":"High","gaps":["Structural basis of PTB-ITAM recognition not resolved"]},{"year":2014,"claim":"Uncovering a positive signaling role in type I IFN production: DOK3 was found to scaffold TRAF3–TBK1 complex formation via its C-terminal tyrosine-rich domain, enabling TBK1 activation and IRF3-dependent IFN-β expression, with Btk identified as a DOK3 kinase. Separately, DOK3-mediated Ca²⁺ attenuation was shown to sustain PDL1/PDL2 expression required for plasma cell differentiation.","evidence":"Dok3⁻/⁻ macrophages, co-IP, IFN-β reporter, bone marrow reconstitution, genetic epistasis with BTK and PLCγ2 KO mice","pmids":["24929003","25053811"],"confidence":"High","gaps":["Whether the IFN-β-promoting and ERK-inhibitory functions are cell-type-specific was not resolved","Btk phosphorylation sites on DOK3 not mapped"]},{"year":2015,"claim":"Defining how DOK3 protein levels are controlled: TRAF6 was identified as the E3 ligase that K48-polyubiquitinates DOK3 at Lys-27, targeting it for degradation during TLR9 stimulation; a K27R mutant resists degradation and suppresses cytokine output.","evidence":"Ubiquitination assays, K27R mutagenesis, lentiviral reconstitution in Dok3⁻/⁻ macrophages, cytokine ELISA","pmids":["26548852"],"confidence":"High","gaps":["Whether other E3 ligases also target DOK3 was unknown","Half-life measurements under basal conditions not reported"]},{"year":2017,"claim":"Extending DOK3's inhibitory role to osteoclast biology: DOK3 was shown to limit osteoclastogenesis by inhibiting Syk and ERK downstream of RANKL/M-CSF, with DAP12/DOK3 double-KO epistasis revealing DOK3 also restrains DAP12-independent osteoclast formation.","evidence":"DOK3⁻/⁻ and DKO mice, osteoclast differentiation assays, bone histomorphometry","pmids":["28650106"],"confidence":"High","gaps":["The DAP12-independent DOK3 activation mechanism in osteoclasts was not identified"]},{"year":2019,"claim":"Identifying phosphatase recruitment as a DOK3 inhibitory mechanism: DOK3 was shown to recruit PP1 to dephosphorylate CARD9, dampening NF-κB and JNK and attenuating antifungal neutrophil responses, demonstrating DOK3 inhibits signaling not only by effector sequestration but also by direct phosphatase delivery.","evidence":"Co-IP of DOK3-PP1-CARD9 complex, Dok3⁻/⁻ mice challenged with Candida albicans, signaling and functional assays","pmids":["31180338"],"confidence":"High","gaps":["How DOK3 selects PP1 over other phosphatases was not determined"]},{"year":2021,"claim":"Establishing DOK3 as a JAK2-STAT3 suppressor in neutrophils: DOK3 was found to limit JAK2/STAT3 activation and calprotectin production in colonic neutrophils, maintaining gut microbial homeostasis; separately, ULK1 was placed upstream of DOK3 in osteoclast differentiation.","evidence":"Dok3⁻/⁻ mice with DSS colitis model, microbiota transfer rescue; ULK1/DOK3 co-knockdown with Syk/JNK assays","pmids":["34743196","34820053"],"confidence":"High","gaps":["Direct ULK1-DOK3 interaction not biochemically demonstrated","Mechanism linking DOK3 to JAK2 inhibition was not fully delineated"]},{"year":2022,"claim":"Delineating the SHP-2/MyD88 axis: DOK3 was shown to recruit SHP-2 to dephosphorylate MyD88 at Y257, providing the molecular mechanism for JAK2-STAT3 suppression downstream of TLR4.","evidence":"Co-IP, MyD88-Y257 phosphorylation assays, DOK3⁻/⁻ neutrophils, TLR4/JAK2/STAT3 inhibitor epistasis","pmids":["36172386"],"confidence":"Medium","gaps":["Single study; independent replication needed","Whether SHP-2 recruitment is direct or bridged by another adaptor was not resolved"]},{"year":2023,"claim":"Extending the phosphatase-recruitment paradigm to T cells: DOK3 was shown to recruit PP4C to dephosphorylate CARD11, dampening TCR signaling and modulating Th cell differentiation, with hypomorphic CARD11 variants in atopic dermatitis patients exhibiting increased DOK3 binding.","evidence":"Co-IP, CARD11 phosphorylation assays, Dok3⁻/⁻ mice with experimental atopic dermatitis, patient variant binding analysis","pmids":["37906628"],"confidence":"High","gaps":["Whether DOK3-PP4C and DOK3-PP1 complexes are mutually exclusive was not tested","Functional impact of enhanced CARD11 variant-DOK3 binding on patient phenotype not fully resolved"]},{"year":2025,"claim":"Identifying a second degradation pathway: PRDX1 was shown to physically interact with DOK3 and promote its autophagy-lysosomal degradation, with the molecular glue Salvianolic acid B enhancing this interaction to suppress plasma cell differentiation and arthritis.","evidence":"Co-IP, autophagy-lysosome inhibition, collagen-induced arthritis mouse model, small molecule treatment","pmids":["40893682"],"confidence":"Medium","gaps":["PRDX1-DOK3 binding site not mapped","Relationship between TRAF6-mediated and PRDX1-mediated degradation pathways not examined"]},{"year":2026,"claim":"Revealing post-transcriptional regulation of DOK3 levels: IGF2BP2 was found to bind and stabilize DOK3 mRNA via m6A modifications at specific sites, with DOK3 reconstitution rescuing hyper-inflammatory NF-κB activation in IGF2BP2-deficient cells.","evidence":"m6A site mapping, RNA immunoprecipitation, IGF2BP2 KD/OE, DOK3 reconstitution, NF-κB and cytokine assays","pmids":["41999269"],"confidence":"Medium","gaps":["Which methyltransferase deposits these m6A marks was not identified","Whether m6A regulation of DOK3 is cell-type-specific is unknown"]},{"year":null,"claim":"Unresolved: the structural basis for DOK3's selective recruitment of different phosphatases (PP1, PP4C, SHP-2) and effectors (SHIP-1, Grb2, TRAF3) in different cell types and signaling contexts, and whether DOK3 post-translational modifications (specific phosphotyrosine sites, ubiquitination patterns) encode effector selectivity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data (crystal/cryo-EM) for DOK3 or its complexes","Phosphosite-to-effector mapping is incomplete","Functional redundancy with DOK1/DOK2 across hematopoietic lineages not systematically addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,3,9,13,16,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4,7,8,9,13,15,16,17]}],"complexes":[],"partners":["SHIP1","GRB2","TRAF3","TBK1","TRAF6","CARD9","CARD11","SHP2"],"other_free_text":[]},"mechanistic_narrative":"DOK3 is a hematopoietic adaptor protein that functions as a broad inhibitory signaling hub downstream of immunoreceptors, Toll-like receptors, and cytokine receptors in B cells, macrophages, neutrophils, T cells, osteoclasts, and platelets. Upon tyrosine phosphorylation by Src-family kinases (principally Lyn) or Btk, DOK3 recruits distinct effectors to suppress specific signaling branches: SHIP-1 to inhibit JNK [PMID:14993273]; Grb2 to sequester the Sos/Shc complex and block Ras-ERK activation [PMID:16436051, PMID:17290227]; PP1 to dephosphorylate CARD9 and dampen NF-κB/JNK in antifungal immunity [PMID:31180338]; PP4C to dephosphorylate CARD11 and attenuate TCR signaling [PMID:37906628]; and SHP-2 to dephosphorylate MyD88-Y257 and suppress JAK2-STAT3 in neutrophils [PMID:36172386]. DOK3 also promotes type I interferon production by scaffolding a TRAF3–TBK1 complex for IRF3 activation [PMID:24929003], and its protein levels are controlled by TRAF6-mediated K48-linked polyubiquitination at Lys-27 [PMID:26548852] and by PRDX1-dependent autophagy-lysosomal degradation [PMID:40893682], while its mRNA is stabilized by IGF2BP2-mediated m6A recognition [PMID:41999269]."},"prefetch_data":{"uniprot":{"accession":"Q7L591","full_name":"Docking protein 3","aliases":["Downstream of tyrosine kinase 3"],"length_aa":496,"mass_kda":53.3,"function":"DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK3 is a negative regulator of JNK signaling in B-cells through interaction with INPP5D/SHIP1. May modulate ABL1 function (By similarity)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q7L591/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOK3","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/DOK3","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":"602919","title":"DOCKING PROTEIN 1; DOK1","url":"https://www.omim.org/entry/602919"},{"mim_id":"211980","title":"LUNG CANCER","url":"https://www.omim.org/entry/211980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":88.4},{"tissue":"lymphoid tissue","ntpm":83.8}],"url":"https://www.proteinatlas.org/search/DOK3"},"hgnc":{"alias_symbol":["FLJ22570"],"prev_symbol":[]},"alphafold":{"accession":"Q7L591","domains":[{"cath_id":"2.30.29.30","chopping":"62-105_124-178","consensus_level":"high","plddt":92.6374,"start":62,"end":178},{"cath_id":"2.30.29.30","chopping":"213-312","consensus_level":"high","plddt":91.9807,"start":213,"end":312}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L591","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L591-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L591-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DOK3","jax_strain_url":"https://www.jax.org/strain/search?query=DOK3"},"sequence":{"accession":"Q7L591","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L591.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L591/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L591"}},"corpus_meta":[{"pmid":"10733577","id":"PMC_10733577","title":"Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10733577","citation_count":148,"is_preprint":false},{"pmid":"21703542","id":"PMC_21703542","title":"B cell receptor-mediated antigen gathering requires ubiquitin ligase Cbl and adaptors Grb2 and Dok-3 to recruit dynein to the signaling microcluster.","date":"2011","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21703542","citation_count":76,"is_preprint":false},{"pmid":"23962980","id":"PMC_23962980","title":"A physical interaction between the adaptor proteins DOK3 and DAP12 is required to inhibit lipopolysaccharide signaling in macrophages.","date":"2013","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/23962980","citation_count":60,"is_preprint":false},{"pmid":"17290227","id":"PMC_17290227","title":"Subcellular localization of Grb2 by the adaptor protein Dok-3 restricts the intensity of Ca2+ signaling in B cells.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17290227","citation_count":57,"is_preprint":false},{"pmid":"14993273","id":"PMC_14993273","title":"Inhibition of the Jun N-terminal protein kinase pathway by SHIP-1, a lipid phosphatase that interacts with the adaptor molecule Dok-3.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14993273","citation_count":50,"is_preprint":false},{"pmid":"19682241","id":"PMC_19682241","title":"Proteomic analysis of integrin alphaIIbbeta3 outside-in signaling reveals Src-kinase-independent phosphorylation of Dok-1 and Dok-3 leading to SHIP-1 interactions.","date":"2009","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/19682241","citation_count":46,"is_preprint":false},{"pmid":"17363732","id":"PMC_17363732","title":"Dok-3 plays a nonredundant role in negative regulation of B-cell activation.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17363732","citation_count":40,"is_preprint":false},{"pmid":"31180338","id":"PMC_31180338","title":"Dok3-protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunity.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31180338","citation_count":35,"is_preprint":false},{"pmid":"22761938","id":"PMC_22761938","title":"DOK3 negatively regulates LPS responses and endotoxin tolerance.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22761938","citation_count":35,"is_preprint":false},{"pmid":"16436051","id":"PMC_16436051","title":"Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein-tyrosine kinases.","date":"2006","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/16436051","citation_count":33,"is_preprint":false},{"pmid":"24929003","id":"PMC_24929003","title":"DOK3 is required for IFN-β production by enabling TRAF3/TBK1 complex formation and IRF3 activation.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24929003","citation_count":31,"is_preprint":false},{"pmid":"28650106","id":"PMC_28650106","title":"DOK3 Modulates Bone Remodeling by Negatively Regulating Osteoclastogenesis and Positively Regulating Osteoblastogenesis.","date":"2017","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/28650106","citation_count":24,"is_preprint":false},{"pmid":"34743196","id":"PMC_34743196","title":"DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34743196","citation_count":24,"is_preprint":false},{"pmid":"25053811","id":"PMC_25053811","title":"Adaptor protein DOK3 promotes plasma cell differentiation by regulating the expression of programmed cell death 1 ligands.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25053811","citation_count":22,"is_preprint":false},{"pmid":"36210538","id":"PMC_36210538","title":"Porphyromonas gingivalis Activation of Tumor-Associated Macrophages via DOK3 Promotes Recurrence of Oral Squamous Cell Carcinoma.","date":"2022","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/36210538","citation_count":18,"is_preprint":false},{"pmid":"33281117","id":"PMC_33281117","title":"DOK3 is involved in microglial cell activation in neuropathic pain by interacting with GPR84.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33281117","citation_count":17,"is_preprint":false},{"pmid":"26548852","id":"PMC_26548852","title":"TRAF6-mediated degradation of DOK3 is required for production of IL-6 and TNFα in TLR9 signaling.","date":"2015","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26548852","citation_count":12,"is_preprint":false},{"pmid":"36867541","id":"PMC_36867541","title":"DOK3 promotes proliferation and inhibits apoptosis of prostate cancer via the NF-κB signaling pathway.","date":"2023","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/36867541","citation_count":10,"is_preprint":false},{"pmid":"34820053","id":"PMC_34820053","title":"ULK1 Suppresses Osteoclast Differentiation and Bone Resorption via Inhibiting Syk-JNK through DOK3.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34820053","citation_count":10,"is_preprint":false},{"pmid":"34245977","id":"PMC_34245977","title":"Dok3 is involved in cisplatin-induced acute kidney injury via regulation of inflammation and apoptosis.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34245977","citation_count":8,"is_preprint":false},{"pmid":"36172386","id":"PMC_36172386","title":"Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36172386","citation_count":6,"is_preprint":false},{"pmid":"28590889","id":"PMC_28590889","title":"DOK3 Degradation is Required for the Development of LPS-induced ARDS in Mice.","date":"2016","source":"Current gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28590889","citation_count":6,"is_preprint":false},{"pmid":"37513967","id":"PMC_37513967","title":"Disrupting the Dok3-Card9 Interaction with Synthetic Peptides Enhances Antifungal Effector Functions of Human Neutrophils.","date":"2023","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/37513967","citation_count":4,"is_preprint":false},{"pmid":"29548825","id":"PMC_29548825","title":"Dok-3 and Dok-1/-2 adaptors play distinctive roles in cell fusion and proliferation during osteoclastogenesis and cooperatively protect mice from osteopenia.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29548825","citation_count":4,"is_preprint":false},{"pmid":"37235715","id":"PMC_37235715","title":"Expression and clinical significance of DOK3 in renal clear cell carcinoma.","date":"2023","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/37235715","citation_count":2,"is_preprint":false},{"pmid":"40893682","id":"PMC_40893682","title":"Augmentation of PRDX1-DOK3 interaction alleviates rheumatoid arthritis progression by suppressing plasma cell differentiation.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/40893682","citation_count":1,"is_preprint":false},{"pmid":"37906628","id":"PMC_37906628","title":"DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11.","date":"2023","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/37906628","citation_count":1,"is_preprint":false},{"pmid":"39726593","id":"PMC_39726593","title":"Cross-disease transcriptomic analysis reveals DOK3 and PAPOLA as therapeutic targets for neuroinflammatory and tumorigenic processes.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39726593","citation_count":0,"is_preprint":false},{"pmid":"40682684","id":"PMC_40682684","title":"Magnolol Ameliorates Depression Through Modulating the TREM2-DOK3-ERK Pathway.","date":"2025","source":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40682684","citation_count":0,"is_preprint":false},{"pmid":"41999269","id":"PMC_41999269","title":"IGF2BP2 condensates stabilize DOK3 to negatively regulate inflammatory responses.","date":"2026","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/41999269","citation_count":0,"is_preprint":false},{"pmid":"41694346","id":"PMC_41694346","title":"M2 macrophage-based classification identifies DOK3 as a driver of pro-tumoral polarization and migration in glioblastoma.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41694346","citation_count":0,"is_preprint":false},{"pmid":"31351483","id":"PMC_31351483","title":"Dok-3 deficient mice display different immune clustering and Tim-3 expression.","date":"2019","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/31351483","citation_count":0,"is_preprint":false},{"pmid":"36970719","id":"PMC_36970719","title":"Loss of Dok-3 in Non-tumor Cells Induces Malignant Transformation of Benign Epithelial Tumor Cells of the Intestine.","date":"2022","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36970719","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17084,"output_tokens":5025,"usd":0.063313},"stage2":{"model":"claude-opus-4-6","input_tokens":8566,"output_tokens":4177,"usd":0.220883},"total_usd":0.284196,"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\": 2000,\n      \"finding\": \"DOK3 undergoes tyrosine phosphorylation by Src family kinases upon immunoreceptor activation, which recruits the inhibitory molecules SHIP and Csk, thereby inhibiting NFAT activation and cytokine release in B cells. A DOK3 mutant with impaired SHIP/Csk binding enhanced B-cell responsiveness.\",\n      \"method\": \"Tyrosine phosphorylation assays, co-immunoprecipitation, overexpression of wild-type and mutant DOK3 in B-cell line with NFAT reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, mutagenesis, functional readout; highly cited foundational paper\",\n      \"pmids\": [\"10733577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DOK3 suppresses BCR-evoked JNK activation selectively through its interaction with SHIP-1, not Csk. The DOK3-SHIP-1 complex inhibits JNK without affecting overall protein tyrosine phosphorylation or Btk/Akt activation. SHIP-1-deficient B cells show enhanced JNK activation, confirming physiological relevance.\",\n      \"method\": \"Biochemical co-immunoprecipitation, loss-of-function studies in SHIP-1-deficient mouse B cells, kinase activation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via SHIP-1 KO mice, multiple orthogonal methods, replicated functional readouts\",\n      \"pmids\": [\"14993273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DOK3 binds Grb2 via its SH2 domain upon tyrosine phosphorylation, sequesters the Grb2-Sos complex away from Shc, and thereby inhibits Ras-ERK activation downstream of Src-family PTKs. A Tyr/Phe mutant (Dok-3-FF) that cannot bind Grb2 fails to inhibit Ras and Erk.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Dok-3-FF), Ras/ERK activation assays, Grb2-Sos-Shc recruitment assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with multiple biochemical assays demonstrating mechanism\",\n      \"pmids\": [\"16436051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DOK3 localizes at the inner leaflet of the plasma membrane and is a major substrate of Lyn. Phosphorylated DOK3 recruits cytosolic Grb2 to the membrane, where Grb2 negatively regulates Btk, reducing PLCγ2 activation and inositol trisphosphate production, thereby inhibiting Ca2+ elevation in B cells.\",\n      \"method\": \"Subcellular fractionation, live-cell imaging, co-immunoprecipitation, PLCγ2 and IP3 activity assays, Dok-3-deficient B cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, multiple orthogonal biochemical readouts\",\n      \"pmids\": [\"17290227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dok-3-deficient mice exhibit hyperproliferation, elevated Ca2+ signaling, and enhanced NF-κB, JNK, and p38MAPK activation in B cells upon BCR engagement. DOK3 loss compromises SHIP-1 phosphorylation (but not membrane localization), suggesting DOK3 facilitates SHIP-1 activation.\",\n      \"method\": \"Dok-3-/- mouse generation, B-cell proliferation assay, Ca2+ flux measurement, kinase activation assays, SHIP-1 phosphorylation/localization analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular phenotypes and multiple signaling readouts\",\n      \"pmids\": [\"17363732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DOK3 is tyrosine-phosphorylated downstream of integrin αIIbβ3 (outside-in signaling) in platelets in a Src kinase-independent manner, and downstream of GPVI in a Src kinase-dependent manner, leading to interaction with Grb2 and SHIP-1.\",\n      \"method\": \"Proteomic/phosphoproteomic analysis, co-immunoprecipitation, Src kinase inhibitor experiments in human platelets\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus co-IP, single study\",\n      \"pmids\": [\"19682241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DOK3, together with Grb2 and ubiquitin ligase Cbl, mediates association of BCR signaling microclusters with the microtubule motor dynein to drive directed microcluster movement and antigen accumulation. Loss of DOK3 abolishes directed movement and antigen gathering without affecting microcluster formation or actin-dependent spreading.\",\n      \"method\": \"High-resolution live imaging, quantitative mass spectrometry, Dok-3-deficient B cells, microtubule network disruption, co-immunoprecipitation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetics, imaging, and MS combined; highly cited\",\n      \"pmids\": [\"21703542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOK3 negatively regulates TLR4 (LPS) signaling by limiting ERK activation and cytokine production. LPS induces ubiquitin-mediated degradation of DOK3, leading to SOS1 degradation and inhibition of ERK. DOK3 also stabilizes SHIP1, IRAK-M, SOCS1, and SOS1 during endotoxin tolerance.\",\n      \"method\": \"Dok-3-/- macrophages and mice, ERK activation assays, ubiquitination assays, protein stability experiments, cytokine ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with multiple mechanistic readouts, in vivo and in vitro\",\n      \"pmids\": [\"22761938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOK3 physically associates with the ITAM of DAP12 through its phosphotyrosine-binding (PTB) domain. In response to LPS, DOK3 is phosphorylated in a DAP12- and Src-dependent manner and translocates to the plasma membrane, where it inhibits ERK activation and proinflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, DOK3-deficient macrophages and mice, phosphorylation assays, domain mapping (PTB domain), subcellular fractionation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-level binding mapping, phosphorylation assay, KO mice with in vivo LPS challenge\",\n      \"pmids\": [\"23962980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOK3 is required for IFN-β production: it binds both TBK1 and TRAF3 via its tyrosine-rich C-terminal domain, enabling TRAF3/TBK1 complex formation, TBK1 activation, IRF3 phosphorylation and nuclear translocation, and IFN-β expression. DOK3 is phosphorylated by Bruton's tyrosine kinase (Btk).\",\n      \"method\": \"dok3-/- macrophages, IFN-β promoter reporter assay, co-immunoprecipitation, IRF3 phosphorylation and localization assays, overexpression studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO macrophages, multiple co-IP interactions, reporter assay, defined C-terminal domain mapping\",\n      \"pmids\": [\"24929003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOK3 promotes plasma cell differentiation by sustaining PDL1 expression and upregulating PDL2 in B cells through attenuation of calcium signaling. Calcium signaling suppresses PD-1 ligand transcription; DOK3 restrains Ca2+ signaling to maintain PDL1/PDL2 levels required for PC differentiation.\",\n      \"method\": \"Dok3-/- mice, bone marrow reconstitution, PDL1/PDL2 overexpression rescue, calcineurin inhibitor (cyclosporine A) treatment, BTK- and PLCγ2-deficient B cells\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via multiple KO models, rescue experiment, bone marrow reconstitution\",\n      \"pmids\": [\"25053811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAF6 mediates Lys48-linked polyubiquitination and degradation of DOK3 at lysine-27 during CpG/TLR9 stimulation. DOK3(K27R) mutant resists degradation and suppresses IL-6 and TNFα production in macrophages, demonstrating that TRAF6-driven DOK3 degradation is required for full TLR9-induced cytokine production.\",\n      \"method\": \"Ubiquitination assays, site-directed mutagenesis (K27R), co-immunoprecipitation with TRAF6, lentiviral reconstitution, cytokine ELISA in DOK3-deficient macrophages\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis identifying specific ubiquitination site, reconstitution in KO cells, biochemical interaction mapping\",\n      \"pmids\": [\"26548852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DOK3 limits osteoclastogenesis by inhibiting Syk and ERK activation downstream of RANKL and M-CSF. DOK3 is phosphorylated in a DAP12-dependent manner and associates with Grb2 and Cbl in osteoclast precursors. In double KO (DOK3/DAP12) mice, bone mass normalizes compared to DAP12-/- alone, indicating DOK3 also limits DAP12-independent osteoclastogenesis.\",\n      \"method\": \"DOK3-/- and DKO mice, in vitro osteoclastogenesis assay, Syk/ERK phosphorylation assays, co-immunoprecipitation, bone histomorphometry\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with genetic epistasis (DKO), biochemical signaling assays, in vivo bone histology\",\n      \"pmids\": [\"28650106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DOK3 recruits protein phosphatase 1 (PP1) to dephosphorylate Card9, dampening downstream NF-κB and JNK activation and antifungal immune responses in neutrophils. DOK3-deficient neutrophils show increased phagocytosis, cytokine production, and NETosis.\",\n      \"method\": \"Co-immunoprecipitation (Dok3-PP1-Card9 complex), Dok3-/- mice with Candida albicans challenge, Card9 phosphorylation assay, NF-κB/JNK activation assays\",\n      \"journal\": \"Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical complex identification, KO mice with in vivo infection model, multiple signaling readouts\",\n      \"pmids\": [\"31180338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ULK1 suppresses osteoclast differentiation through DOK3: knockdown of DOK3 offsets ULK1's inhibitory effect and induces phosphorylation of JNK and Syk, defining a ULK1/DOK3/Syk signaling axis in osteoclastogenesis.\",\n      \"method\": \"siRNA knockdown of DOK3 and ULK1, osteoclast differentiation assays, JNK/Syk phosphorylation assays, OVX mouse model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via co-knockdown, multiple signaling readouts; single study\",\n      \"pmids\": [\"34820053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DOK3 suppresses JAK2/STAT3 signaling in colonic neutrophils to limit S100a8/9 (calprotectin) production, thereby maintaining gut microbial ecology and intestinal homeostasis. DOK3-/- mice show gut microbial dysbiosis and enhanced colitis susceptibility reversible by microbiota transfer.\",\n      \"method\": \"Dok3-/- mice, DSS-induced colitis model, JAK2/STAT3 phosphorylation assays, microbiota transfer experiments, S100a8/9 production assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice, defined mechanistic pathway (JAK2/STAT3), functional rescue by microbiota transfer\",\n      \"pmids\": [\"34743196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DOK3 recruits SHP-2 to mediate dephosphorylation of MyD88 at Y257, attenuating downstream JAK2-STAT3 signaling and calprotectin (S100a8/9) production in neutrophils responding to SARS-CoV-2 spike protein via TLR4.\",\n      \"method\": \"Co-immunoprecipitation, MyD88 Y257 phosphorylation assay, DOK3-/- neutrophils, TLR4/JAK2/STAT3 inhibitor experiments\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical mechanism with KO cells; single study but multiple readouts\",\n      \"pmids\": [\"36172386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DOK3 interacts with CARD11 in T cells and recruits the catalytic subunit of protein phosphatase 4 (PP4C) to decrease CARD11 phosphorylation, dampening downstream TCR signaling and skewing helper T cell differentiation. Hypomorphic CARD11 variants found in atopic dermatitis patients bind DOK3 more strongly than wild-type CARD11.\",\n      \"method\": \"Co-immunoprecipitation, CARD11 phosphorylation assay, Dok3-/- mice, experimental atopic dermatitis model, T cell cytokine assay, domain binding analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical complex identification with phosphatase recruitment, KO mice, patient variant binding analysis\",\n      \"pmids\": [\"37906628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRDX1 physically interacts with DOK3 and promotes its degradation via the autophagy-lysosome pathway, inhibiting plasma cell differentiation. The small molecule Salvianolic acid B acts as a molecular glue to enhance PRDX1-DOK3 interaction, impeding plasma cell differentiation and collagen-induced arthritis progression.\",\n      \"method\": \"Co-immunoprecipitation, autophagy-lysosome pathway inhibition experiments, collagen-induced arthritis mouse model, small molecule treatment\",\n      \"journal\": \"Acta pharmaceutica Sinica B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein interaction with defined degradation mechanism, in vivo model; single recent study\",\n      \"pmids\": [\"40893682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IGF2BP2, an m6A reader protein, binds and stabilizes DOK3 mRNA via m6A modifications at nucleotides 1056 and 1101, maintaining DOK3 protein levels to limit NF-κB signaling and inflammatory cytokine production. Restoration of DOK3 in IGF2BP2-deficient cells rescues the hyper-inflammatory phenotype.\",\n      \"method\": \"m6A site mapping, RNA immunoprecipitation, IGF2BP2 knockdown/overexpression, DOK3 reconstitution in KO cells, NF-κB activation and cytokine assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A mapping with functional rescue; single study\",\n      \"pmids\": [\"41999269\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOK3 is a hematopoietic adaptor protein that, upon tyrosine phosphorylation by Src-family kinases (and Btk), assembles inhibitory signaling complexes at the plasma membrane: it recruits SHIP-1 to suppress JNK, sequesters Grb2 away from the Sos/Shc complex to inhibit Ras-ERK, recruits PP1 to dephosphorylate Card9 dampening antifungal NF-κB/JNK responses, recruits PP4C to dephosphorylate CARD11 dampening TCR signaling, recruits SHP-2 to dephosphorylate MyD88-Y257 suppressing JAK2-STAT3 in neutrophils, and enables TRAF3/TBK1 complex formation for IRF3-driven IFN-β production; its levels are regulated by TRAF6-mediated Lys48 polyubiquitination at K27 and by PRDX1-dependent autophagy-lysosomal degradation, while its mRNA is stabilized by IGF2BP2-dependent m6A recognition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DOK3 is a hematopoietic adaptor protein that functions as a broad inhibitory signaling hub downstream of immunoreceptors, Toll-like receptors, and cytokine receptors in B cells, macrophages, neutrophils, T cells, osteoclasts, and platelets. Upon tyrosine phosphorylation by Src-family kinases (principally Lyn) or Btk, DOK3 recruits distinct effectors to suppress specific signaling branches: SHIP-1 to inhibit JNK [PMID:14993273]; Grb2 to sequester the Sos/Shc complex and block Ras-ERK activation [PMID:16436051, PMID:17290227]; PP1 to dephosphorylate CARD9 and dampen NF-κB/JNK in antifungal immunity [PMID:31180338]; PP4C to dephosphorylate CARD11 and attenuate TCR signaling [PMID:37906628]; and SHP-2 to dephosphorylate MyD88-Y257 and suppress JAK2-STAT3 in neutrophils [PMID:36172386]. DOK3 also promotes type I interferon production by scaffolding a TRAF3–TBK1 complex for IRF3 activation [PMID:24929003], and its protein levels are controlled by TRAF6-mediated K48-linked polyubiquitination at Lys-27 [PMID:26548852] and by PRDX1-dependent autophagy-lysosomal degradation [PMID:40893682], while its mRNA is stabilized by IGF2BP2-mediated m6A recognition [PMID:41999269].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing DOK3 as an inhibitory adaptor: the first study showed that Src-family-kinase-dependent tyrosine phosphorylation of DOK3 recruits SHIP and Csk to suppress NFAT activation and cytokine release in B cells, defining it as a negative regulator of immunoreceptor signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, mutagenesis, and NFAT reporter assays in B-cell lines\",\n      \"pmids\": [\"10733577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of SHIP vs. Csk to inhibition were unclear\", \"In vivo role not yet tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolving which effector mediates JNK suppression: SHIP-1, not Csk, was identified as the DOK3 partner responsible for selectively inhibiting BCR-evoked JNK, with SHIP-1-deficient B cells phenocopying DOK3 loss for this pathway.\",\n      \"evidence\": \"Co-immunoprecipitation and kinase assays in SHIP-1 knockout mouse B cells\",\n      \"pmids\": [\"14993273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DOK3 activates SHIP-1 catalytic activity was not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying the Grb2-sequestration mechanism for Ras-ERK inhibition: DOK3 was shown to bind Grb2 via phosphotyrosine-SH2 interaction, sequestering Grb2-Sos away from Shc and thereby blocking Ras-ERK, establishing a second distinct inhibitory pathway through the same adaptor.\",\n      \"evidence\": \"Site-directed mutagenesis (Dok-3-FF) with Ras/ERK activation and Grb2-Sos-Shc recruitment assays\",\n      \"pmids\": [\"16436051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Grb2-sequestration and SHIP-1 recruitment operate simultaneously or in distinct contexts was unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining the membrane-proximal spatial mechanism and in vivo requirement: DOK3 was localized to the plasma membrane inner leaflet as a major Lyn substrate, where phosphorylated DOK3 recruits Grb2 to inhibit Btk-PLCγ2-Ca²⁺ signaling; Dok3-knockout mice confirmed hyperproliferation and hyperactivation of NF-κB, JNK, and p38 in B cells.\",\n      \"evidence\": \"Subcellular fractionation, live-cell imaging, Dok-3⁻/⁻ mice with Ca²⁺ flux, proliferation, and kinase assays\",\n      \"pmids\": [\"17290227\", \"17363732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which PH/PTB domain determinants drive membrane association was not fully mapped\", \"Redundancy with DOK1/DOK2 in vivo was not assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealing a non-inhibitory scaffolding function: DOK3, together with Grb2 and Cbl, was found to couple BCR microclusters to dynein-dependent directed movement on microtubules, showing DOK3 also organizes spatial signaling architecture beyond simple inhibition.\",\n      \"evidence\": \"High-resolution live imaging, quantitative MS, and Dok-3-deficient B cells\",\n      \"pmids\": [\"21703542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DOK3-dynein interaction not demonstrated\", \"Whether this function operates in non-B hematopoietic cells was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending DOK3 function to innate immunity: DOK3 was shown to negatively regulate TLR4/LPS-induced ERK and cytokine production in macrophages and to stabilize negative regulators (SHIP1, IRAK-M, SOCS1) during endotoxin tolerance.\",\n      \"evidence\": \"Dok3⁻/⁻ macrophages and mice, ERK/ubiquitination assays, cytokine ELISA\",\n      \"pmids\": [\"22761938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DOK3 stabilizes IRAK-M and SOCS1 was not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying the DAP12 ITAM–PTB domain interaction: DOK3 was shown to bind the DAP12 ITAM through its PTB domain, providing the molecular basis for its recruitment and Src-dependent phosphorylation at the membrane during TLR4 signaling in macrophages.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mapping, Dok3⁻/⁻ macrophages with in vivo LPS challenge\",\n      \"pmids\": [\"23962980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PTB-ITAM recognition not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Uncovering a positive signaling role in type I IFN production: DOK3 was found to scaffold TRAF3–TBK1 complex formation via its C-terminal tyrosine-rich domain, enabling TBK1 activation and IRF3-dependent IFN-β expression, with Btk identified as a DOK3 kinase. Separately, DOK3-mediated Ca²⁺ attenuation was shown to sustain PDL1/PDL2 expression required for plasma cell differentiation.\",\n      \"evidence\": \"Dok3⁻/⁻ macrophages, co-IP, IFN-β reporter, bone marrow reconstitution, genetic epistasis with BTK and PLCγ2 KO mice\",\n      \"pmids\": [\"24929003\", \"25053811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the IFN-β-promoting and ERK-inhibitory functions are cell-type-specific was not resolved\", \"Btk phosphorylation sites on DOK3 not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining how DOK3 protein levels are controlled: TRAF6 was identified as the E3 ligase that K48-polyubiquitinates DOK3 at Lys-27, targeting it for degradation during TLR9 stimulation; a K27R mutant resists degradation and suppresses cytokine output.\",\n      \"evidence\": \"Ubiquitination assays, K27R mutagenesis, lentiviral reconstitution in Dok3⁻/⁻ macrophages, cytokine ELISA\",\n      \"pmids\": [\"26548852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases also target DOK3 was unknown\", \"Half-life measurements under basal conditions not reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extending DOK3's inhibitory role to osteoclast biology: DOK3 was shown to limit osteoclastogenesis by inhibiting Syk and ERK downstream of RANKL/M-CSF, with DAP12/DOK3 double-KO epistasis revealing DOK3 also restrains DAP12-independent osteoclast formation.\",\n      \"evidence\": \"DOK3⁻/⁻ and DKO mice, osteoclast differentiation assays, bone histomorphometry\",\n      \"pmids\": [\"28650106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The DAP12-independent DOK3 activation mechanism in osteoclasts was not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying phosphatase recruitment as a DOK3 inhibitory mechanism: DOK3 was shown to recruit PP1 to dephosphorylate CARD9, dampening NF-κB and JNK and attenuating antifungal neutrophil responses, demonstrating DOK3 inhibits signaling not only by effector sequestration but also by direct phosphatase delivery.\",\n      \"evidence\": \"Co-IP of DOK3-PP1-CARD9 complex, Dok3⁻/⁻ mice challenged with Candida albicans, signaling and functional assays\",\n      \"pmids\": [\"31180338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DOK3 selects PP1 over other phosphatases was not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing DOK3 as a JAK2-STAT3 suppressor in neutrophils: DOK3 was found to limit JAK2/STAT3 activation and calprotectin production in colonic neutrophils, maintaining gut microbial homeostasis; separately, ULK1 was placed upstream of DOK3 in osteoclast differentiation.\",\n      \"evidence\": \"Dok3⁻/⁻ mice with DSS colitis model, microbiota transfer rescue; ULK1/DOK3 co-knockdown with Syk/JNK assays\",\n      \"pmids\": [\"34743196\", \"34820053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ULK1-DOK3 interaction not biochemically demonstrated\", \"Mechanism linking DOK3 to JAK2 inhibition was not fully delineated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Delineating the SHP-2/MyD88 axis: DOK3 was shown to recruit SHP-2 to dephosphorylate MyD88 at Y257, providing the molecular mechanism for JAK2-STAT3 suppression downstream of TLR4.\",\n      \"evidence\": \"Co-IP, MyD88-Y257 phosphorylation assays, DOK3⁻/⁻ neutrophils, TLR4/JAK2/STAT3 inhibitor epistasis\",\n      \"pmids\": [\"36172386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study; independent replication needed\", \"Whether SHP-2 recruitment is direct or bridged by another adaptor was not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending the phosphatase-recruitment paradigm to T cells: DOK3 was shown to recruit PP4C to dephosphorylate CARD11, dampening TCR signaling and modulating Th cell differentiation, with hypomorphic CARD11 variants in atopic dermatitis patients exhibiting increased DOK3 binding.\",\n      \"evidence\": \"Co-IP, CARD11 phosphorylation assays, Dok3⁻/⁻ mice with experimental atopic dermatitis, patient variant binding analysis\",\n      \"pmids\": [\"37906628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOK3-PP4C and DOK3-PP1 complexes are mutually exclusive was not tested\", \"Functional impact of enhanced CARD11 variant-DOK3 binding on patient phenotype not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying a second degradation pathway: PRDX1 was shown to physically interact with DOK3 and promote its autophagy-lysosomal degradation, with the molecular glue Salvianolic acid B enhancing this interaction to suppress plasma cell differentiation and arthritis.\",\n      \"evidence\": \"Co-IP, autophagy-lysosome inhibition, collagen-induced arthritis mouse model, small molecule treatment\",\n      \"pmids\": [\"40893682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PRDX1-DOK3 binding site not mapped\", \"Relationship between TRAF6-mediated and PRDX1-mediated degradation pathways not examined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealing post-transcriptional regulation of DOK3 levels: IGF2BP2 was found to bind and stabilize DOK3 mRNA via m6A modifications at specific sites, with DOK3 reconstitution rescuing hyper-inflammatory NF-κB activation in IGF2BP2-deficient cells.\",\n      \"evidence\": \"m6A site mapping, RNA immunoprecipitation, IGF2BP2 KD/OE, DOK3 reconstitution, NF-κB and cytokine assays\",\n      \"pmids\": [\"41999269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which methyltransferase deposits these m6A marks was not identified\", \"Whether m6A regulation of DOK3 is cell-type-specific is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Unresolved: the structural basis for DOK3's selective recruitment of different phosphatases (PP1, PP4C, SHP-2) and effectors (SHIP-1, Grb2, TRAF3) in different cell types and signaling contexts, and whether DOK3 post-translational modifications (specific phosphotyrosine sites, ubiquitination patterns) encode effector selectivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data (crystal/cryo-EM) for DOK3 or its complexes\", \"Phosphosite-to-effector mapping is incomplete\", \"Functional redundancy with DOK1/DOK2 across hematopoietic lineages not systematically addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 13, 16, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 7, 8, 13, 15, 16, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 4, 7, 8, 9, 13, 15, 16, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SHIP1\", \"GRB2\", \"TRAF3\", \"TBK1\", \"TRAF6\", \"CARD9\", \"CARD11\", \"SHP2\"],\n    \"other_free_text\": []\n  }\n}\n```"}