Affinage

DOK1

Docking protein 1 · UniProt Q99704

Length
481 aa
Mass
52.4 kDa
Annotated
2026-04-28
92 papers in source corpus 39 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DOK1 is a multi-domain docking protein that functions as a broad negative regulator of Ras/ERK, JAK/STAT, and Akt signaling downstream of diverse receptor and non-receptor tyrosine kinases in hematopoietic, mesenchymal, and epithelial cells. Upon tyrosine phosphorylation by kinases including BCR-ABL, c-Abl, Lck, Tec, RET, insulin receptor, and Src family members, DOK1 is recruited to the plasma membrane via PI3K-dependent PH-domain binding to phosphoinositides and assembles inhibitory signaling complexes through its phosphorylated C-terminal tyrosines—recruiting RasGAP (via Y295/Y314/Y361/Y376/Y397/Y408), NCK (via Y361), Csk, SHIP1, and SHP-1/SHP-2—to attenuate mitogenic signaling, suppress oncogenic transformation, and modulate cell migration and integrin outside-in signaling (PMID:9008160, PMID:10688886, PMID:10640270, PMID:11489947, PMID:15148308, PMID:26790499). Dok-1/Dok-2 double-knockout mice spontaneously develop CML-like myeloproliferative disease, establishing DOK1 as a bona fide tumor suppressor in the hematopoietic compartment (PMID:15611295). DOK1 activity is regulated at multiple levels: CRM1-dependent nucleocytoplasmic shuttling controls its cytoplasmic availability, IKKβ-mediated serine phosphorylation modulates its signaling output, and oncogenic kinases target it for ubiquitin-proteasome-mediated degradation to overcome its tumor-suppressive function (PMID:16705178, PMID:15574499, PMID:21536658).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1997 High

    Identification of DOK1 as a BCR-ABL and c-Kit substrate that associates with RasGAP established the founding paradigm of DOK1 as a tyrosine-phosphorylated docking protein linking oncogenic kinases to Ras pathway regulation.

    Evidence Protein purification and co-IP from CML progenitor cells and c-Kit-stimulated cells

    PMID:9008160

    Open questions at the time
    • Identity of the kinase(s) phosphorylating DOK1 in normal hematopoiesis was unknown
    • Functional consequence of DOK1-RasGAP association on Ras activity was not tested
    • No in vivo loss-of-function data
  2. 1999 High

    Demonstration that DOK1 requires its PH domain for membrane localization and tyrosine phosphorylation, and that phospho-Y361 recruits NCK to promote cell migration, defined the modular logic of DOK1 signaling: membrane recruitment precedes phosphorylation, which templates distinct effector outputs.

    Evidence Mutagenesis of PH domain and Y361F, subcellular fractionation, insulin-stimulated migration assay in overexpression system

    PMID:10202139

    Open questions at the time
    • The lipid ligand for the PH domain was not identified
    • Endogenous DOK1 localization dynamics not shown
  3. 1999 High

    Discovery that SHP-1 constitutively associates with DOK1 and directly dephosphorylates it in macrophages revealed a phosphatase-based feedback loop controlling DOK1 activation state.

    Evidence Far Western, co-IP from SHP-1-deficient motheaten macrophages, catalytic-mutant trapping

    PMID:10585470

    Open questions at the time
    • Specific tyrosine sites dephosphorylated by SHP-1 not mapped
    • Functional consequence of SHP-1 loss on DOK1-dependent signaling outputs not tested
  4. 2000 High

    Reconstitution of DOK1 as a direct inhibitor of RasGAP catalytic activity and mapping of five RasGAP-binding tyrosines provided the first biochemical mechanism for how DOK1 dampens Ras signaling.

    Evidence In vitro RasGAP activity assay with purified phospho-DOK1, site-directed mutagenesis

    PMID:10688886

    Open questions at the time
    • Later work (PMID:37507023) challenged whether RasGAP catalytic activity is allosterically regulated by DOK1 binding
    • Cellular context dependency not explored
  5. 2000 High

    Genetic knockout revealed DOK1 as indispensable for FcγRIIB-mediated inhibition of B cell proliferation and showed that DOK1 loss causes sustained MAP kinase activation, establishing DOK1 as a physiological negative regulator rather than just a BCR-ABL substrate.

    Evidence Dok-1 homologous recombination knockout mice, BCR/FcγRIIB co-crosslinking, MAPK assays

    PMID:10640270 PMID:10755621

    Open questions at the time
    • Relative contribution of DOK1 vs DOK2 in B cell inhibition not resolved
    • Whether DOK1 acts identically in all inhibitory receptor pathways unknown
  6. 2000 Medium

    Identification of SHIP1-DOK1 and DOK1-RasGAP as mutually exclusive complexes, together with multiple kinase inputs (Lck, Tec), revealed that DOK1 serves as a combinatorial signaling hub whose effector output depends on which upstream kinase phosphorylates it and which complex it enters.

    Evidence Co-IP with domain-deletion mutants, subcellular fractionation, chimeric kinase systems, dominant-negative Tec

    PMID:10799545 PMID:10822173 PMID:10823839

    Open questions at the time
    • Quantitative selectivity between SHIP1 vs RasGAP binding not measured
    • Whether complex exclusivity holds in all cell types not tested
  7. 2001 High

    Reconstitution experiments in DOK1-null cells showed that PI3K-dependent PH-domain membrane recruitment is essential for DOK1's negative regulation of PDGFR/MAPK signaling and that this can occur independently of RasGAP and NCK binding, implying additional effector pathways.

    Evidence Retroviral reconstitution in KO MEFs, PI3K inhibitor, membrane-targeting domain chimeras

    PMID:11489946 PMID:11489947

    Open questions at the time
    • Identity of the RasGAP/NCK-independent effector unknown
    • Specific PI(3,4,5)P3 vs PI(3,4)P2 dependence not resolved
  8. 2001 High

    Dok-1/Dok-2 double knockout mice spontaneously developed CML-like myeloproliferative disease with aberrant Ras/MAPK activation, definitively establishing both proteins as hematopoietic tumor suppressors.

    Evidence Double gene knockout, bone marrow transplantation, replicated by two independent groups

    PMID:15611294 PMID:15611295

    Open questions at the time
    • Individual contribution of DOK1 vs DOK2 to tumor suppression not separated
    • Human genetic evidence for DOK1 loss in CML not provided
  9. 2002 High

    Mapping of DOK1's interaction with RET and systematic mutagenesis of six C-terminal tyrosines delineated a tyrosine code: RasGAP binding (Y295, Y314, Y361, Y376, Y397, Y408) suppresses Ras/Erk, while NCK binding (Y361) activates JNK/c-Jun, showing DOK1 routes different signaling outcomes through distinct phosphotyrosines.

    Evidence Yeast two-hybrid, site-directed mutagenesis, kinase and JNK/Erk activation assays

    PMID:12087092

    Open questions at the time
    • In vivo relevance of DOK1-RET signaling axis not demonstrated
    • Whether all six tyrosines are simultaneously phosphorylated unknown
  10. 2003 High

    Crystal structure of the DOK1 PTB domain in complex with a RET phosphopeptide revealed the molecular basis for receptor selectivity, showing binding occurs via a groove between β5 and the C-terminal α-helix distinct from Shc/IRS1 PTB recognition.

    Evidence X-ray crystallography at atomic resolution

    PMID:14607833

    Open questions at the time
    • Full-length DOK1 structure unavailable
    • How PH domain orientation relative to PTB domain affects receptor engagement unknown
  11. 2004 High

    Identification of c-Abl as the kinase phosphorylating DOK1-Y361 during cell adhesion, and demonstration that the c-Abl/DOK1/NCK pathway drives filopodia formation, connected DOK1 to cytoskeletal remodeling beyond its role as a purely inhibitory signal dampener.

    Evidence Mass spectrometry substrate identification, KO fibroblasts, live imaging of spreading cells

    PMID:15148308

    Open questions at the time
    • Downstream effectors of NCK linking DOK1 to actin polymerization not identified
    • Whether this pathway operates in hematopoietic cells not tested
  12. 2004 High

    Discovery that IKKβ phosphorylates DOK1 at four C-terminal serines in response to TNF-α/IL-1 revealed cross-talk between NF-κB and RTK signaling, with serine phosphorylation required for DOK1's ability to inhibit PDGF-induced ERK activation and promote cell motility.

    Evidence In vitro kinase assay, phospho-specific antibodies, serine-to-alanine mutagenesis, proliferation and migration assays

    PMID:15574499

    Open questions at the time
    • Whether IKKβ and tyrosine kinase phosphorylation are cooperative or sequential unknown
    • Structural basis for serine phosphorylation-dependent activation not determined
  13. 2004 High

    Demonstration that DOK1 recruits Csk to attenuate Src kinase activity and suppress PDGF-induced c-myc, in parallel with RasGAP-mediated MAPK inhibition, established that DOK1 operates through at least two independent inhibitory arms to block mitogenesis.

    Evidence KO reconstitution with binding-deficient DOK1 mutants, Src kinase activity assays

    PMID:16537894

    Open questions at the time
    • Direct Csk-DOK1 binding interface not mapped
    • Quantitative contribution of each arm to proliferation control not determined
  14. 2005 High

    Extension of DOK1's inhibitory role to innate immunity showed that DOK1/DOK2 are essential negative regulators of TLR4-Erk signaling in macrophages, preventing TNF-α hyperproduction, broadening DOK1's role beyond receptor tyrosine kinase pathways.

    Evidence Dok-1/Dok-2 KO macrophages, forced expression of phosphorylation-deficient DOK1, cytokine assays

    PMID:15699069

    Open questions at the time
    • How TLR4 (a non-tyrosine kinase receptor) triggers DOK1 tyrosine phosphorylation not defined
    • Whether DOK1 acts on TLR4-proximal or distal signaling steps unclear
  15. 2006 High

    Identification of a CRM1-dependent NES in DOK1 and demonstration that both Src-mediated tyrosine and IKKβ-mediated serine phosphorylation promote cytoplasmic retention resolved how DOK1 subcellular localization is regulated and why cytoplasmic localization is required for its anti-proliferative and pro-migratory functions.

    Evidence Leptomycin B treatment, NES mutagenesis, live cell imaging, functional assays

    PMID:16705178

    Open questions at the time
    • Nuclear function of DOK1, if any, not characterized
    • Whether nuclear-cytoplasmic shuttling is dynamically regulated during cell cycle unknown
  16. 2007 High

    Structural and biophysical studies showed that phosphorylation of integrin β3-Y747 switches binding preference from talin to the DOK1 PTB domain, establishing DOK1 as a phosphorylation-dependent integrin activation switch.

    Evidence NMR titrations and X-ray crystallography with quantitative affinity measurements

    PMID:18156175

    Open questions at the time
    • In vivo validation of this switch in platelet or endothelial integrin signaling not provided at the time
    • Whether DOK1 binding actively inactivates integrin or simply displaces talin not resolved
  17. 2008 High

    DOK1 was linked to metabolic regulation: DOK1-null mice are lean because elevated ERK activity causes inhibitory phosphorylation of PPARγ-S112, impairing adipogenesis—a phenotype rescued by PPARγ-S112A mutation.

    Evidence KO mice, MEF adipogenesis assay, ERK and PPARγ phosphorylation, genetic rescue

    PMID:18204460

    Open questions at the time
    • Whether DOK1 acts cell-autonomously in adipocytes or through systemic effects not fully resolved
    • Upstream kinase phosphorylating DOK1 in adipocyte precursors not identified
  18. 2011 High

    Discovery that oncogenic kinases (BCR-ABL, Src) target DOK1 for lysine-dependent polyubiquitination and proteasomal degradation provided a mechanism by which oncogenes neutralize DOK1 tumor suppression, and a degradation-resistant DOK1 mutant showed enhanced anti-transformation activity.

    Evidence Ubiquitination assays, proteasome inhibitor, lysine-to-arginine mutants, transformation assays

    PMID:21536658

    Open questions at the time
    • The E3 ubiquitin ligase responsible not identified
    • Whether this degradation pathway operates in primary human leukemias unknown
  19. 2016 High

    DOK1-knockout platelet studies demonstrated that DOK1 negatively regulates integrin αIIbβ3 outside-in signaling, controlling PLCγ2 phosphorylation, clot retraction, and in vivo thrombosis, directly validating the structural prediction that DOK1 modulates integrin signaling in a physiological context.

    Evidence Dok-1 KO mice, platelet aggregation, clot retraction, intravital thrombosis model

    PMID:26790499

    Open questions at the time
    • Mechanism by which DOK1 restrains PLCγ2 phosphorylation not defined
    • Whether DOK1 acts through Csk or RasGAP in platelets not tested
  20. 2023 Medium

    Quantitative binding and enzymatic studies revealed that while RasGAP SH2 domains engage doubly phosphorylated DOK1 with high affinity, this binding does not allosterically alter RasGAP catalytic activity, suggesting DOK1 regulates Ras spatiotemporally by relocalizing RasGAP rather than activating it.

    Evidence Affinity measurements, SAXS, in vitro RasGAP activity assay

    PMID:37507023

    Open questions at the time
    • Contradicts earlier claim (PMID:10688886) that DOK1 inhibits RasGAP activity; resolution unclear
    • Spatial redistribution model not validated in cells
    • Single study without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ligase mediating DOK1 degradation, the nuclear function (if any) of DOK1, the full set of effectors recruited by Y336/Y340 that operate independently of RasGAP, and whether DOK1 loss or silencing is causally linked to human cancers.
  • E3 ubiquitin ligase for DOK1 not identified
  • Nuclear role of DOK1 uncharacterized
  • No human genetic evidence for DOK1 as a tumor suppressor in patients

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0098772 molecular function regulator activity 6 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-168256 Immune System 4 R-HSA-109582 Hemostasis 2 R-HSA-1643685 Disease 2
Partners
CSKGRB2NCK1RASA1SHIP1SHP1SHP2YWHAZ

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 p62(dok)/DOK1 was identified as a novel protein constitutively tyrosine-phosphorylated in CML progenitor cells by p210(bcr-abl), and its association with p120 RasGAP correlates with its tyrosine phosphorylation state. DOK1 is also rapidly phosphorylated downstream of c-Kit receptor activation. Protein purification, co-immunoprecipitation, SDS-PAGE Cell High 9008160
2000 Tyrosine-phosphorylated p62(dok) directly inhibits RasGAP catalytic activity. p210(bcr-abl) directly phosphorylates p62(dok) at C-terminal tyrosine residues, and five tyrosine residues are involved in RasGAP binding in vitro. In vitro kinase assay, in vitro RasGAP activity assay, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 10688886
2000 DOK1 negatively regulates BCR signaling and is indispensable for FcγRIIB-mediated negative regulation of B cell proliferation. DOK1 tyrosine phosphorylation is Lyn-dependent upon BCR or BCR/FcγRIIB cross-linking, and loss of dok gene results in sustained MAP kinase activation. Homologous recombination knockout, co-immunoprecipitation, kinase assays Genes & development High 10640270
2000 FcγRIIB-BCR coaggregation leads to increased DOK1 tyrosine phosphorylation and RasGAP binding. SHIP recruits DOK1 via its phosphotyrosine-binding (PTB) domain, and DOK1 contains all structural information required to mediate FcγRIIB inhibitory effect on Erk activation. Co-immunoprecipitation, chimeric receptor functional assay, phosphorylation assays Immunity High 10755621
1999 DOK1 undergoes tyrosine phosphorylation in response to cell adhesion to extracellular matrix (mediated by Src family kinases) and insulin. The PH domain is required for membrane localization and tyrosine phosphorylation. Phosphorylation at Y361 mediates NCK binding, and overexpression of wild-type DOK1 (but not PH-domain or Y361F mutants) enhances insulin-stimulated cell migration. Dominant-negative mutant overexpression, co-immunoprecipitation, cell migration assays, subcellular fractionation The EMBO journal High 10202139
2000 DOK1 inhibits cellular transformation by Src tyrosine kinase. Both the PTB domain and C-terminal tail (residues 336-363) are necessary for this inhibitory activity. DOK1 homodimerizes through its PTB domain and Y146, and mutations blocking homodimerization reduce Dok1's ability to inhibit Src transformation. Combinatorial peptide library, transformation assay, co-immunoprecipitation, mutagenesis The Journal of biological chemistry High 11042170
2001 DOK1 acts as a negative regulator of growth factor-induced Ras/MAPK signaling and cell proliferation. Loss of p62(dok) in mice results in increased proliferation and sustained Ras/MAPK activation after growth factor removal, and accelerates p210(bcr-abl)-induced myeloproliferative disease. Gene knockout (homologous recombination), retroviral bone marrow transduction, MAPK activation assays The Journal of experimental medicine High 11489947
2001 Plasma membrane recruitment of DOK1 via PI3-kinase-dependent binding of its PH domain to 3'-phosphorylated phosphoinositides is essential for its negative regulatory function on the PDGFR/MAPK pathway. This negative effect can occur independently of DOK1's ability to associate with RasGAP and Nck. Retroviral reconstitution in knockout cells, PI3K inhibitor treatment, membrane targeting constructs, cell proliferation assay The Journal of experimental medicine High 11489946
2001 Dok-1 and Dok-2 double knockout mice spontaneously develop CML-like myeloproliferative disease with aberrant Ras/MAP kinase activation, demonstrating that these proteins are critical tumor suppressors in the hematopoietic compartment. Double gene knockout, bone marrow transplantation, MAPK activation assays The Journal of experimental medicine High 15611294 15611295
2001 The insulin receptor directly phosphorylates p62(dok) at Y362 and Y398. Y362 phosphorylation mediates NCK binding, Y362/Y398 phosphorylation mediates GAP binding, and these sites are essential for DOK1 to inhibit insulin-stimulated Ras and Akt activation. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, Ras and Akt activation assays The Journal of biological chemistry High 11551902
2002 DOK1 interacts with RET receptor tyrosine kinase (identified by yeast two-hybrid). Y361 in DOK1 is the binding site for Nck; Y295, Y314, Y361, Y376, Y397, and Y408 are involved in RasGAP binding. RasGAP binding to DOK1 is required to suppress Ras/Erk activation by RET-MEN2B, while Nck binding to Y361 is necessary for JNK and c-Jun activation. Yeast two-hybrid, site-directed mutagenesis, co-immunoprecipitation, kinase assays The Journal of biological chemistry High 12087092
2002 DOK1 acts as an adaptor linking activin receptors (serine/threonine kinase receptors) to Smad proteins. DOK1 associates with both type I and II activin receptors and with Smad3, facilitating Smad3/Smad4 association, without requiring DOK1 tyrosine phosphorylation. Co-immunoprecipitation, gene trap screen, apoptosis assays The EMBO journal Medium 11927552
2003 Crystal structure of the DOK1 PTB domain alone and in complex with a phosphopeptide from RET receptor reveals that the RET phosphopeptide binds to a surface groove between strand β5 and the C-terminal α-helix of the PTB domain. DOK1 PTB domain does not recognize peptides from TrkA or IL-4 receptor recognized by Shc and IRS1. X-ray crystallography The Journal of biological chemistry High 14607833
2004 c-Abl tyrosine kinase phosphorylates DOK1 at Y361 upon cell adhesion, promoting DOK1 association with the SH2/SH3 adaptor Nck. This c-Abl/DOK1/Nck pathway is critical for filopodia formation during cell spreading; fibroblasts lacking c-Abl, DOK1, or Nck have fewer filopodia. DOK1 and c-Abl were both detected in filopodia of spreading cells. Mass spectrometry substrate identification, site-directed mutagenesis, knockout fibroblasts, live imaging, co-immunoprecipitation The Journal of cell biology High 15148308
2004 IKKβ associates with and phosphorylates DOK1 at S439, S443, S446, and S450 in response to TNF-α, IL-1, or γ-radiation. This serine phosphorylation is required for DOK1's ability to inhibit PDGF-induced ERK1/2 phosphorylation, cell growth inhibition, and promotion of cell motility. In vitro kinase assay, phospho-specific antisera, site-directed mutagenesis, cell proliferation and migration assays Proceedings of the National Academy of Sciences of the United States of America High 15574499
2004 DOK1 negatively regulates PDGF-stimulated c-myc induction by recruiting Csk to active Src kinases (attenuating their activity), and negatively regulates PDGF-induced MAPK activation by acting on RasGAP and other binding partners. Both pathways contribute to DOK1's inhibitory effect on mitogenesis. Knockout cells, binding-deficient DOK1 mutants, Src kinase assays, proliferation assays Molecular and cellular biology High 16537894
2004 DOK1 tyrosine residues Y336 and Y340 are essential for negative regulation of Ras-Erk signaling downstream of PTKs (Lyn, Fyn) and for inhibiting v-Abl-induced cellular transformation, but are dispensable for RasGAP binding, indicating DOK1 recruits additional unidentified molecules that cooperate with RasGAP. C-terminal deletion mutants, Tyr→Phe substitutions, Ras/Erk activation assays, transformation assays Genes to cells High 15189452
2004 DOK1 mediates SHP-2 binding to the αVβ3 integrin β3 subunit in response to IGF-I in vascular smooth muscle cells. DOK1 binds both β3 and SHP-2, and disrupting either interaction prevents IGF-I-dependent Akt and MAPK phosphorylation and cell migration/proliferation. Co-immunoprecipitation, blocking peptides, DOK1 binding-mutant expression, signaling assays, migration assay The Journal of biological chemistry Medium 15546884
2005 DOK1 and DOK2 are essential negative regulators downstream of TLR4 in macrophages. LPS induces DOK1 tyrosine phosphorylation; knockout macrophages show elevated Erk activation and hyperproduction of TNF-α. This negative regulation requires DOK1 tyrosine phosphorylation (Tyr/Phe mutant loses activity). Knockout mice, forced expression with phosphorylation mutants, cytokine production assays, kinase activation assays The Journal of experimental medicine High 15699069
2006 DOK1 shuttles between the nucleus and cytoplasm via a functional nuclear export signal (NES: 348LLKAKLTDPKED359) dependent on CRM1. Src-induced tyrosine phosphorylation and IKKβ-dependent serine phosphorylation both promote cytoplasmic retention. Cytoplasmic localization is required for DOK1's functions in inhibiting cell proliferation and promoting cell spreading and motility. Leptomycin B treatment, NES mutant expression, live cell imaging, Src/IKKβ co-expression, functional assays Molecular and cellular biology High 16705178
2007 NMR spectroscopy and X-ray crystallography reveal that unphosphorylated β3 integrin tail binds more strongly to talin than DOK1 PTB domain, but phosphorylation of Y747 in the β3 tail switches the preference, allowing DOK1 to bind much more strongly than talin, acting as an integrin activation switch. NMR spectroscopy (15N-1H HSQC titrations), X-ray crystallography, affinity measurements The Journal of biological chemistry High 18156175
2008 DOK1 promotes adipocyte hypertrophy by counteracting ERK-mediated inhibitory phosphorylation of PPARγ at S112. DOK1-deficient embryonic fibroblasts show increased ERK activity and elevated PPARγ-S112 phosphorylation, impairing adipogenic differentiation. Mutation of PPARγ-S112 blocks the lean phenotype caused by DOK1 ablation. Knockout mice, embryonic fibroblast differentiation assays, ERK activation assays, PPARγ phosphorylation assays, rescue experiments Nature medicine High 18204460
2009 DOK1 and DOK2 PH domains bind phosphatidylinositol 5-phosphate (PtdIns5P) in vitro. PtdIns5P production in T cells correlates with and regulates DOK tyrosine phosphorylation in vivo upon TCR triggering. In vitro lipid binding assay, PtdIns5P manipulation in T cells, phosphorylation assays Journal of immunology Medium 19299694
2009 CD45 recruits DOK1 via its SH2 domain (requiring DOK1-Y296), promotes DOK1 membrane targeting, and through DOK1, negatively regulates JAK2/STAT3/5 phosphorylation downstream of IL-3 and IFN-α stimulation. Co-immunoprecipitation, Y296F point mutant, stable DOK1 expression, DOK1 siRNA, JAK/STAT phosphorylation assays Molecular immunology Medium 19481264
2011 Oncogenic tyrosine kinases (p210bcr-abl and oncogenic Src) target DOK1 for degradation through the ubiquitin-proteasome pathway via lysine-dependent polyubiquitination, in a manner dependent on their tyrosine kinase activity. A DOK1 mutant largely refractory to this degradation shows enhanced suppression of oncogenic transformation. Proteasome inhibitor treatment, ubiquitination assays, lysine-mutant DOK1, transformation assays Molecular and cellular biology High 21536658
2000 SHIP1 forms a complex with DOK1 in BCR-ABL-transformed hematopoietic cells. Both the SH2 domain of SHIP1 and the PTB domain of DOK1 are required for complex formation, which is mutually exclusive with DOK1-RasGAP association. The DOK1/SHIP1 complex is only detected in the cytosolic fraction. Co-immunoprecipitation, domain-deletion mutants, subcellular fractionation Cellular signalling Medium 10822173
2000 Lck phosphorylates DOK1 (p62dok) downstream of CD2 (but not CD3) receptor stimulation in T cells. Phospho-DOK1 binds the SH2 domain of Lck in vitro, suggesting a feedback interaction. Lck/EGFR chimeric receptor system, JCaM1.6 cells, in vitro SH2 binding assay The Journal of biological chemistry Medium 10799545
2000 Tec protein tyrosine kinase directly phosphorylates DOK1 in vivo and in vitro and mediates signaling from the B cell antigen receptor to DOK1. This requires the Tec homology and SH2 domains of Tec plus kinase activity. DOK1 expression inhibits Ras activity in 293 cells, and dominant-negative Tec blocks BCR-induced DOK1 phosphorylation. In vitro kinase assay, dominant-negative mutants, Ras activity assay, co-immunoprecipitation The Journal of biological chemistry Medium 10823839
1999 SHP-1 is constitutively associated with p62(DOK)/DOK1 in macrophages and is a direct DOK1 phosphatase. The interaction occurs independently of DOK1 tyrosine phosphorylation (constitutive), but the SHP-1 catalytic domain associates directly and inducibly with tyrosine-phosphorylated DOK1. DOK1 is a major CSF-1R-associated tyrosine-phosphorylated protein in macrophages. Far Western analysis, co-immunoprecipitation, SHP-1-deficient motheaten mouse macrophages, catalytic mutant SHP-1 The Journal of biological chemistry High 10585470
2000 SH2D1A (XLP gene product) associates with DOK1 at phosphorylated Y449 via its SH2 domain; an XLP-associated SH2D1A mutant fails to associate with DOK1. Overexpression of SH2D1A activates NF-κB through a mechanism requiring IKKβ but not the SH2 domain. Co-immunoprecipitation, XLP mutant analysis, NF-κB reporter assay, dominant-negative IKKβ Proceedings of the National Academy of Sciences of the United States of America Medium 10852966
2002 DOK1 phosphorylation at Y295 and Y361 allows the SH2 domains of p120 RasGAP to bind, suppressing CrkI-driven Ras pathway activity. Abl family kinases phosphorylate these DOK1 tyrosines in the context of CrkI-transformed cells to restrain localized Ras activation. Co-immunoprecipitation, mutagenesis, FRET Ras activation sensor, RasGAP knockdown, transformation assays Oncogene Medium 25043303
2014 DOK1 regulates PDGF-BB-induced glioma cell invasion and migration through a p130Cas-Rap1 signaling pathway. DOK1 tyrosine phosphorylation (at Y362 and Y398) is required for PDGF-BB-induced p130Cas tyrosine phosphorylation and Rap1 activation. DOK1 colocalizes with phospho-p130Cas at the cell membrane. siRNA knockdown, phosphorylation-deficient DOK1 mutant (DOK1FF), Rap1 activation assay, 3D spheroid invasion assay, co-localization imaging Journal of cell science Medium 24762811
2014 BRK (breast tumor kinase/PTK6) interacts with and phosphorylates DOK1 specifically at Y362, leading to ubiquitin-proteasome-mediated DOK1 degradation to promote cell proliferation and migration. Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, proteasome inhibitor treatment PloS one Medium 24523872
2023 RasGAP SH2 domains generate distinct binding interactions with doubly phosphorylated DOK1 (and p190RhoGAP and EphB4). RasGAP-DOK1 binding involves dual SH2 domain engagement with high affinity, but these interactions do not alter RasGAP catalytic activity, implying RasGAP uses SH2 domains for spatial-temporal Ras regulation rather than allosteric activation. Affinity measurements, small-angle X-ray scattering (SAXS), RasGAP activity assay The Journal of biological chemistry Medium 37507023
2002 p62(dok)/DOK1 is tyrosine-phosphorylated and forms a complex with SHIP and RasGAP upon FcγRIIB/FcεRI coaggregation in mast cells. Recruitment of DOK1 to FcεRI is sufficient to inhibit FcεRI-induced calcium mobilization and ERK1/2 activation. Both the PH/PTB domains and the C-terminal proline/tyrosine-rich region can independently mediate inhibition. Co-immunoprecipitation, chimeric receptor expression, calcium mobilization assay, ERK activation assay, knockout mast cells Journal of immunology Medium 11970986
2025 14-3-3ζ interacts with the PTB domain of DOK1 even in the absence of phosphorylated integrin β tails. The 14-3-3ζ/DOK1 binary complex can simultaneously bind phosphorylated integrin β2 and β3 cytoplasmic tails, with different phosphorylated motifs preferentially recognized by each protein, constituting a bi-molecular switch in integrin regulation. NMR spectroscopy, co-immunoprecipitation, integrin tail peptide binding assays Journal of molecular biology Medium 30243836
2009 Proteomics of integrin αIIbβ3 outside-in signaling in platelets identified DOK1 and DOK3 as tyrosine-phosphorylated proteins upon platelet spreading on fibrinogen. DOK1 phosphorylation downstream of αIIbβ3 is Src kinase-independent (unlike GPVI-dependent phosphorylation). Both DOK1 and DOK3 inducibly interact with Grb2 and SHIP-1 in fibrinogen-spread platelets. Proteomics/mass spectrometry, Src kinase inhibitors, co-immunoprecipitation, platelet spreading assay Journal of thrombosis and haemostasis Medium 19682241
2016 DOK1 deficiency in platelets leads to increased clot retraction, enhanced PLCγ2 phosphorylation, and augmented spreading on fibrinogen after thrombin stimulation, demonstrating that DOK1 negatively regulates integrin αIIbβ3 outside-in (but not inside-out) signaling. Dok-1-/- mice show shortened bleeding times and accelerated arterial thrombosis. Dok-1 knockout mice, platelet aggregation assay, JON/A binding assay, clot retraction assay, PLCγ2 phosphorylation, intravital thrombosis model Thrombosis and haemostasis High 26790499

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell 331 9008160
2000 The RasGAP-binding protein p62dok is a mediator of inhibitory FcgammaRIIB signals in B cells. Immunity 185 10755621
2001 Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. The Journal of cell biology 142 11470823
2000 Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling. Genes & development 137 10640270
1999 Tyrosine phosphorylation of p62(Dok) induced by cell adhesion and insulin: possible role in cell migration. The EMBO journal 100 10202139
2007 An integrin phosphorylation switch: the effect of beta3 integrin tail phosphorylation on Dok1 and talin binding. The Journal of biological chemistry 96 18156175
2001 p62(dok), a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210(bcr-abl). The Journal of experimental medicine 96 11489947
2008 Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation. Nature medicine 92 18204460
2004 Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia. The Journal of experimental medicine 86 15611294
2007 Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. International immunology 76 17329234
2005 Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. The Journal of experimental medicine 74 15699069
2004 Role of Dok-1 and Dok-2 in leukemia suppression. The Journal of experimental medicine 74 15611295
2002 Downstream of kinase, p62(dok), is a mediator of Fc gamma IIB inhibition of Fc epsilon RI signaling. Journal of immunology (Baltimore, Md. : 1950) 68 11970986
2000 Domain-dependent function of the rasGAP-binding protein p62Dok in cell signaling. The Journal of biological chemistry 68 11042170
2004 c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. The Journal of cell biology 62 15148308
2001 Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on mitogen-activated protein (MAP) kinase activation. The Journal of experimental medicine 61 11489946
2002 Role of Dok1 in cell signaling mediated by RET tyrosine kinase. The Journal of biological chemistry 58 12087092
2000 Tyrosine phosphorylation of p62dok by p210bcr-abl inhibits RasGAP activity. Proceedings of the National Academy of Sciences of the United States of America 55 10688886
2009 Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells. Journal of immunology (Baltimore, Md. : 1950) 51 19299694
2004 Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1. Blood 51 15345598
2001 Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt. The Journal of biological chemistry 48 11551902
2000 SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL. The Journal of biological chemistry 47 11031258
2009 Proteomic analysis of integrin alphaIIbbeta3 outside-in signaling reveals Src-kinase-independent phosphorylation of Dok-1 and Dok-3 leading to SHIP-1 interactions. Journal of thrombosis and haemostasis : JTH 46 19682241
2000 The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B. Proceedings of the National Academy of Sciences of the United States of America 46 10852966
2002 Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling. The Journal of biological chemistry 43 11825908
2002 The rasGAP-binding protein, Dok-1, mediates activin signaling via serine/threonine kinase receptors. The EMBO journal 43 11927552
2004 DOK1 mediates SHP-2 binding to the alphaVbeta3 integrin and thereby regulates insulin-like growth factor I signaling in cultured vascular smooth muscle cells. The Journal of biological chemistry 41 15546884
2004 IkappaB kinase beta phosphorylates Dok1 serines in response to TNF, IL-1, or gamma radiation. Proceedings of the National Academy of Sciences of the United States of America 41 15574499
1999 SHP-1 regulation of p62(DOK) tyrosine phosphorylation in macrophages. The Journal of biological chemistry 40 10585470
2006 Dok-1 independently attenuates Ras/mitogen-activated protein kinase and Src/c-myc pathways to inhibit platelet-derived growth factor-induced mitogenesis. Molecular and cellular biology 39 16537894
2014 Dok1 and Dok2 proteins regulate natural killer cell development and function. The EMBO journal 35 24963146
2011 Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Molecular oncology 32 21856257
2004 Dexamethasone up-regulates the inhibitory adaptor protein Dok-1 and suppresses downstream activation of the mitogen-activated protein kinase pathway in antigen-stimulated RBL-2H3 mast cells. Molecular pharmacology 32 15608142
2004 Functional interaction of RasGAP-binding proteins Dok-1 and Dok-2 with the Tec protein tyrosine kinase. Oncogene 31 14647425
2001 p62dok negatively regulates CD2 signaling in Jurkat cells. Journal of immunology (Baltimore, Md. : 1950) 31 11254695
2000 Evidence that Llck-mediated phosphorylation of p56dok and p62dok may play a role in CD2 signaling. The Journal of biological chemistry 29 10799545
2013 Differential role of Dok1 and Dok2 in TLR2-induced inflammatory signaling in glia. Molecular and cellular neurosciences 28 23659921
2011 Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers. International journal of cancer 28 21796618
2003 Structural basis for the specific recognition of RET by the Dok1 phosphotyrosine binding domain. The Journal of biological chemistry 28 14607833
2001 Inhibition of the motility and growth of B16F10 mouse melanoma cells by dominant negative mutants of Dok-1. Molecular and cellular biology 28 11463826
1998 Interactions of p62(dok) with p210(bcr-abl) and Bcr-Abl-associated proteins. The Journal of biological chemistry 26 9822717
2004 Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia. Oncogene 25 14730347
2002 Clustering the mast cell function-associated antigen (MAFA) leads to tyrosine phosphorylation of p62Dok and SHIP and affects RBL-2H3 cell cycle. Immunology letters 25 12008030
2000 Mediation by the protein-tyrosine kinase Tec of signaling between the B cell antigen receptor and Dok-1. The Journal of biological chemistry 25 10823839
2017 Anti-inflammation conferred by stimulation of CD200R1 via Dok1 pathway in rat microglia after germinal matrix hemorrhage. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 24 28792282
2009 CD45 recruits adapter protein DOK-1 and negatively regulates JAK-STAT signaling in hematopoietic cells. Molecular immunology 24 19481264
2006 A nuclear export signal and phosphorylation regulate Dok1 subcellular localization and functions. Molecular and cellular biology 22 16705178
2004 Molecular basis of distinct interactions between Dok1 PTB domain and tyrosine-phosphorylated EGF receptor. Journal of molecular biology 22 15476828
2000 The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells. Cellular signalling 22 10822173
2004 Dok-1 tyrosine residues at 336 and 340 are essential for the negative regulation of Ras-Erk signalling, but dispensable for rasGAP-binding. Genes to cells : devoted to molecular & cellular mechanisms 21 15189452
2015 Photoactivation of Dok1/ERK/PPARγ signaling axis inhibits excessive lipolysis in insulin-resistant adipocytes. Cellular signalling 20 25813581
2011 Oncogenic tyrosine kinases target Dok-1 for ubiquitin-mediated proteasomal degradation to promote cell transformation. Molecular and cellular biology 20 21536658
2016 RASSF1A and DOK1 Promoter Methylation Levels in Hepatocellular Carcinoma, Cirrhotic and Non-Cirrhotic Liver, and Correlation with Liver Cancer in Brazilian Patients. PloS one 19 27078152
2014 Epstein-Barr virus down-regulates tumor suppressor DOK1 expression. PLoS pathogens 19 24809689
2014 A crucial role for DOK1 in PDGF-BB-stimulated glioma cell invasion through p130Cas and Rap1 signalling. Journal of cell science 18 24762811
2016 Dok1 and Dok2 Proteins Regulate Cell Cycle in Hematopoietic Stem and Progenitor Cells. Journal of immunology (Baltimore, Md. : 1950) 17 27183638
2014 BRK targets Dok1 for ubiquitin-mediated proteasomal degradation to promote cell proliferation and migration. PloS one 17 24523872
2005 Phosphotyrosine binding-mediated oligomerization of downstream of tyrosine kinase (Dok)-1 and Dok-2 is involved in CD2-induced Dok phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 17 16177091
2012 Transcriptional regulation of the human tumor suppressor DOK1 by E2F1. Molecular and cellular biology 16 23028047
2006 Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin alphaIIbbeta3. Journal of thrombosis and haemostasis : JTH 16 17092301
2001 T cell regulation of p62(dok) (Dok1) association with Crk-L. The Journal of biological chemistry 16 11553620
2017 Intratumoral Heterogeneity of Somatic Mutations for NRIP1, DOK1, ULK1, ULK2, DLGAP3, PARD3 and PRKCI in Colon Cancers. Pathology oncology research : POR 15 28844109
2017 DOK1/PPARgamma pathway mediates anti-tumor ability of all-trans retinoic acid in breast cancer MCF-7 cells. Biochemical and biophysical research communications 14 28396148
2015 An Alternative Phosphorylation Switch in Integrin β2 (CD18) Tail for Dok1 Binding. Scientific reports 14 26108885
2014 mRNA expression of DOK1-6 in human breast cancer. World journal of clinical oncology 13 24829863
2014 Arabidopsis DOK1 encodes a functional dolichol kinase involved in reproduction. The Plant journal : for cell and molecular biology 13 25406445
2011 A computational analysis of the dynamic roles of talin, Dok1, and PIPKI for integrin activation. PloS one 13 22110576
2005 Dok1 expression and mutation in Burkitt's lymphoma cell lines. Cancer letters 12 16338067
2016 Dok-1 negatively regulates platelet integrin αIIbβ3 outside-in signalling and inhibits thrombosis in mice. Thrombosis and haemostasis 11 26790499
2005 Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation. Cell cycle (Georgetown, Tex.) 11 15655368
2007 Dok-1 is a positive regulator of IL-4 signalling and IgE response. Journal of biochemistry 10 17827176
2004 High-level expression of Dok-1 in neurons of the primate prefrontal cortex and hippocampus. Journal of neuroscience research 10 14705142
2018 Interaction Analyses of 14-3-3ζ, Dok1, and Phosphorylated Integrin β Cytoplasmic Tails Reveal a Bi-molecular Switch in Integrin Regulation. Journal of molecular biology 9 30243836
2017 Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8+ T Cells in a Murine Model of Ocular Infection. Journal of virology 9 28490594
2023 Diverse p120RasGAP interactions with doubly phosphorylated partners EphB4, p190RhoGAP, and Dok1. The Journal of biological chemistry 8 37507023
2016 Dok-1 and Dok-2 Regulate the Formation of Memory CD8+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 8 27664281
2012 The inositol 5-phosphatase SHIP-1 and adaptors Dok-1 and 2 play central roles in CD4-mediated inhibitory signaling. Immunology letters 8 22370159
2011 Dok-1 and Dok-2 deficiency induces osteopenia via activation of osteoclasts. Journal of cellular physiology 8 21732353
2014 NMR characterization of the near native and unfolded states of the PTB domain of Dok1: alternate conformations and residual clusters. PloS one 7 24587391
2014 Phosphorylation of Dok1 by Abl family kinases inhibits CrkI transforming activity. Oncogene 7 25043303
2021 Expression of the EGFR-RAS Inhibitory Proteins DOK1 and MTMR7 and its Significance in Colorectal Adenoma and Adenoma Recurrence. Journal of gastrointestinal and liver diseases : JGLD 6 34941983
2012 Dok-1 overexpression promotes development of γδ natural killer T cells. European journal of immunology 6 22736313
2005 Germline mutations in Dok1 do not predispose to chronic lymphocytic leukemia. Leukemia research 6 15541476
2000 Priming of CD2-induced p62Dok tyrosine phosphorylation by CD3 in Jurkat T cells. European journal of immunology 6 11093148
2020 Analysis of the DOK1 gene in breast cancer. Molecular biology reports 5 31919752
2016 Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22. Biochemical and biophysical research communications 5 27450811
2024 DOK1 and DOK2 regulate CD8 T cell signaling and memory formation without affecting tumor cell killing. Scientific reports 4 38956389
2024 DOK1 facilitates the advancement of ccRCC. Journal of Cancer 4 39513119
2022 Dok-1 regulates mast cell degranulation negatively through inhibiting calcium-dependent F-actin disassembly. Clinical immunology (Orlando, Fla.) 4 35421591
2016 Expression of DOK1, 2, and 3 genes in HTLV-1-infected T cells. Acta virologica 3 27265473
2000 In vitro-generated stem cell leukaemia showing altered cell cycle progression with distinct signalling of the tyrosine-phosphorylated rasGAP-associated p62(dok) protein. The Journal of pathology 3 11054720
2004 Expression, crystallization and preliminary X-ray studies of the recombinant PTB domain of mouse dok1 protein. Acta crystallographica. Section D, Biological crystallography 0 14747716