Disease relevance of DOK1

• Originally identified in chronic myelogenous leukemia cells as a highly phosphorylated substrate for the chimeric p210(bcr-abl) protein, DOK1 was suspected to play a role in leukemogenesis [1].
• Germline mutations in Dok1 do not predispose to chronic lymphocytic leukemia [2].
• The cell signaling docking protein p130cas became tyrosine-phosphorylated in SH-SY5Y human neuroblastoma cells during induced differentiation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum or a combination of basic fibroblast growth factor (bFGF) and insulin-like growth factor-I (IGF-I) [3].
• BCAR1/p130Cas is a docking protein involved in intracellular signaling pathways and in vitro resistance of estrogen-dependent breast cancer cells to antiestrogens [4].
• Finally, a dimer of the WXXF motif was fused to the chloramphenicol acetyl transferase (CAT) gene, and it was demonstrated that the WXXF dimer-CAT fusion protein construct produces CAT activity within virions in the presence of Vpr as a docking protein [5].

Psychiatry related information on DOK1

• Neurons and plaques of Alzheimer's disease patients highly express the neuronal membrane docking protein p42IP4/centaurin alpha [6].

High impact information on DOK1

• In cells, v-Abl tyrosine kinase binds and strongly phosphorylates p62dok, which then binds rasGAP [7].
• From peptide sequence, molecular cloning revealed a cDNA encoding a novel protein, p62dok, with little homology to others but with a prominent set of tyrosines and nearby sequences suggestive of SH2 binding sites [7].
• Secretory protein translocation across membranes-the role of the "docking protein' [8].
• We show that Pax-5 functions as a cell type-specific docking protein that facilitates binding of the early B-cell-specific mb-1 promoter by proteins of the Ets proto-oncogene family [9].
• EGF induced Ras activation in epidermal cells along with phosphorylation of the multisubstrate docking protein Gab1 and its binding to SHP-2 [10].

Chemical compound and disease context of DOK1

• In MCF-7 breast cancer cells Gab2 was markedly tyrosine phosphorylated in response to heregulin and also following EGF, insulin or bFGF administration, indicating that a variety of RTKs implicated in breast cancer development or progression couple to this docking protein [11].

Biological context of DOK1

• Transient expression of either Gq- or Gi-coupled receptors in COS-7 cells allowed GPCR agonist-induced EGFR transactivation, and lysophosphatidic acid (LPA)-generated signals involved the docking protein Gab1 [12].
• The association of SH2D1A with Dok1 also depends on phosphorylation of Dok1 Y(449) in the sequence ALYSQVQK [13].
• The data provide evidence that DOK1 and DOK2 proteins have a similar role in regulating cell proliferation and differentiation and are positive regulators of the MAPK signaling pathway in this context [1].
• p62(DOK1) (DOK1) and p56(DOK2) (DOK2) are sequence homologs that act as docking proteins downstream of receptor or nonreceptor tyrosine kinases [1].
• Mutant Dok1 A(439), A(443), A(446), and A(450) also did not promote cell motility, whereas wild-type Dok1 promoted cell motility, and Dok1 E(439), E(443), E(446), and E(450) further enhanced cell motility [14].

Anatomical context of DOK1

• The data in this report show that both the DOK1 and the DOK2 adaptor proteins are constitutively expressed in the myelomonoblastic leukemia cell line, HL-60, and that expression of both proteins is induced by the chemotherapeutic differentiation causing agents, all-trans retinoic acid (atRA) and 1,25-dihydroxyvitamin D3 (VD3) [1].
• However, p62(DOK1-/-) fibroblast knockout cells were found to have enhanced MAPK signaling and proliferation due to growth factors, suggesting negative regulatory capabilities for DOK1 [1].
• We now find that IkappaB kinase beta (IKKbeta) associated with and phosphorylated Dok1 in human epithelial cells and B lymphocytes [14].
• Taken together, Cas-L might be the bi-modal docking protein that assembles the signals through beta1-integrins and TCR/CD3, and participates in a variety of T-cell functions [15].
• Dok1 inhibits MAP kinase activity, down-regulates cell proliferation and has a suppressive effect on cellular transformation and B-cell signalling pathways [2].

Associations of DOK1 with chemical compounds

• Dok, a 62-kDa Ras GTPase-activating protein (rasGAP)-associated phosphotyrosyl protein, is thought to act as a multiple docking protein downstream of receptor or non-receptor tyrosine kinases [16].
• Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells [17].
• This PGF2alpha-induced tyrosine phosphorylation of proteins (except for pp62) was blocked by down-regulating protein kinase C (PKC) by 12-O-tetradecanoylphorbol 13-acetate pretreatment and by GF 109203X, a potent specific PKC inhibitor [18].
• Src-induced tyrosine phosphorylation prevented the LMB-mediated nuclear accumulation of Dok1 [19].
• To identify a candidate pp60src docking protein or receptor in the membrane, a radiolabelled peptide corresponding to the pp60src NH2-terminal membrane binding domain was cross-linked to fibroblast membranes and found to specifically label a 32-kDa protein [20].

Physical interactions of DOK1

• However, the Dok1/SHIP1 complex was only detected in the cytosolic fraction of Bcr-Abl transformed hematopoietic cells [21].
• Our results show that IGF-I induces DOK1 binding to beta3 and to SHP-2 [22].
• Therefore, receptor dephosphorylation may be the result of the combined activity of receptor-bound SHP-1 and SHP-1 bound to an auxiliary docking protein [23].
• 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 [24].
• Although we identified p130Cas in platelets for the first time, this docking protein failed to interact with PYK2 [25].

Enzymatic interactions of DOK1

• In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET [26].
• In this study, we have investigated the molecular basis of specific association between the Dok1 PTB domain and the tyrosine-phosphorylated EGFR [27].
• Upon activation, the HGF-receptor c-Met binds and phosphorylates the multisite docking protein Gab1 [28].
• Recombinant IKKbeta also phosphorylated Dok1 or Dok1 amino acids 430-481 in vitro [14].
• Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells [29].

Regulatory relationships of DOK1

• Surprisingly, mutant Dok1 A(439), A(443), A(446), and A(450) differed from wild-type Dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth [14].
• p62dok negatively regulates CD2 signaling in Jurkat cells [30].
• Tyrosine phosphorylation of p62dok by p210bcr-abl inhibits RasGAP activity [31].
• Moreover, both receptors stimulate tyrosine phosphorylation of the docking protein FRS2alpha and induce mitogen-activated protein kinase stimulation with a time course and intensity that depends on the ligand that is applied [32].

Other interactions of DOK1

• We now report that SH2D1A associates with Dok1, a protein that interacts with Ras-GAP, Csk, and Nck [13].
• Our structure-based mutational analyses define the molecular determinants for the two distinct Dok1 PTB domain/EGFR interactions and provide the structural understanding of the specific interactions between EGFR and PTB domains in the divergent Dok homologues [27].
• A major substrate of Bcr-Abl was recently identified as the RasGAP-associated 62 kDa docking protein Dok1 [21].
• The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells [21].
• SNT/FRS2 is a lipid anchored docking protein that contains an amino-terminal myristylation signal, followed by a phosphotyrosine-binding (PTB) domain and a carboxy-terminal region with multiple tyrosine residues [33].

Analytical, diagnostic and therapeutic context of DOK1

• We have screened the Dok1 gene for mutations from 46 individuals with B-CLL using heteroduplex analysis [34].
• Confluent cultures of rat bone cells synthesize several forms of secreted phosphoprotein 1 (SPP-1, osteopontin), the major phosphorylated forms of which migrate at 55 and 44 kDa on 15% cross-linked SDS-PAGE gels and correspond to the transformation-associated proteins pp 69 and pp 62 [35].

References