Disease relevance of Dok1

• Dok1 encoding p62(dok) maps to mouse chromosome 6 and human chromosome 2 in a region of translocation in chronic lymphocytic leukemia [1].
• Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia [2].
• Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML [3].
• Inhibition of the motility and growth of B16F10 mouse melanoma cells by dominant negative mutants of Dok-1 [4].
• The docking protein CD2AP (CD2-associated protein) serves a nonredundant function in podocytes as CD2AP knockout mice die of renal failure at the age of 6-7 wk [5].

High impact information on Dok1

• FRS2 functions as a lipid-anchored docking protein that targets signaling molecules to the plasma membrane in response to FGF stimulation to link receptor activation with the MAPK and other signaling pathways essential for cell growth and differentiation [6].
• Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling [7].
• Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras-Erk signaling downstream of protein tyrosine kinases (PTKs) [8].
• Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia [2].
• We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells [3].

Chemical compound and disease context of Dok1

• Overexpression of each of the mutants in highly metastatic B16F10 mouse melanoma cells thus both inhibited the tyrosine phosphorylation of endogenous Dok-1 induced by cell adhesion as well as reduced the association of the endogenous protein with cellular membranes and the cytoskeleton [4].
• In the present study, we have immunocaptured a cell surface complex from B16 mouse melanoma cells which contains alpha 6 beta 1 integrin, two molecular forms of calreticulin, and KDEL docking protein (KDEL-R) [9].
• The effect of HSV-1 infection on the shut-off of the cellular genes (or mRNA degradation) was studied specifically with the cellular genes for beta-actin, fibronectin, glucose transporter-1, and the docking protein [10].

Biological context of Dok1

• When activated by cell adhesion, c-Abl phosphorylates Y361 of Dok1, promoting its association with the Src homology 2 domain (SH2)/SH3 adaptor protein Nck [11].
• A nuclear export signal and phosphorylation regulate Dok1 subcellular localization and functions [12].
• Functionally, nuclear NES-mutant Dok1 had impaired ability to inhibit cell proliferation and to promote cell spreading and cell motility [12].
• Dok1 is believed to be a mainly cytoplasmic adaptor protein which down-regulates mitogen-activated protein kinase activation, inhibits cell proliferation and transformation, and promotes cell spreading and cell migration [12].
• Analysis by site-directed mutagenesis revealed that tyrosine 361 in mouse Dok1 represents a binding site for the Nck adaptor protein and tyrosines 295, 314, 361, 376, 397, and 408 for the Ras-GTPase-activating protein [13].

Anatomical context of Dok1

• c-Abl phosphorylates Dok1 to promote filopodia during cell spreading [11].
• Using an unbiased approach, we identified Dok1 as a specific c-Abl substrate in spreading fibroblasts [11].
• Our data suggest a novel pathway by which c-Abl transduces signals to the actin cytoskeleton through phosphorylating Dok1 Y361 and recruiting Nck [11].
• These data indicate that both SHIP and Dok1 functionally regulate the activation of Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bone marrow cells [14].
• 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 [15].

Associations of Dok1 with chemical compounds

• Src-induced tyrosine phosphorylation prevented the LMB-mediated nuclear accumulation of Dok1 [12].
• Here we report the crystal structure of the Dok1 PTB domain alone and in complex with a phosphopeptide derived from RET receptor tyrosine kinase [16].
• The N-terminal phosphotyrosine binding (PTB) domain of Dok1 can recognize and bind specifically to phosphotyrosine-containing motifs of receptors [16].
• Because the SH2-containing inositol 5'-phosphatase (SHIP) and Downstream of tyrosine kinase 1 (Dok1) have been shown to interact with Abl, the effect of SHIP and Dok1 deficiency on v-Abl transformation was investigated [14].
• Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin alphabeta [17].

Physical interactions of Dok1

• Addition of the K-Ras membrane-targeting motif to Dok-1 generated a constitutively membrane-bound Dok-1 protein whose tyrosine phosphorylation was independent of PI 3-kinase [18].
• However, the Dok-1 mutant having YF substitutions at the rasGAP-binding sites (Tyr-295 and Tyr-361) also showed incapability of Ras and Erk inhibition [19].

Enzymatic interactions of Dok1

• Crk-associated substrate (Cas) is a tyrosine-phosphorylated docking protein that is indispensable for the regulation of the actin cytoskeletal organization and cell migration in fibroblasts [20].

Regulatory relationships of Dok1

• Lyn promoted phosphorylation of c-Kit and association of c-Kit and Dok-1 [18].
• Here we show that stimulation of Mo7 hematopoietic cells with c-Kit ligand (KL) induces phosphatidylinositol (PI) 3-kinase-dependent tyrosine phosphorylation and membrane recruitment of Dok-1 [18].
• Mutations of this domain or Tyr(146) that block homodimerization significantly reduce the ability of Dok to inhibit Src transformation [21].

Other interactions of Dok1

• Complementation of SHIP(-/-) or Dok1(-/-) cells abrogates their hyperproliferation and intracellular Erk activation [14].
• Furthermore, treatment of these cells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increased proliferation of SHIP(-/-) or Dok1(-/-) cells in a dose-dependent manner [14].
• The RET phosphopeptide binds to Dok1 via a surface groove formed between strand beta5 and the C-terminal alpha-helix of the PTB domain [16].
• Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling [18].
• However, the use of primary bone marrow mast cells from normal and Lyn-deficient mice demonstrated that Lyn is required for KL-dependent Dok-1 tyrosine phosphorylation [18].

Analytical, diagnostic and therapeutic context of Dok1

• These results identify Dok as a signal transducer that potentially links, through its interaction with NCK or rasGAP, cell adhesion and insulin receptors to the machinery that controls cell motility [22].
• The docking protein Gab1 binds phosphorylated c-Met receptor tyrosine kinase directly and mediates signals of c-Met in cell culture [23].
• Aeginetia indica Roxbert (Dok Din Daeng, DDD), a parasitic plant that grows on bamboo, is extensively used in Thai traditional medicine to treat various diseases [24].

References