Disease relevance of Dok2

• 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 [1].

High impact information on Dok2

• FRIP expression is significantly reduced in T cells from hr/hr mice [2].
• Here, we describe a PTB domain protein, FRIP, that is phosphorylated in response to cytokine stimulation [2].
• Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras-Erk signaling downstream of protein tyrosine kinases (PTKs) [3].
• Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling [3].
• However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2 [3].

Biological context of Dok2

• Tyrosine phosphorylation induces DokR to bind the signal relay molecules, RasGTPase-activating protein (RasGAP) and Nck [4].
• Here, we have examined the function of DokR during hematopoietic development and the requirement for RasGAP and Nck binding sites in its biological function [4].
• The molecular basis of the interactions involving DokR with GAP and Nck was investigated using a novel glutathione S-transferase fusion protein binding assay and/or site-directed mutagenesis [5].
• Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia [1].
• Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity [3].

Anatomical context of Dok2

• Most notably, DokR dramatically reduced repopulation of the thymus, in part by reducing the number of T cell precursors seeding in the thymus, but equally, through inhibiting the transition of CD4(-)CD8(-) to CD4(+)CD8(+) T cells [4].
• When introduced into lethally irradiated mice, hematopoietic cells expressing DokR showed a drastically reduced capacity to repopulate lymphoid tissues [4].
• Retroviral-mediated expression of DokR in bone marrow cells dramatically inhibited their capacity to form colonies in vitro in response to the cytokines macrophage colony-stimulating factor and stem cell factor, whereas responses to interleukin-3 and granulocyte macrophage colony-stimulating factor were only weakly affected [4].
• Dok-R is coexpressed with Tek in a number of endothelial cell lines [6].

Associations of Dok2 with chemical compounds

• We found that upon ligand binding, CD200R is phosphorylated on tyrosine and subsequently binds to adapter proteins Dok1 and Dok2 [7].
• Further, they raise the interesting possibility that Dok2 plays an important role in integrin outside-in signaling through a physical and functional interaction with integrin alpha(IIb)beta(3) [8].
• Background: We previously demonstrated that Dok2 is rapidly phosphorylated on tyrosine residues in platelets in response to thrombin, the immunoreceptor tyrosine-based activation motif-coupled collagen receptor glycoprotein (GP) VI, and by integrin alpha(IIb)beta(3) [8].
• A unique autophosphorylation site on Tie2/Tek mediates Dok-R phosphotyrosine binding domain binding and function [9].

Physical interactions of Dok2

• Importantly, functional RasGAP and Nck binding sites were found to be essential for the biological effects of DokR in vitro and in vivo [4].
• Mapping of the phosphotyrosine-interaction domain within Dok-R shows that Dok-R interacts with Tek through a PTB domain [6].

Regulatory relationships of Dok2

• Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites [4].

Other interactions of Dok2

• Dok-3 is a Dok-related adaptor expressed in B cells and macrophages [10].

Analytical, diagnostic and therapeutic context of Dok2

• Immunoprecipitation experiments using DokR-specific antibodies revealed an interaction between endogenous DokR and a 150-kDa protein that is tyrosine-phosphorylated in EGF-stimulated BaF/3 cells [5].

References