The roles of Dok family adapters in immunoreceptor signaling.
The mammalian Dok protein family has seven members (Dok-1-Dok-7). The Dok proteins share structural similarities characterized by the NH2-terminal pleckstrin homology and phosphotyrosine-binding domains followed by SH2 target motifs in the COOH-terminal moiety, indicating an adapter function. Indeed, Dok-1 was originally identified as a 62 kDa protein that binds with p120 rasGAP, a potent inhibitor of Ras, upon tyrosine phosphorylation by a variety of protein tyrosine kinases. Among the Dok family, only Dok-1, Dok-2, and Dok-3 are preferentially expressed in hematopoietic/immune cells. Dok-1 and its closest relative Dok-2 act as negative regulators of the Ras-Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is believed that recruitment of p120 rasGAP by Dok-1 and Dok-2 is critical to their negative regulation. By contrast, Dok-3 does not bind with p120 rasGAP. However, accumulating evidence has demonstrated that Dok-3 is a negative regulator of the activation of JNK and mobilization of Ca2+ in B-cell receptor-mediated signaling, where the interaction of Dok-3 with SHIP-1 and Grb2 appears to be important. Here, we review the physiological roles and underlying mechanisms of Dok family proteins.
Mashima
Ryuichi
R
Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Hishida
Yukihiro
Y
Tezuka
Tohru
T
Yamanashi
Yuji
Y
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D008213:Lymphocyte Activation; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D020729:p120 GTPase Activating Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C518789:DOK3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C435927:PLEKHA1 protein, human; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D020729:p120 GTPase Activating Protein; D048670:MAP Kinase Kinase 4; D016283:Proto-Oncogene Proteins p21(ras)