The roles of Dok family adapters in immunoreceptor signaling

Summary: The mammalian Dok protein family has seven members (Dok‐1–Dok‐7). The Dok proteins share structural similarities characterized by the NH 2 ‐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 Ca 2+ 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.