Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Immunol Rev. 2009 Nov;232(1):273-85. doi: 10.1111/j.1600-065X.2009.00844.x.
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.
哺乳动物 Dok 蛋白家族有七个成员（Dok-1-Dok-7）。Dok 蛋白具有结构相似性，其特征是 NH2 末端的pleckstrin 同源结构域和磷酸酪氨酸结合结构域，其后是 COOH 末端的 SH2 靶标结构域，表明其具有衔接功能。事实上，Dok-1 最初被鉴定为一种 62 kDa 的蛋白质，在各种蛋白酪氨酸激酶的酪氨酸磷酸化作用下，可与 Ras 抑制剂 p120 rasGAP 结合。在 Dok 家族中，只有 Dok-1、Dok-2 和 Dok-3 优先在造血/免疫细胞中表达。Dok-1 和其最接近的同源物 Dok-2 作为许多免疫受体介导的信号转导系统下游 Ras-Erk 途径的负调节剂，据信，Dok-1 和 Dok-2 通过招募 p120 rasGAP 对其负调节作用至关重要。相比之下，Dok-3 不与 p120 rasGAP 结合。然而，越来越多的证据表明，Dok-3 是 B 细胞受体介导的信号转导中 JNK 激活和 Ca2+动员的负调节剂，其中 Dok-3 与 SHIP-1 和 Grb2 的相互作用似乎很重要。在这里，我们综述了 Dok 家族蛋白的生理作用和潜在机制。
