Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth
Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth
复制标题
DOI：
10.1016/j.yexcr.2006.11.017
复制
发表时间：
2007-02-15
影响因子：
3.7
通讯作者：
Tanoue, Akito
中科院分区：
文献类型：
--
作者：
Miyamoto, Yuki;Yamauchi, Junji;Tanoue, Akito
Rho家族的小GTP酶Rho、Rac和Cdc 42是肌动蛋白细胞骨架变化的关键调节因子。Rho GTP酶通常被含有Dbl-同源（DH）结构域的鸟嘌呤核苷酸交换因子（GEF）激活。最近的遗传和生物化学研究揭示了Rho GTP酶的一种新型GEF。该家族由11个基因组成，命名为Dock 1至Dock 11，并且在结构上分为Dock-A、-B、-C和-D四类。Dock-A和-B亚家族通常是对Rac 1特异的GEF，而Dock-D亚家族对Cdc 42特异。在这里，我们表明Dock 6，Dock-C亚家族的成员，在体外和体内将GDP交换为Racl和Cdc 42的GTP。此外，我们发现，在小鼠N1 E-115神经母细胞瘤细胞中，分化后Dock 6的表达增加。Dock 6的催化性Dock同源区-2（DHR-2）结构域的转染促进由Rac 1和Cdc 42介导的神经突生长。相反，通过小干扰RNA敲低内源性Dock 6减少了Racl和Cdc 42的活化和神经突生长。综上所述，这些结果表明，Dock 6不同于所有鉴定的Dock 180相关蛋白，因为它是Racl和Cdc 42特异性的GEF，并且可能是神经突生长的生理调节因子之一。(c)2006年爱思唯尔公司All rights reserved.
Small GTPases of the Rho family, Rho, Rac, and Cdc42, are critical regulators of the changes in the actin cytoskeleton. Rho GTPases are typically activated by Dbl-homology (DH)domain- containing guanine nucleotide exchange factors (GEFs). Recent genetic and biochemical studies revealed a new type of GEF for the Rho GTPases. This family is composed of 11 genes, designated as Dock1 to Dock11, and is structurally divided into four classes Dock-A, -B, -C, and -D. Dock-A and -B subfamilies are typically GEFs specific for Rac1, while the Dock-D subfamily is specific for Cdc42. Here we show that Dock6, a member of the Dock-C subfamily, exchanges GDP for GTP for Racl and Cdc42 in vitro and in vivo. Furthermore, we find that, in mouse N1E-115 neuroblastoma cells, expression of Dock6 is increased following differentiation. Transfection of the catalytic Dock Homology Region-2 (DHR-2) domain of Dock6 promotes neurite outgrowth mediated by Rac1 and Cdc42. Conversely, knockdown of endogenous Dock6 by small interference RNA reduces activation of Racl and Cdc42 and neurite outgrowth. Taken together, these results suggest that Dock6 differs from all of the identified Dock180-related proteins, in that it is the GEF specific for both Racl and Cdc42 and may be one of physiological regulators of neurite outgrowth. (c) 2006 Elsevier Inc. All rights reserved.