Vav2 is an activator of Cdc42, Rac1, and RhoA
Vav2 is an activator of Cdc42, Rac1, and RhoA
复制标题
DOI：
10.1074/jbc.275.14.10141
复制
发表时间：
2000-04-07
影响因子：
4.8
通讯作者：
Der, CJ
中科院分区：
文献类型：
--
作者：
Abe, K;Rossman, KL;Der, CJ
Vav 和 Vav2 是 Dbl 蛋白家族的成员，充当 Rho 家族蛋白的鸟嘌呤核苷酸交换因子 (GEF)。 Vav 表达仅限于造血来源的细胞，而 Vav2 则广泛表达。尽管 Vav 和 Vav2 在其 Dbl 同源域中具有高度相关的结构相似性和高序列同一性，但据报道，它们是活性 GEF，对 Rho 家族成员具有不同的底物特异性。 Vav 对 Rac1、Cdc42、RhoA 和 RhoG 显示 GEF 活性，而据报道 Vav2 对 RhoA、RhoB 和 RhoG 显示 GEF 活性，但对 Rad 或 Cdc42 不显示 GEF 活性。与它们不同的底物靶标一致，我们发现组成型激活的 Vav 和 Vav2 在 NIH 3T3 细胞中表达时会引起不同的转化表型。与之前的研究结果相反，我们发现 Vav2 在体外可以充当 Cdc42、Rac1 和 RhoA 的有效 GEF。此外，我们发现 NH2 末端截短并激活的 Vav 和 Vav2 在需要 Cdc42、Rad 和 RhoA 功能的 NIH 3T3 细胞中引起难以区分的转化作用。此外，与Vav和Rad一样，我们发现Vav2激活Jun NH2末端激酶级联反应，并导致NIH 3T3细胞中板状伪足和膜皱褶的形成。最后，Vav2 转化的 NIH 3T3 细胞显示 Rac-GTP 水平上调。我们得出结论，Vav2 和 Vav 共享重叠的下游靶标，并且是多个 Rho 家族蛋白的激活剂。因此，Vav2 在非造血细胞中可能介导与 Vav 在造血细胞中相同的细胞后果。
Vav and Vav2 are members of the Dbl family of proteins that act as guanine nucleotide exchange factors (GEFs) for Rho family proteins. Whereas Vav expression is restricted to cells of hematopoietic origin, Vav2 is widely expressed. Although Vav and Vav2 share highly related structural similarities and high sequence identity in their Dbl homology domains, it has been reported that they are active GEFs with distinct substrate specificities toward Rho family members. Whereas Vav displayed GEF activity for Rac1, Cdc42, RhoA, and RhoG, Vav2 was reported to exhibit GEF activity for RhoA, RhoB, and RhoG but not for Rad or Cdc42. Consistent with their distinct substrate targets, it was found that constitutively activated versions of Vav and Vav2 caused distinct transformed phenotypes when expressed in NIH 3T3 cells. In contrast to the previous findings, we found that Vav2 can act as a potent GEF for Cdc42, Rac1, and RhoA in vitro. Furthermore, we found that NH2-terminally truncated and activated Vav and Vav2 caused indistinguishable transforming actions in NIH 3T3 cells that required Cdc42, Rad, and RhoA function. In addition, like Vav and Rad, we found that Vav2 activated the Jun NH2-terminal kinase cascade and also caused the formation of lamellipodia and membrane ruffles in NIH 3T3 cells. Finally, Vav2-transformed NIH 3T3 cells showed up-regulated levels of Rac-GTP. We conclude that Vav2 and Vav share overlapping downstream targets and are activators of multiple Rho family proteins. Therefore, Vav2 may mediate the same cellular consequences in nonhematopoietic cells as Vav does in hematopoietic cells.