Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
1] Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
Oncogene. 2014 Jul 31;33(31):4021-35. doi: 10.1038/onc.2013.362. Epub 2013 Sep 16.
The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly in disease by indirect mechanisms. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflects the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2 (epithelial cell transforming squence 2), Tiam1 (T-cell lymphoma invasion and metastasis 1), Vav and P-Rex1/2 (PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-triphosphate)-dependent Rac exchanger).
Ras 同源（Rho）家族小 GTP 酶（20 个人类成员）的异常活性与癌症和其他人类疾病有关。然而，与癌症和发育障碍中发现的 Ras 的直接突变激活相反，Rho GTP 酶通常通过间接机制在疾病中被激活。一种常见的机制涉及通过 Rho 家族鸟嘌呤核苷酸交换因子（RhoGEFs）的失调表达和/或活性导致异常的 Rho 激活。RhoGEFs 促进 Rho GTP 酶形成活性的 GTP 结合状态。最大的 RhoGEF 家族由包含 70 个人类成员的 Dbl 家族 RhoGEFs 组成。激活单个 Rho GTPase 的大量 RhoGEF 反映了每个 RhoGEF 在控制 Rho 激活中涉及的独特信号机制方面的非常具体的作用。在这篇综述中，我们总结了 Dbl RhoGEFs 在发育和疾病中的作用，重点介绍了 Ect2（上皮细胞转化序列 2）、Tiam1（T 细胞淋巴瘤侵袭和转移 1）、Vav 和 P-Rex1/2（PtdIns(3,4,5)P3（磷脂酰肌醇 (3,4,5)-三磷酸）依赖性 Rac 交换蛋白）。
