Functions and regulation of Dbl-family guanine nucleotide exchange factors

描述（由申请人提供）：Rho GTP酶起二元开关的作用，从GDP结合的“关闭”状态循环到GTP结合的“开启”状态，能够接合无数效应物以协调通常需要细胞骨架变化的过多细胞应答。例如，需要Rho GTP酶的细胞应答包括：趋化性、分化和分裂、伤口愈合、吞噬作用、轴突寻路和极化分泌。与Rho GTP酶结合的鸟嘌呤核苷酸的循环在几个点上受到严格控制。特别地，鸟嘌呤核苷酸交换因子（GEF）直接结合Rho GTP酶以加速结合的GDP的排出和GTP的加载。在人类中具有大约70个成员，Dbl蛋白质家族代表了Rho GTP酶的最大GEF组。所有Dbl家族成员都具有接合Rho GTP酶和催化交换所必需的特征性Dbl同源（DH）结构域。普列克底物蛋白同源（PH）结构域被发现紧邻绝大多数DH结构域的C-末端。这些相关的PH结构域的性质尚未完全了解，但一般来说，这种串联连接用于协调Rho GT3激活与特定磷酸肌醇与DH相关PH结构域的结合。考虑到Db 1家族GEF在调节Rho GTP酶激活中的重要性以及这些GTP酶对细胞生物学的许多方面的中心作用，我们大量投资于了解这些交换因子的调节及其在控制生物事件中的相关作用。因此，本申请具有三个具体目的：1.定义调节Dbl-家族GEF的自抑制的保守机制。2.确定Dbl家族GEF的一个子集在癌症和神经元发育中的作用。3.确定DH/PH盒协同功能的一般机制。 公共卫生相关性：Rho GTP酶的失调激活通常由Dbl家族鸟嘌呤核苷酸交换因子（GEF）介导，与许多发育、免疫和增殖性疾病（包括癌症）相关。拟议的工作旨在阐明Dbl家族GEF调节Rho GTP酶激活的保守机制，并将这种调节置于癌症进展和神经元发育模型的背景下。

DESCRIPTION (provided by applicant): Rho GTPases function as binary switches, cycling from GDP-bound "off" states to GTP-bound "on" states capable of engaging myriad effectors to coordinate a plethora of cellular responses that typically require changes in the cytoskeleton. For example, cellular responses that require Rho GTPases include: chemotaxis, differentiation and division, wound-healing, phagocytosis, axonal pathfinding, and polarized secretion. The cycling of guanine nucleotides bound to Rho GTPases is tightly controlled at several points. In particular, guanine nucleotide exchange factors (GEFs) directly bind Rho GTPases to accelerate the ejection of bound GDP and the loading of GTP. With approximately seventy members in humans, the Dbl-family of proteins represents the largest groups of GEFs for Rho GTPases. All Dbl-family members possess a characteristic Dbl homology (DH) domain necessary to engage Rho GTPases and catalyze exchange. A pleckstrin homology (PH) domain is found immediately C-terminal to the vast majority of DH domains. The nature of these associated PH domains is not fully understood, but in general, this tandem linkage serves to coordinate Rho GTPase activation with the binding of specific phosphoinositides to the DH-associated PH domains. Given the importance of Dbl-family GEFs in regulating the activation of Rho GTPases and the central role of these GTPases to numerous facets of cell biology, we are heavily invested in understanding the regulation of these exchange factors and their associated roles in controlling biological events. Accordingly, this application has three specific aims: 1. To define conserved mechanisms regulating the auto-inhibition of Dbl-family GEFs. 2. To define roles for a subset of Dbl-family GEFs in cancer and neuronal development. 3. To define general mechanisms underlying the cooperative functioning of DH/PH cassettes. Public Health Relevance: The dysregulated activation of Rho GTPases, often mediated by Dbl-family guanine nucleotide exchange factors (GEFs), is associated with numerous developmental, immunological, and proliferative diseases, including cancer. The proposed work is designed to illuminate conserved mechanisms regulating the activation of Rho GTPases by Dbl-family GEFs and to place this regulation within the context of models of cancer progression and neuronal development.