Regulating Rac in the nervous system: molecular function and disease implication of Rac GEFs and GAPs.

Yanyang Bai,Xiaoliang Xiang,Chunmei Liang,Lei Shi

doi:10.1155/2015/632450

Yanyang Bai, Xiaoliang Xiang + Show 2 more

Open Access

https://doi.org/10.1155/2015/632450

Copy DOI

Abstract

Rho family GTPases, including RhoA, Rac1, and Cdc42 as the most studied members, are master regulators of actin cytoskeletal organization. Rho GTPases control various aspects of the nervous system and are associated with a number of neuropsychiatric and neurodegenerative diseases. The activity of Rho GTPases is controlled by two families of regulators, guanine nucleotide exchange factors (GEFs) as the activators and GTPase-activating proteins (GAPs) as the inhibitors. Through coordinated regulation by GEFs and GAPs, Rho GTPases act as converging signaling molecules that convey different upstream signals in the nervous system. So far, more than 70 members of either GEFs or GAPs of Rho GTPases have been identified in mammals, but only a small subset of them have well-known functions. Thus, characterization of important GEFs and GAPs in the nervous system is crucial for the understanding of spatiotemporal dynamics of Rho GTPase activity in different neuronal functions. In this review, we summarize the current understanding of GEFs and GAPs for Rac1, with emphasis on the molecular function and disease implication of these regulators in the nervous system.

Highlights

Rho family GTPases constitute a distinct family of guanine nucleotide-binding proteins which belongs to the superfamily of Ras-related GTPases
Activity of Rho GTPases is tightly controlled by the coordinated action of two classes of regulatory proteins: guanine nucleotide exchange factors (GEFs), which activate Rho GTPases by catalyzing the exchange of bound GDP for GTP, enabling them to recognize and activate downstream effectors, and GTPase-activating proteins (GAPs), which suppress Rho GTPases by enhancing their intrinsic rate of GTP hydrolysis to GDP
DHR1-DHR2 module plays similar roles as PH-DH module, of which DHR1 is important for the phospholipid-binding and membrane targeting of Docks, and DHR2 is responsible for its GEF activity [9]

Summary

Introduction

The DH domain is known to be responsible for the catalytic exchange activity of Rho GEFs, whereas the PH domain regulates lipid binding and membrane targeting Another type of GEFs is the Dock (dedicator of cytokinesis) family atypical GEFs, which contains a Dock homology region (DHR) 1-DHR2 module instead of the PH-DH module. To understand the spatiotemporally dynamic regulation of Rac activity in the nervous system, this review summarizes the current findings of more than 30 Rac GEFs (including both the Dbl-like and atypical GEFs) and GAPs (Table 1) Both the molecular functions and the disease relevance of these regulators in the nervous system will be discussed. Most of these Rac GEFs or GAPs act on other Rho GTPases (such as RhoA or Cdc42) or even other subfamilies of Ras-related GTPases (such as Ras and Rab). We will emphasize their actions on Rac and will try to discuss how their actions on Rac or other GTPases are differentially regulated

Dbl-Like Rac GEFs

Dock Family Atypical Rac GEFs

Rac GAPs