GEF-H1: orchestrating the interplay between cytoskeleton and vesicle trafficking

Abstract

Vesicle trafficking is crucial for delivery of membrane compartments as well as signaling molecules to specific sites on the plasma membrane for regulation of diverse processes such as cell division, migration, polarity establishment and secretion. Rho GTPases are well-studied signaling molecules that regulate actin cytoskeleton in response to variety of extracellular stimuli. Increasing amounts of evidence suggest that Rho proteins play a critical role in vesicle trafficking in both the exocytic and endocytic pathways; however, the molecular mechanism underlying the process remains largely unclear. We recently defined a mechanism of action for RhoA in membrane trafficking pathways through regulation of the octameric complex exocyst in a manuscript published in Developmental Cell. We have shown that microtubule-associated RhoA-activating factor GEF-H1 is involved in endocytic and excocytic vesicle trafficking. GEF-H1 activates RhoA in response to RalA GTPase, which in turn regulates the localization and the assembly of exocyst components and exocytosis. Our work defines a mechanism for RhoA activation in response to RalA signaling and during vesicle trafficking. These results provide a framework for understanding how RhoA/GEF-H1 regulates the coordination of actin and microtubule cytoskeleton modulation and vesicle trafficking during migration and cell division.

Keywords: GEF-H1; Rho GTPase; endocytic recycling; exocyst; exocytosis; vesicle fusion; vesicle trafficking.

Figure 1. A putative model for the regulation of membrane trafficking by GEF-H1/RhoA pathway. (A) Vesicles carrying exocyst components, and possibly RhoA, are targeted to specific sites marked by Exo70 at the PM using microtubules as tracks. (B) GEF-H1 associated with microtubules is inactive. Upon microtubule depolymerization, GEF-H1 is released and then binds directly with the exocyst component Sec5. (C) The interaction between exocyst and GEF-H1 leads to RhoA activation in the vicinity of vesicles. (D) RhoA in turn regulates the exocyst function by affecting the complex formation which then promotes the fusion of vesicles.