Rga4 Modulates the Activity of the Fission Yeast Cell Integrity MAPK Pathway by Acting as a Rho2 GTPase-activating Protein

Pilar Pérez,Jero Vicente,Marisa Madrid,Teresa Soto,Maria Antonia Villar-Tajadura,José Cansado,Mariano Gacto

doi:10.1074/jbc.m109.071027

Abstract

Rho GTPase-activating proteins (GAPs) are responsible for the inactivation of Rho GTPases, which are involved in the regulation of critical biological responses in eukaryotic cells, ranging from cell cycle control to cellular morphogenesis. The genome of fission yeast Schizosaccharomyces pombe contains six genes coding for putative Rho GTPases, whereas nine genes code for predicted Rho GAPs (Rga1 to Rga9). One of them, Rga4, has been recently described as a Cdc42 GAP, involved in the control of cell diameter and symmetry in fission yeast. In this work we show that Rga4 is also a Rho2 GAP that negatively modulates the activity of the cell integrity pathway and its main effector, MAPK Pmk1. The DYRK-type protein kinase Pom1, which regulates both the localization and phosphorylation state of Rga4, is also a negative regulator of the Pmk1 pathway, but this control is not dependent upon the Rga4 role as a Rho2-GAP. Hence, two subsets of Rga4 negatively regulate Cdc42 and Rho2 functions in a specific and unrelated way. Finally, we show that Rga7, another Rho2 GAP, down-regulates the Pmk1 pathway in addition to Rga4. These results reinforce the notion of the existence of complex mechanisms determining the selectivity of Rho GAPs toward Rho GTPases and their functions.

Highlights

GDP for GTP to activate the switch [4]; (ii) GTPase-activating proteins (GAPs)5 that stimulate the intrinsic GTPase activity to inactivate the switch [5]; and (iii) guanine nucleotide dissociation inhibitors, whose role appears to block spontaneous activation [1]
We have recently reported the characterization of Rga2 as a Rho2 GAP that plays a role in the regulation of cell morphogenesis and the cell integrity MAPK pathway [26]
In this paper we present evidence to show that Rga4 is a Rho2 GAP that negatively regulates the activity of the Pmk1 cell integrity pathway and that this role is independent of its function as a GAP for Cdc42

Summary

Introduction

GDP for GTP to activate the switch [4]; (ii) GTPase-activating proteins (GAPs)5 that stimulate the intrinsic GTPase activity to inactivate the switch [5]; and (iii) guanine nucleotide dissociation inhibitors, whose role appears to block spontaneous activation [1]. In this paper we present evidence to show that Rga4 is a Rho2 GAP that negatively regulates the activity of the Pmk1 cell integrity pathway and that this role is independent of its function as a GAP for Cdc42.

Results

Conclusion