Regulation of Cdc42 protein turnover modulates the filamentous growth MAPK pathway

Abstract

González and Cullen demonstrate that the Rho GTPase Cdc42 is degraded by a NEDD4 ubiquitin ligase and HSP40 and HSP70 proteins to regulate the activity of the protein. Moreover, a Cdc42p-interacting protein prevents its degradation to control the filamentous growth MAPK pathway.

Abstract

Rho GTPases are central regulators of cell polarity and signaling. How Rho GTPases are directed to function in certain settings remains unclear. Here, we show the protein levels of the yeast Rho GTPase Cdc42p are regulated, which impacts a subset of its biological functions. Specifically, the active conformation of Cdc42p was ubiquitinated by the NEDD4 ubiquitin ligase Rsp5p and HSP40/HSP70 chaperones and turned over in the proteasome. A GTP-locked (Q61L) turnover-defective (TD) version, Cdc42p ^Q61L+TD, hyperactivated the MAPK pathway that regulates filamentous growth (fMAPK). Cdc42p ^Q61L+TD did not influence the activity of the mating pathway, which shares components with the fMAPK pathway. The fMAPK pathway adaptor, Bem4p, stabilized Cdc42p levels, which resulted in elevated fMAPK pathway signaling. Our results identify Cdc42p turnover regulation as being critical for the regulation of a MAPK pathway. The control of Rho GTPase levels by stabilization and turnover may be a general feature of signaling pathway regulation, which can result in the execution of a specific developmental program.