Cdc42 prevents precocious Rho1 activation during cytokinesis in a Pak1-dependent manner

Abstract

During cytokinesis a series of coordinated events partition a dividing cell. Accurate regulation of cytokinesis is essential for proliferation and genome integrity. In fission yeast, these coordinated events ensure that the actomyosin ring and septum start ingressing only after chromosome segregation. How cytokinetic events are coordinated remains unclear. The GTPase Cdc42 promotes recruitment of certain cell wall-building enzymes while the GTPase Rho1 activates these enzymes. We show that Cdc42 prevents early Rho1 activation during cytokinesis. Using an active Rho-probe, we find that although the Rho1 activators Rgf1 and Rgf3 localize to the division site in early anaphase, Rho1 is not activated until late anaphase, just before the onset of ring constriction. We find that loss of Cdc42 activation enables precocious Rho1 activation in early anaphase. Furthermore, we provide functional and genetic evidence that Cdc42-dependent Rho1 inhibition is mediated by the Cdc42 target Pak1 kinase. Our work proposes a mechanism of Rho1 regulation by active Cdc42 to coordinate timely septum formation and cytokinesis fidelity.

Regulation of the DLC3 tumor suppressor by a novel phosphoswitch

“…Of note, the biosensor also integrates activities of the closely related RhoB and RhoC, which were shown to partially compensate for RhoA during cytokinesis. 35 Recently, it was reported that timely activation of the RhoA homolog in yeast is dependent on Cdc42, 36 toward which DLC3 also shows some GAP activity. 12 , 37 In addition, previous studies have described the binding of specific lipid species to DLC1 through the PBR directly adjacent to the GAP domain and the carboxyterminal StAR (steroidogenic acute regulatory)-related lipid transfer (START) domain, regulating its GAP activity.…”