ARHGEF17/TEM4 regulates the cell cycle through control of G1 progression

Abstract

The Ras homolog (Rho) small GTPases coordinate diverse cellular functions including cell morphology, adhesion and motility, cell cycle progression, survival, and apoptosis via their role in regulating the actin cytoskeleton. The upstream regulators for many of these functions are unknown. ARHGEF17 (also known as TEM4) is a Rho family guanine nucleotide exchange factor (GEF) implicated in cell migration, cell-cell junction formation, and the mitotic checkpoint. In this study, we characterize the regulation of the cell cycle by TEM4. We demonstrate that TEM4-depleted cells exhibit multiple defects in mitotic entry and duration, spindle morphology, and spindle orientation. In addition, TEM4 insufficiency leads to excessive cortical actin polymerization and cell rounding defects. Mechanistically, we demonstrate that TEM4-depleted cells delay in G1 as a consequence of decreased expression of the proproliferative transcriptional co-activator YAP. TEM4-depleted cells that progress through to mitosis do so with decreased levels of cyclin B as a result of attenuated expression of CCNB1. Importantly, cyclin B overexpression in TEM4-depleted cells largely rescues mitotic progression and chromosome segregation defects in anaphase. Our study thus illustrates the consequences of Rho signaling imbalance on cell cycle progression and identifies TEM4 as the first GEF governing Rho GTPase-mediated regulation of G1/S.