Rho GTPases are small enzymes with important roles in essential cell functions such as migration, mitosis and cytokinesis. Rho GTPase activity is typically regulated by co-factors including GTPase-activating proteins (GAPs), guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). The atypical Rho GTPase RhoU, however, does not bind to GDIs, and has not yet been associated with any GAPs or GEFs. RhoU expression is significantly elevated in prostate cancer, where it has been suggested to influence invasive cell migration behaviour via regulation of focal adhesions. In this Short Report (Clayton et al., 2024), Anne Ridley and colleagues investigate alternative mechanisms of RhoU activation in PC3 prostate cancer cells. Unexpectedly, they find that RhoU can self-associate to form homo-oligomers in vitro and in living cells. The self-interaction of RhoU is dependent on a unique C-terminal region not found in other Rho GTPases. In support of a function for RhoU in cell migration, overexpression of a C-terminal RhoU fragment in PC3 cells competitively inhibits homo-oligomerisation of endogenous RhoU, which reduces activation of p21-activated kinase 2 (PAK2) and suppresses migratory cell phenotypes. This study therefore uncovers the first instance of a Rho GTPase family member that can be activated via self-association and improves our understanding of the role of this prognostic prostate cancer marker.
