Ubiquitin-mediated regulation of RhoGTPase signalling: IAPs and HACE1 enter the fray.

Activation of members of the Rho-like family of guanosine triphosphatases GTPases (RhoGTPases) controls diverse physiological processes and is frequently found in cancer, contributing to tumour malignancy, cancer cell migration, invasion and metastasis. While the regulation of nucleotide binding to RhoGTPases is well understood, little is currently known regarding the molecular mechanisms through which RhoGTPase signalling is regulated by ubiquitylation. Two reports in this issue of The EMBO Journal and Developmental Cell now identify inhibitor of apoptosis (IAP) proteins and HACE1 as E3 ubiquitin (Ub)-protein ligases for Rac1 regulating Rac1 levels and activity. Most members of the RhoGTPase protein family function as molecular switches that cycle between an inactive GDPbound form and an active GTP-bound state (Vega and Ridley, 2008). Binding of GTP to RhoGTPases, such as Rac1, triggers a conformational change that allows binding and activation of downstream effector proteins, through which Rac1 modulates actin assembly, actomyosin contractility, and microtubule formation. Activation of RhoGTPases, and hence their potential to interact with downstream signalling molecules, is influenced by a range of auxiliary proteins. Guanine-nucleotide exchange factors (GEFs) catalyse the exchange of GDP for GTP, thus activating the RhoGTPase. By contrast, GTPaseactivating proteins (GAPs) promote the intrinsic GTPase activity, thereby accelerating the hydrolysis of GTP to GDP and returning RhoGTPases to their inactive configuration. RhoGTPases can also be kept inactive by association with