SUMOylation of the GTPase Rac1 is required for optimal cell migration

The Rho-like GTPase Rac1 induces cytoskeletal rearrangements required for cell migration. Rac activity is regulated through a number of mechanisms, including control of nucleotide exchange and hydrolysis, regulation of subcellular localization, or modulation of protein expression levels1-3. Here, we identify the Small Ubiquitin-like MOdifier (SUMO) E3-ligase, PIAS3, as a new Rac1 interactor required for increased Rac activity and optimal cell migration in response to Hepatocyte Growth Factor (HGF) signalling. We show that Rac1 can be conjugated to SUMO-1 in response to HGF and that SUMOylation is enhanced by PIAS3. Moreover, we identify non-consensus sites within the polybasic region of Rac1 as the main locations for SUMO conjugation. We demonstrate that PIAS3-mediated SUMOylation of Rac1 controls its GTP-bound levels and its ability to stimulate lamellipodia, cell migration and invasion. This is the first time that a Ras superfamily member is found to be SUMOylated, providing a new insight into the regulation of these critical mediators of cell behaviour. Moreover, our data reveal a previously undescribed role for SUMO in the regulation of cell migration and invasion.