SUMOylation of the GTPase Rac1 is required for optimal cell migration

Abstract

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.

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

“…These results suggest that overexpression of PIAS3 may contribute to aberrant migration and invasion of RA FLSs. Consistent with our findings, PIAS3 knockdown decreased directional migration of HEK293T cells (17). PIASy also enhanced migration of epithelial cells (16).…”

“…For example, PIASy enhances epithelial cell migration through alteration of C/EBPd nuclear localization and reduction of C/EBPd transcriptional activity (16). PIAS3 controls migration by SUMOylation of Rac1 (17). Although previous reports have shown the role of SUMO in synovial proliferation and inflammation of RA (18,19), it is still unclear whether PIAS proteins are involved in the pathogenic FLSs behavior observed in RA.…”

Rho GTPases: Regulation and roles in cancer cell biology

“…The only Rho GTPase that is known to be regulated by SUMOylation is Rac1, which becomes more active following addition of SUMO close to its C-terminus. 38 Phosphorylation is another covalent modification that regulates Rho GTPases. Some protein kinases such as PKA, ROCK1, Src and Akt have been shown to phosphorylate RhoA, Rnd3 (RhoE), Cdc42 and Rac1, respectively.…”

The Rac1 hypervariable region in targeting and signaling

“…Castillo-Lluva showed that Rac1 can be sumoylated on lysine residues in the PBR, promoting its activation and the induction of cell migration and invasion. 137 This post-translational modification is distinct from Rac1 ubiquitylation, which occurs on Lys147 and triggers its degradation. 88 Preventing Rac1 sumoylation did not alter its localization to membranes, nor the binding to GEFs and effector proteins, but did reduce GTP binding.…”