Recently, Lao et al. studied how PIAS3, the protein inhibitor of activated signal transducer and activator of transcription 3 (the transcription factor STAT3) regulates the migration, invasion, and activation of fibroblast-like synoviocytes (FLSs), a key component in the pathophysiology of rheumatoid arthritis (RA), specifically joint destruction. Rate of joint destruction is positively correlated with increased FLS motility, invasion, and activity. Here, the authors examined PIAS3-mediated regulation of FLS migration and invasion, and expression of matrix metalloproteinases in RA. Among other findings, PIAS3 knockdown with short hairpin RNA demonstrated that PIAS3 controls lamellipodium formation during FLS migration through activation of Rac1 GTPase as PIAS3 knockdown reduced both the activity of Rac1 and its downstream effector PAK1. Activation of this Rac1 pathway is integral in actin cytoskeleton remodeling which underlies lamellipodium formation and protrusion. Additional results strongly suggest that PIAS3-mediated regulation of Rac1 activation involves SUMOylation (specifically SUMO-1) of Rac1 by PIAS3, as it can act as a SUMO-E3 ligase. Cytoskeleton's Rac1 G-LISA activation assay kit (Cat. # BK128) was an essential reagent in this study, providing a sensitive and quantitative measurement of Rac1 activity following PIAS3 knockdown. These results expand understanding of the molecular pathways regulating FLS migration, invasion, and activation, and the subsequent joint destruction the cells mediate in RA.