SCF FBXW17 E3 ubiquitin ligase regulates FBXL19 stability and cell migration

The Skp1‐Cul1‐F‐box protein (SCF) E3 ligase complex is one of the largest ubiquitin E3 ligase families. FBXL19, a F‐box protein in SCFFBXL19 E3 ligase complex, regulates a variety of cellular responses including cell migration. We have shown that FBXL19 is not stable and its degradation is mediated by the ubiquitin–proteasome system, while the ubiquitin E3 ligase for FBXL19 ubiquitination and degradation has not been identified. In the study, we discovered that a new ubiquitin E3 ligase, SCFFBXW17, ubiquitinates and induces FBXL19 degradation. Exogenous FBXW17 targets FBXL19 for its ubiquitination and degradation. Lysine 114 in FBXL19 is a potential ubiquitin acceptor site. Acetylation of FBXL19 attenuated SCFFBXW17‐mediated FBXL19 degradation. SCFFBXL19 E3 ligase reduced Rac1 levels and cell migration, while the effects were attenuated by exogenous FBXW17. Downregulation of FBXW17 attenuated lysophosphatidic acid‐induced lamellipodia formation and Rac1 accumulation at migration leading edge. Taken together with our previous studies, FBXL19 is degraded by the ubiquitin–proteasome system and its site‐specific ubiquitination is mediated by SCFFBXW17 E3 ligase, which promotes cell migration. In the current study, we reveal the molecular regulation of FBXL19 by a new SCF E3 ligase, SCFFBXW17, that has not been described previously in any system. Further, we show that acetylation of FBXL19 attenuates SCFFBXW17‐mediated FBXL19 degradation. A new cellular function of FBXW17 is discovered in this study.