Abstract
The rho guanine nucleotide exchange factor H1 (GEF‐H1) is a critical regulator of cytokinesis, but the requirement and mechanism for its timely destruction for proper execution of cytokinesis are unknown. Here we show that GEF‐H1 is regulated by the evolutionarily conserved E3 ligase SCFFbxo45. Fbxo45 promotes GEF‐H1 ubiquitylation upon PLK1‐mediated phosphorylation of GEF‐H1 on serine 644, and this event is necessary for GEF‐H1 degradation during mitosis. Fbxo45 silencing causes stabilization and abnormal cellular distribution of GEF‐H1 with diffuse RhoA hyperactivation. A GEF‐H1 mutant that is unable to bind Fbxo45 is stabilized in mitosis, and results in an uncoordinated hyperactive membrane phenotype, with abnormal aberrant cytokinesis leading to cell death or multinucleation. Our studies provide evidence that limiting activation of the RhoAGTPase via Fbxo45‐mediated degradation of the GEF‐H1 activator is essential for proper execution of cytokinesis. This work was supported by NIH grants R01 DE119249 and R01 CA136905 to KSJ E‐J, R01 CA140806 to MSL.
Published Version
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