SCFFbxw5 mediates transient degradation of actin remodeller Eps8 to allow proper mitotic progression

Nat Cell Biol. 2013 Feb;15(2):179-88. doi: 10.1038/ncb2661. Epub 2013 Jan 13.

Abstract

Eps8, a bi-functional actin cytoskeleton remodeller, is a positive regulator of cell proliferation and motility. Here, we describe an unrecognized mechanism regulating Eps8 that is required for proper mitotic progression: whereas Eps8 is stable in G1 and S phase, its half-life drops sharply in G2. This requires G2-specific proteasomal degradation mediated by the ubiquitin E3 ligase SCF(Fbxw5). Consistent with a short window of degradation, Eps8 disappears from the cell cortex early in mitosis, but reappears at the midzone of dividing cells. Failure to reduce Eps8 levels in G2 prolongs its localization at the cell cortex and markedly delays cell rounding and prometaphase duration. However, during late stages of mitosis and cytokinesis, Eps8 capping activity is required to prevent membrane blebbing and cell-shape deformations. Our findings identify SCF(Fbxw5)-driven fluctuation of Eps8 levels as an important mechanism that contributes to cell-shape changes during entry into-and exit from-mitosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Binding, Competitive
  • Cell Shape*
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • G2 Phase Cell Cycle Checkpoints
  • HEK293 Cells
  • Half-Life
  • HeLa Cells
  • Humans
  • Metaphase
  • Mice
  • Mice, Knockout
  • Microscopy, Video
  • Mitosis*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Stability
  • Proteolysis
  • RNA Interference
  • Time Factors
  • Transfection
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • EPS8 protein, human
  • Eps8 protein, mouse
  • F-Box Proteins
  • FBXW5 protein, human
  • Proteasome Endopeptidase Complex