A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis

EMBO J. 2006 Oct 18;25(20):4740-51. doi: 10.1038/sj.emboj.7601324. Epub 2006 Oct 5.

Abstract

Cytosolic division in mitotic cells involves the function of a number of cytoskeletal proteins, whose coordination in the spatio-temporal control of cytokinesis is poorly defined. We studied the role of p85/p110 phosphoinositide kinase (PI3K) in mammalian cytokinesis. Deletion of the p85alpha regulatory subunit induced cell accumulation in telophase and appearance of binucleated cells, whereas inhibition of PI3K activity did not affect cytokinesis. Moreover, reconstitution of p85alpha-deficient cells with a Deltap85alpha mutant, which does not bind the catalytic subunit, corrected the cytokinesis defects of p85alpha(-/-) cells. We analyzed the mechanism by which p85alpha regulates cytokinesis; p85alpha deletion reduced Cdc42 activation in the cleavage furrow and septin 2 accumulation at this site. As Cdc42 deletion also triggered septin 2 and cytokinesis defects, a mechanism by which p85 controls cytokinesis is by regulating the local activation of Cdc42 in the cleavage furrow and in turn septin 2 localization. We show that p85 acts as a scaffold to bind Cdc42 and septin 2 simultaneously. p85 is thus involved in the spatial control of cytosolic division through regulation of Cdc42 and septin 2, in a PI3K-activity independent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Gene Deletion
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Subunits / deficiency
  • Protein Subunits / metabolism*
  • Protein Transport / genetics
  • Septins
  • Telophase* / genetics
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism

Substances

  • Cytoskeletal Proteins
  • Protein Subunits
  • Phosphatidylinositol 3-Kinases
  • GTP Phosphohydrolases
  • Sept2 protein, mouse
  • Septins
  • cdc42 GTP-Binding Protein