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Mol Biol Cell. 2011 Feb 15;22(4):437-47. doi: 10.1091/mbc.E10-06-0522. Epub 2010 Dec 17.

Disruption of PKB signaling restores polarity to cells lacking tumor suppressor PTEN.

Author information

1
Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

Abstract

By limiting phosphotidylinositol 3,4,5-triphosphate (PIP(3)) levels, tumor suppressor PTEN not only controls cell growth but also maintains cell polarity required for cytokinesis and chemotaxis. To identify the critical targets of PIP(3) that link it to the cytoskeleton, we deleted secondary genes to reverse the deficiencies of pten- cells in Dictyostelium. The polarity defects in pten- cells correlate with elevated phosphorylations of PKB substrates. Deletion of AKT orthologue, PkbA, or a subunit of its activator TORC2, reduced the phosphorylations and suppressed the cytokinesis and chemotaxis defects in pten- cells. In these double mutants, the excessive PIP(3) levels and, presumably, activation of other PIP(3)-binding proteins had little or no effect on the cytoskeleton. In bands with increased phosphorylation in pten- cells, we found PKB substrates, PI5K, GefS, GacG, and PakA. Disruption of PakA in pten- cells restored a large fraction of the cells to normal behavior. Consistently, expression of phosphomimetic PakA in pten- cells exacerbated the defects but nonphosphorylatable PakA had no effect. Thus, among many putative PTEN- and PIP(3)-dependent events, phosphorylation of PKB substrates is the key downstream regulator of cell polarity.

PMID:
21169559
PMCID:
PMC3038642
DOI:
10.1091/mbc.E10-06-0522
[Indexed for MEDLINE]
Free PMC Article

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