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Disruption of PKB Signaling Restores Chemotaxis of Cells Lacking Tumor Suppressor PTEN
Author(s) -
tang michelle,
Iijima Miho,
Kamimura Yoichiro,
Chen Lingfeng,
Long Yu,
Devreotes Peter
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.930.14
Subject(s) - pten , cytokinesis , microbiology and biotechnology , cell polarity , pi3k/akt/mtor pathway , protein kinase b , phosphorylation , biology , chemotaxis , suppressor , cell growth , signal transduction , cell , chemistry , cancer research , cell division , gene , biochemistry , receptor
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 non‐phosphorylatable 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.