Control of cell polarity and chemotaxis by Akt/PKB and PI3 kinase through the regulation of PAKa.
We demonstrate that PI3 kinase and protein kinase B (PKB or Akt) control cell polarity and chemotaxis, in part, through the regulation of PAKa, which is required for myosin II assembly. We demonstrate that PI3K and PKB mediate PAKa's subcellular localization, PAKa's activation in response to chemoattractant stimulation, and chemoattractant-mediated myosin II assembly. Mutation of the PKB phosphorylation site in PAKa to Ala blocks PAKa's activation and inhibits PAKa redistribution in response to chemoattractant stimulation, whereas an Asp substitution leads to an activated protein. Addition of the PI3K inhibitor LY294002 results in a rapid loss of cell polarity and the axial distribution of actin, myosin, and PAKa. These results provide a mechanism by which PI3K regulates chemotaxis.
Chung
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Section of Cell and Developmental Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA.
Potikyan
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Firtel
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D000818:Animals; D016764:Cell Polarity / Q000187:drug effects*; D002633:Chemotaxis / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000502:physiology; D004023:Dictyostelium / Q000166:cytology / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology* / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000494:pharmacology* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013347:Subcellular Fractions / Q000187:drug effects / Q000502:physiology; D014162:Transfection
D003598:Cytoskeletal Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C400275:PAKa protein, Dictyostelium discoideum