Caenorhabditis elegans PIAK, a phospholipid-independent kinase that activates the AKT/PKB survival kinase.
Phospholipid-dependent kinase 1 (PDK 1) is a 3'-phospholipid-responsive serine/threonine kinase that plays a critical role in cell survival by phosphorylating and activating the anti-apoptotic AKT/PKB kinase. While PDK 1 is clearly an important component of the cell survival machinery, the potential for phospholipid-independent activation of the AKT/PKB survival pathway has not been extensively examined at the molecular level. We have identified a second form of PDK 1 in the nematode Caenorhabditis elegans that we have termed PIAK (phospholipid-independent AKT/PKB kinase). PIAK is highly homologous to C. elegans and mammalian PDK 1 with the exception that the novel kinase lacks a phospholipid binding pleckstrin homology domain. The domain structure of PIAK suggests that it might be a phospholipid-independent kinase, and PIAK phosphorylates mammalian AKT/PKB at the activating Thr(308) residue in the presence of the phosphatidylinositol (PI) 3-kinase inhibitors as well as in the absence of growth factors. In addition, PIAK is capable of inducing the phospholipid-independent, AKT/PKB-induced phosphorylation of the AFX-type forkhead transcription factor, resulting in its cytoplasmic localization. Because the nuclear localization of this transcription factor induces an apoptotic state, this PIAK-mediated cytoplasmic sequestration allows for cell survival. Finally, PIAK activity appears to be induced by various inhibitors of cell cycle G(1) progression. These data suggest an alternate, phosphatidylinositol 3-kinase-independent mechanism for the activation of the AKT/PKB survival pathway that may be utilized during periods of cellular quiescence.
Li
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Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080.
Dowbenko
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Lasky
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D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C430236:PIAK protein, C elegans; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C494915:akt-1 protein, C elegans