A novel role for phosphatidylinositol 3-kinase beta in signaling from G protein-coupled receptors to Akt.
The protein kinase Akt plays a central role in a number of key biological functions including protein synthesis, glucose homeostasis, and the regulation of cell survival or death. The mechanism by which tyrosine kinase growth factor receptors stimulate Akt has been recently defined. In contrast, the mechanism of activation of Akt by other cell surface receptors is much less understood. For G protein-coupled receptors (GPCRs), conflicting data suggest that these receptors stimulate Akt in a cell type-specific manner by a yet to be fully elucidated mechanism. Here, we took advantage of the availability of cells, where Akt activity could not be enhanced by agonists acting on this large family of cell surface receptors, such as NIH 3T3 cells, to investigate the pathway linking GPCRs to Akt. We present evidence that expression of phosphatidylinositol 3-kinase (PI3K) beta is necessary and sufficient to transmit signals from G proteins to Akt in these murine fibroblasts and that the activation of PI3Kbeta may represent the most likely mechanism whereby GPCRs stimulate Akt, as the vast majority of cells do not express PI3Kgamma, a known G protein-sensitive PI3K isoform. Furthermore, available evidence indicates that GPCRs activate Akt by a pathway distinct from that utilized by growth factor receptors, as it involves the tyrosine phosphorylation-independent activation of PI3Kbeta by G protein betagamma dimers.
Murga
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Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4330, USA.
Fukuhara
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Gutkind
J S
JS
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D019204:GTP-Binding Proteins / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D019204:GTP-Binding Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D014443:Tyrosine