Activation of Akt/protein kinase B by G protein-coupled receptors. A role for alpha and beta gamma subunits of heterotrimeric G proteins acting through phosphatidylinositol-3-OH kinasegamma.
The serine/threonine protein kinase Akt has recently been shown to be implicated in the pathway leading to cell survival in response to serum and growth factors in a variety of cellular systems. However, the existence of a biochemical route connecting this kinase to the large family of receptors that signal through heterotrimeric G proteins is yet to be explored. In this study, we set out to investigate whether GTP-binding protein (G protein)-coupled receptors (GPCRs) can stimulate Akt activity and survival pathways and, if so, to define the mechanism(s) whereby this class of cell surface receptors could regulate Akt function. Using ectopic expression of GPCRs in COS-7 cells as a model, we have observed that both m1 and m2 muscarinic acetylcholine receptors, representative of those GPCRs coupled to Gq and Gi proteins, respectively, can readily activate an epitope-tagged form of Akt kinase and prevent UV-induced apoptosis. We have also found that the pathway connecting G proteins to Akt implicates signals emanating from Galphaq, Galphai, and beta gamma dimers, but not from Galphas or Galpha12, in each case acting through a pathway that involves a phosphatidylinositol-3-OH kinase activity. Moreover, our findings suggest a role for a novel beta gamma-sensitive complex, p101.phosphatidylinositol-3-OH kinase-gamma, in the transduction of signals leading to Akt stimulation and cell survival by GPCRs and open new avenues for research on the function of the large family of G protein-linked receptors in the regulation of anti-apoptotic pathways.
Murga
C
C
Oral and Pharyngeal Cancer Branch, NIDR, National Institutes of Health, Bethesda, Maryland 20892-4330, USA.
Laguinge
L
L
Wetzker
R
R
Cuadrado
A
A
Gutkind
J S
JS
D000818:Animals; D019556:COS Cells; D002217:Carbachol / Q000494:pharmacology; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008916:Miotics / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction
D002217:Carbachol; D019204:GTP-Binding Proteins; D007527:Isoenzymes; D008916:Miotics; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface