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J Biol Chem, Vol. 275, Issue 16, 12069-12073, April 21, 2000
From the Oral and Pharyngeal Cancer Branch, NIDCR, National
Institutes of Health, Bethesda, Maryland 20892-4330
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)
A Novel Role for Phosphatidylinositol 3-Kinase
in Signaling
from G Protein-coupled Receptors to Akt*
is
necessary and sufficient to transmit signals from G proteins to Akt in
these murine fibroblasts and that the activation of PI3K may
represent the most likely mechanism whereby GPCRs stimulate Akt, as the
vast majority of cells do not express PI3K
, 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 PI3K by G protein dimers.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Oral and Pharyngeal
Cancer Branch, National Institute of Dental and Craniofacial Research,
National Institutes of Health, 9000 Rockville Pike, Bldg. 30, Rm. 211, Bethesda, MD 20892-4330. E-mail: sg39v@nih.gov.
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