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J. Biol. Chem., Vol. 276, Issue 40, 37242-37249, October 5, 2001
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From the Departments of Cyclic AMP inhibited both ERK and Akt activities
in rat C6 glioma cells. A constitutively active form of
phosphatidylinositol 3-kinase (PI3K) prevented cAMP from
inhibiting Akt, suggesting that the inactivation of Akt by cAMP is a
consequence of PI3K inhibition. Neither protein kinase A nor Epac
(Exchange protein directly
activated by cAMP), two known direct effectors
of cAMP, mediated the cAMP-induced inhibition of ERK and Akt
phosphorylation. Cyclic AMP inhibited Rap1 activation in C6 cells.
Moreover, inhibition of Rap1 by a Rap1 GTPase-activating protein-1 also
resulted in a decrease in ERK and Akt phosphorylation, which was not
further decreased by cAMP, suggesting that cAMP inhibits ERK and Akt by inhibiting Rap1. The role of Rap1 in ERK and Akt activity was further
demonstrated by our observation that an active form of Epac, which
activated Rap1 in the absence of cAMP, increased ERK and Akt
phosphorylation. Inhibition of ERK and/or PI3K pathways mediated the
inhibitory effects of cAMP on insulin-like growth factor-I (IGF-I) and
IGF-binding protein-3 gene expression. Moreover, cAMP, as well as ERK
and PI3K inhibitors produced equivalent stimulation and inhibition,
respectively, of p27Kip1 and cyclin D2 protein
levels, potentially explaining the observation that cAMP prevented C6
cells from entering S phase.
Cyclic AMP Inhibits Extracellular Signal-regulated Kinase and
Phosphatidylinositol 3-Kinase/Akt Pathways by Inhibiting Rap1*
,§, and¶
Biochemistry and
§ Pharmacology, The University of Texas Health Science
Center, San Antonio, Texas 78229-3900
*
This study was supported by Grant DK-47357 from NIDDK,
National Institutes of Health, Grant AQ-1385 from the Robert A. Welch Foundation, and Grant 07 from the Children's Cancer Research Center of
University of Texas Health Science Center at San Antonio (to M. L. A.) and by Grant DK-56166 (to F. L.) from NIDDK,
National Institutes of Health.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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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