Cyclic AMP Inhibits Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase/Akt Pathways by Inhibiting Rap1

Lai Wang, Feng Liu, Martin L Adamo

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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 p27 Kip1 and cyclin D2 protein levels, potentially explaining the observation that cAMP prevented C6 cells from entering S phase.

Original languageEnglish (US)
Pages (from-to)37242-37249
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number40
DOIs
StatePublished - Oct 5 2001

Fingerprint

Phosphatidylinositol 3-Kinase
Extracellular Signal-Regulated MAP Kinases
Cyclic AMP
Phosphorylation
Cyclin D2
GTPase-Activating Proteins
Insulin-Like Growth Factor Binding Protein 3
Proteins
Cyclic AMP-Dependent Protein Kinases
Insulin-Like Growth Factor I
S Phase
Gene expression
Glioma
Rats
Chemical activation
Gene Expression

ASJC Scopus subject areas

  • Biochemistry

Cite this

Cyclic AMP Inhibits Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase/Akt Pathways by Inhibiting Rap1. / Wang, Lai; Liu, Feng; Adamo, Martin L.

In: Journal of Biological Chemistry, Vol. 276, No. 40, 05.10.2001, p. 37242-37249.

Research output: Contribution to journalArticle

@article{a857a97e50d4470cac330e68f6add1b5,
title = "Cyclic AMP Inhibits Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase/Akt Pathways by Inhibiting Rap1",
abstract = "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 p27 Kip1 and cyclin D2 protein levels, potentially explaining the observation that cAMP prevented C6 cells from entering S phase.",
author = "Lai Wang and Feng Liu and Adamo, {Martin L}",
year = "2001",
month = "10",
day = "5",
doi = "10.1074/jbc.M105089200",
language = "English (US)",
volume = "276",
pages = "37242--37249",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "40",

}

TY - JOUR

T1 - Cyclic AMP Inhibits Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase/Akt Pathways by Inhibiting Rap1

AU - Wang, Lai

AU - Liu, Feng

AU - Adamo, Martin L

PY - 2001/10/5

Y1 - 2001/10/5

N2 - 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 p27 Kip1 and cyclin D2 protein levels, potentially explaining the observation that cAMP prevented C6 cells from entering S phase.

AB - 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 p27 Kip1 and cyclin D2 protein levels, potentially explaining the observation that cAMP prevented C6 cells from entering S phase.

UR - http://www.scopus.com/inward/record.url?scp=0035813228&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035813228&partnerID=8YFLogxK

U2 - 10.1074/jbc.M105089200

DO - 10.1074/jbc.M105089200

M3 - Article

VL - 276

SP - 37242

EP - 37249

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 40

ER -