Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes.
Cyclic AMP (cAMP)-dependent processes are pivotal during the early stages of adipocyte differentiation. We show that exchange protein directly activated by cAMP (Epac), which functions as a guanine nucleotide exchange factor for the Ras-like GTPases Rap1 and Rap2, was required for cAMP-dependent stimulation of adipocyte differentiation. Epac, working via Rap, acted synergistically with cAMP-dependent protein kinase (protein kinase A [PKA]) to promote adipogenesis. The major role of PKA was to down-regulate Rho and Rho-kinase activity, rather than to enhance CREB phosphorylation. Suppression of Rho-kinase impaired proadipogenic insulin/insulin-like growth factor 1 signaling, which was restored by activation of Epac. This interplay between PKA and Epac-mediated processes not only provides novel insight into the initiation and tuning of adipocyte differentiation, but also demonstrates a new mechanism of cAMP signaling whereby cAMP uses both PKA and Epac to achieve an appropriate cellular response.
Petersen
Rasmus Koefoed
RK
BioLigands, International Science Park Odense, DK-5230 Odense M, Denmark.
Madsen
Lise
L
Pedersen
Lone Møller
LM
Hallenborg
Philip
P
Hagland
Hanne
H
Viste
Kristin
K
Døskeland
Stein Ove
SO
Kristiansen
Karsten
K
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C486707:Rapgef4 protein, mouse; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C492137:Rap2a protein, mouse; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins