TY - JOUR
T1 - Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes
AU - Petersen, Rasmus Koefoed
AU - Madsen, Lise
AU - Pedersen, Lone Møller
AU - Hallenborg, Philip
AU - Hagland, Hanne
AU - Viste, Kristin
AU - Døskeland, Stein Ove
AU - Kristiansen, Karsten
PY - 2008/6/1
Y1 - 2008/6/1
N2 - 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.
AB - 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.
KW - 3T3-L1 Cells
KW - Adipocytes
KW - Adipogenesis
KW - Animals
KW - Carrier Proteins
KW - Cyclic AMP
KW - Cyclic AMP Response Element-Binding Protein
KW - Cyclic AMP-Dependent Protein Kinases
KW - Guanine Nucleotide Exchange Factors
KW - Insulin-Like Growth Factor I
KW - Mice
KW - rap GTP-Binding Proteins
KW - rap1 GTP-Binding Proteins
KW - rho-Associated Kinases
U2 - 10.1128/MCB.00709-07
DO - 10.1128/MCB.00709-07
M3 - Journal article
C2 - 18391018
SN - 0270-7306
VL - 28
SP - 3804
EP - 3816
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 11
ER -