Novel mechanisms of the regulation of Protein kinase B in adipocytes; implications for Protein kinase A, Epac, Phosphodiesterases 3 and 4

Zmuda-Trzebiatowska, Emilia; Manganiello, Vincent C.; Degerman, Eva

doi:10.1016/j.cellsig.2006.05.024

Cited by 30 publications

(34 citation statements)

References 39 publications

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“…Similarly, the channeling of cAMP signaling via Epac also seems to vary between preadipocytes and adipocytes. In preadipocytes, our results show that activation of Epac increases Ins/IGF-1 signaling and PKB activation, whereas activation of Epac by 8-pCPT-2Ј-O-Me-cAMP in primary rat adipocytes decreases Ins-dependent activation of PKB (73). Thus, cAMP-dependent signals appear to follow different routes in preadipocytes and mature adipocytes.…”

Section: Discussionmentioning

confidence: 61%

Cyclic AMP (cAMP)-Mediated Stimulation of Adipocyte Differentiation Requires the Synergistic Action of Epac- and cAMP-Dependent Protein Kinase-Dependent Processes

Petersen¹,

Madsen

Pedersen

et al. 2008

Molecular and Cellular Biology

139

122

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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.Adipocytes are derived from multipotent mesenchymal stem cells in a process involving commitment to the adipocyte lineage followed by terminal differentiation of the committed preadipocytes. The process is regulated via complex interaction of external and internal clues, where cell shape and cytoskeletal tension converging on regulation of Rho and Rhokinase activity have been demonstrated to play pivotal roles (48,63). Whereas our understanding of the early steps of lineage determination still is limited, regulatory cascades controlling terminal adipocyte differentiation have been elucidated in great detail, particularly the sequential action of different transcription factors culminating in the expression of adipocyte-specific genes (25,30,58). Much information on terminal adipocyte differentiation has been obtained using model cell lines such as 3T3-L1 and 3T3-F442A or mouse embryo fibroblasts (MEFs). In both MEFs and 3T3-L1 preadipocytes, terminal differentiation is initiated upon treatment with fetal calf serum, glucocorticoids, and high levels of insulin or physiological concentrations of insulin-like growth factor 1 (IGF-1). Factors that increase cellular cyclic AMP (cAMP), such as isobutylmethylxanthine (IBMX) or forskolin, strongly accelerate the initiation of the differentiation program (for review, see references 25 and 45).Elevation of cellular cAMP concentration has been associated with crucial events in the early program of differentiation, such as suppression of Wnt10b (5) and Sp1 (64) and induction of CCAAT/enhancer-binding protein ␤ (C/EBP␤) (10,29,70). Moreover, the transcriptional activity of peroxisome proliferator-activated receptor ␦ (PPAR␦) is regulated synergistically by ligands and cAMP (32). In addition, cAMP has been implicated in the production of endogenous PPAR␥ ligand(s) occurring during the initial stages of differentiation (46, 67). The cAMP-responsive element-binding protein (CREB) is a central transcriptional activator of the adipocyte differentiation program. Activated CREB induces expres...

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Section: Discussionmentioning

confidence: 61%

Cyclic AMP (cAMP)-Mediated Stimulation of Adipocyte Differentiation Requires the Synergistic Action of Epac- and cAMP-Dependent Protein Kinase-Dependent Processes

Petersen¹,

Madsen

Pedersen

et al. 2008

Molecular and Cellular Biology

139

122

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“…cAMP modulates Akt in different cell types, including fibroblasts (33,34,45,63), hepatocytes (42), adipocytes (41,64), cardiomyocytes (40), skeletal muscle (43), neurons (48), Schwann (39), endothelial (46), and endocrine cells (38,65). Specifically, in thyroid cells, the role of Akt in TSH-mediated proliferation of nontransformed cells is still controversial; either no effects (66) or both positive (67-69) and negative (47) effects of TSH on Akt phosphorylation/activity have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…A dual cAMP action on Akt was recently proposed, where a finely tuned regulation is achieved by a balance between opposite Epac/Rap1-dependent and PKA-dependent actions (63). It has recently been suggested that distinct cAMP pools, shaped by the action of phosphodiesterases, might be responsible for these specific cAMP effector responses (64). Our results in thyroid cells differ markedly with this model; effector-specific cAMP analogs do not show any effect on Akt when added independently, despite the fact that Epac-and PKA-selective analogs activated Rap1b and CREB phosphorylation, respectively (2).…”

Section: Discussionmentioning

confidence: 99%

A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation

Hong

Lou²,

Gupta

et al. 2008

Journal of Biological Chemistry

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“…An HSPDE3B interaction with the insulin receptor in human adipocytes has been reported (19). Recently, rat adipocyte PDE3B was reported to interact with caveolin-1 (20) placing this enzyme in lipid rafts in these cells (20,21). Disruption of an interaction between the murine PDE3B and phosphoinositide 3-kinase ␥ (PI3K␥) (22), likely coordinated by one of its regulatory subunits p87 PIKAP (PI3K␥ adapter protein of 87 kDa) (23), reduced cardiomyocyte contractility (22,23).…”

mentioning

confidence: 99%

Protein Kinase A Phosphorylation of Human Phosphodiesterase 3B Promotes 14-3-3 Protein Binding and Inhibits Phosphatase-catalyzed Inactivation

Palmer

Jimmo

Raymond

et al. 2007

Journal of Biological Chemistry

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Recent studies confirm that intracellular cAMP concentrations are nonuniform and that localized subcellular cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) is important in maintaining these cAMP compartments. Human phosphodiesterase 3B (HSPDE3B), a member of the PDE3 family of PDEs, represents the dominant particulate cAMP-PDE activity in many cell types, including adipocytes and cells of hematopoietic lineage. Although several previous reports have shown that phosphorylation of HSPDE3B by either protein kinase A (PKA) or protein kinase B (PKB) activates this enzyme, the mechanisms that allow cells to distinguish these two activated forms of HSPDE3B are unknown. Here we report that PKA phosphorylates HSPDE3B at several distinct sites (Ser-73, Ser-296, and Ser-318), and we show that phosphorylation of HSPDE3B at Ser-318 activates this PDE and stimulates its interaction with 14-3-3 proteins. In contrast, although PKB-catalyzed phosphorylation of HSPDE3B activates this enzyme, it does not promote 14-3-3 protein binding. Interestingly, we report that the PKA-phosphorylated, 14-3-3 protein-bound, form of HSPDE3B is protected from phosphatase-dependent dephosphorylation and inactivation. In contrast, PKA-phosphorylated HSPDE3B that is not bound to 14-3-3 proteins is readily dephosphorylated and inactivated. Our data are presented in the context that a selective interaction between PKAactivated HSPDE3B and 14-3-3 proteins represents a mechanism by which cells can protect this enzyme from deactivation. Moreover, we propose that this mechanism may allow cells to distinguish between PKA-and PKB-activated HSPDE3B.

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Novel mechanisms of the regulation of Protein kinase B in adipocytes; implications for Protein kinase A, Epac, Phosphodiesterases 3 and 4

Cited by 30 publications

References 39 publications

Cyclic AMP (cAMP)-Mediated Stimulation of Adipocyte Differentiation Requires the Synergistic Action of Epac- and cAMP-Dependent Protein Kinase-Dependent Processes

Cyclic AMP (cAMP)-Mediated Stimulation of Adipocyte Differentiation Requires the Synergistic Action of Epac- and cAMP-Dependent Protein Kinase-Dependent Processes

A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation

Protein Kinase A Phosphorylation of Human Phosphodiesterase 3B Promotes 14-3-3 Protein Binding and Inhibits Phosphatase-catalyzed Inactivation

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