Journal
BIOCHEMISTRY
Volume 47, Issue 44, Pages 11682-11692Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi801451f
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Funding
- National Institutes of Health [DK58283]
- Department of Veterans Affairs Merit
- Research Enhancement Award Program
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Adiponectin is an adipocyte-derived cytokine that has attracted much attention because of its insulin-sensitizing effects in liver and skeletal muscle. Two adiponectin receptors, AdipoR1/R2, have been cloned, but relatively little is known about their intracellular signaling mechanisms. We found that full-length adiponectin rapidly and robustly activates the ERK1/2 mitogen-activated protein kinase pathway in primary vascular smooth muscle, vascular endothelial cells, and hepatocytes. In a HEK293 cell model, we found that downregulating AdipoR1/R2 simultaneously, but not individually, by RNA interference attenuated adiponectin-induced ERK1/2 activation, suggesting that either receptor was sufficient to mediate the response. Downregulation of T-cadherin, another adiponectin binding protein, enhanced. the response. Downregulation of APPL1, an adapter protein and putative mediator of AdipoR1/R2 signaling, impaired adiponectin-stimulated ERK1/2 activation. Inhibiting PKA modestly attenutated ERK1/2 activation, while inhibition of Src family tyrosine kinases with PP2 abolished the response. The small GTPase inhibitor Clostridium difficile toxin B also produced complete inhibition. Adiponectin caused rapid, PP2-sensitive activation of Ras, but not the cAMP-regulated small GTPase, Rap1, suggesting that Src-dependent Ras activation is the dominant mechanism of adiponectin-stimulated ERK1/2 activation. To test whether Ras-ERK1/2 signaling by adiponectin was physiologically relevant, we determined the effects of overexpressing AdipoR1, adiponectin, or both on the rate of HEK293 cell growth. Overexpression of adiponectin alone, but not AdipoR1 alone, supported growth under serum-free conditions, while simultaneous expression of both led to further enhancement. These results suggest that adiponectin can exert proliferative effects by activating Ras signaling pathways.
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