The adiponectin receptors AdipoR1 and AdipoR2 activate ERK1/2 through a Src/Ras-dependent pathway and stimulate cell growth.
The adiponectin receptors AdipoR1 and AdipoR2 activate ERK1/2 through a Src/Ras-dependent pathway and stimulate cell growth.
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DOI：
10.1021/bi801451f
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发表时间：
2008-11-04
期刊：
影响因子：
2.9
通讯作者：
Luttrell, Louis M.
中科院分区：
文献类型：
--
作者：
Lee, Mi-Hye;Klein, Richard L.;El-Shewy, Hesham M.;Luttrell, Deirdre K.;Luttrell, Louis M.
脂联素是一种脂肪细胞源性细胞因子，因其在肝脏和骨骼肌中具有胰岛素增敏作用而备受关注。已克隆了两种脂联素受体AdipoR 1和AdipoR 2，但对其细胞内信号传导机制知之甚少。我们发现，全长脂联素快速和强大的激活ERK 1/2丝裂原活化蛋白激酶途径在原代血管平滑肌，血管内皮细胞，肝细胞。在HEK 293细胞模型中，我们发现通过RNA干扰同时下调AdipoR 1和AdipoR 2，而不是单独下调AdipoR 1和AdipoR 2，会减弱脂联素诱导的ERK 1/2激活，这表明任何一种受体都足以介导这种反应。下调另一种脂联素结合蛋白T-cadherin的表达增强了这种反应。APPL 1是一种衔接蛋白，也是AdipoR 1/R2信号转导的假定介质，其下调可损害脂联素刺激的ERK 1/2活化。抑制PKA适度减弱ERK 1/2激活，而抑制Src家族酪氨酸激酶与PP 2取消的反应。小GT3抑制剂艰难梭菌毒素B也产生完全抑制。脂联素引起Ras的快速、PP 2敏感性激活，但不引起cAMP调节的小GT3、Rap 1的激活，这表明Src依赖性Ras激活是脂联素刺激的ERK 1/2激活的主要机制。为了测试脂联素的Ras-ERK 1/2信号传导是否具有生理相关性，我们确定了过表达AdipoR 1、脂联素或两者对HEK 293细胞生长速率的影响。单独过表达脂联素，而不是单独的AdipoR 1，支持无血清条件下的生长，而同时表达两者导致进一步增强。另外的结果表明，脂联素可以通过激活Ras信号通路发挥增殖作用。
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 and AdipoR2, 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 and AdipoR2 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. Additional results suggest that adiponectin can exert proliferative effects by activating Ras signaling pathways.
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