The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms
The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms
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DOI：
10.1074/jbc.m702838200
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发表时间：
2007-10-19
影响因子：
4.8
通讯作者：
Myers, Martin G., Jr.
中科院分区：
文献类型：
--
作者：
Gong, Yusong;Ishida-Takahashi, Ryoko;Myers, Martin G., Jr.
瘦素通过其长链受体（LepRb）的作用对控制机体能量稳态和神经内分泌功能至关重要，但LepRb调节细胞内信号传导的机制仍不完全清楚。在这里，我们证明了瘦素刺激小鼠下丘脑弓状核中STAT5和核糖体蛋白S6的磷酸化。在培养细胞中，我们研究了瘦素调节这些途径的机制。我们的分析揭示了LepRb Tyr（1077）的主导作用（我们证明其在受体激活过程中被磷酸化），而LepRb Tyr（1138）在STAT5a和STAT5b的急性磷酸化中起次要作用。然而，Tyr（1138）和STAT3在长期内减弱stat5依赖的转录。相反，Tyr(985) （ERK激活所需的LepRb磷酸化位点）介导核糖体S6激酶（RSK）和S6的磷酸化，以及帽依赖翻译。因此，这些数据证明了在受体激活过程中Tyr（1077）对LepRb的磷酸化，证实了瘦素对STAT5和S6的下丘脑调节，并定义了介导这些信号的LepRb信号通路及其在培养细胞中的作用。解剖这些个体途径对瘦素作用的贡献将对我们最终理解体内调节能量平衡的过程非常重要。
The action of leptin via the long form of its receptor (LepRb) is central to the control of body energy homeostasis and neuroendocrine function, but the mechanisms by which LepRb regulates intracellular signaling have remained incompletely understood. Here we demonstrate that leptin stimulates the phosphorylation of STAT5 and ribosomal protein S6 in the hypothalamic arcuate nucleus in mice. In cultured cells, we investigate the mechanisms by which leptin regulates each of these pathways. Our analysis reveals a dominant role for LepRb Tyr(1077) ( which we demonstrate to be phosphorylated during receptor activation) and a secondary role for LepRb Tyr(1138) in the acute phosphorylation of STAT5a and STAT5b. Tyr(1138) and STAT3 attenuate STAT5-dependent transcription over the long-term, however. In contrast, Tyr(985) ( the LepRb phosphorylation site required for ERK activation) mediates the phosphorylation of the ribosomal S6 kinase (RSK) and S6, as well as cap-dependent translation. Thus, these data demonstrate the phosphorylation of Tyr(1077) on LepRb during receptor activation, substantiate the hypothalamic regulation of STAT5 and S6 by leptin, and define the alternate LepRb signaling pathways that mediate each of these signals and their effects in cultured cells. Dissecting the contributions of these individual pathways to leptin action will be important for our ultimate understanding of the processes that regulate energy balance in vivo.