Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor
Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor
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DOI：
10.1073/pnas.95.11.6061
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Stahl, N
中科院分区：
文献类型：
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作者：
Carpenter, LR;Farruggella, TJ;Stahl, N
瘦素是脂肪细胞来源的细胞因子，其通过与其Ob受体（ObR）的相互作用来调节食物摄入和体重。肥胖人群中血清瘦素水平长期升高，表明肥胖可能与瘦素抵抗和不能产生足够的ObR应答有关。有证据表明，下丘脑中STAT 3（信号转导和转录激活因子）对靶基因的转录激活是介导瘦素作用的关键途径。在本文中，我们报告了ObR的激活诱导了酪氨酸磷酸酶SH 2-含有磷酸酶2（SHP-2）的酪氨酸磷酸化，并证明了在ObR胞质结构域内的Tyr（986）是介导SHP-2磷酸化和SHP-2与ObR结合所必需的。令人惊讶的是，Tyr（986）突变为Phe，消除了SHP-2磷酸化和与受体的结合，显著增加了由STAT 3介导的基因诱导。我们的研究结果表明，SHP-2是一个负调节STAT 3介导的基因诱导后激活的ObR和提高的可能性，阻断SHP-2与ObR的相互作用，可以克服瘦素抵抗，提高瘦素的减肥效果在肥胖个体。
Leptin is an adipocyte-derived cytokine that regulates food intake and body weight via interaction with its Ob receptor (ObR), Serum leptin levels are chronically elevated in obese humans, suggesting that obesity may be associated with leptin resistance and the inability to generate an adequate ObR response. Evidence suggests that transcriptional activation of target genes by STAT3 (signal transducer and activator of transcription) in the hypothalamus is a critical pathway that mediates leptin's action. Herein we report that activation of ObR induces the tyrosine phosphorylation of the tyrosine phosphatase SH2-containing phosphatase 2 (SHP-2) and demonstrate that Tyr(986) within the ObR cytoplasmic domain is essential to mediate phosphorylation of SHP-2 and binding of SHP-2 to ObR. Surprisingly, mutation of Tyr(986) to Phe, which abrogates SHP-2 phosphorylation and binding to the receptor, dramatically increases gene induction mediated by STAT3. Our findings indicate that SHP-2 is a negative regulator of STAT3-mediated gene induction after activation of ObR and raise the possibility that blocking the interaction of SHP-2 with ObR could overcome leptin resistance by boosting leptin's weight-reducing effects in obese individuals.