Altered cell surface expression and signaling of leptin receptors containing the fatty mutation
Altered cell surface expression and signaling of leptin receptors containing the fatty mutation
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DOI：
10.1074/jbc.273.29.18365
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发表时间：
1998-07-17
影响因子：
4.8
通讯作者：
Pacifici, RE
中科院分区：
文献类型：
--
作者：
Crouse, JA;Elliott, GE;Pacifici, RE
瘦素和瘦素受体是调节体重的关键因素。为了分析Zucker脂肪大鼠瘦素受体突变（Gln(269) -> Pro）的分子机制，我们分析了该突变在三种不同表达系统中对瘦素受体信号传导和表达的影响：1)表达瘦素/红细胞生成素受体嵌合体的32D细胞，2)表达瘦素受体短形式的COS-7细胞，以及3)表达可溶性受体形式的293细胞。为了确定Gln(269) -> Pro突变是否对观察到的表型至关重要，我们在脂肪突变上游两个氨基酸的邻近残基处进行了类似的Gln -> Pro突变，以观察它是否会产生类似的影响。将Gln -> Pro突变中的任何一种纳入野生型受体形式都不会干扰瘦素的结合，但会导致信号不正常的受体。此外，大多数突变受体蛋白定位于细胞内。我们的研究结果表明，由Zucker肥胖大鼠瘦素受体Gln(269) -> Pro突变引起的肥胖表型可能不仅是由于这种形式的瘦素受体的细胞表面表达减少，而且还由于瘦素后受体结合功能障碍，干扰了随后的信号转导。
Leptin and the leptin receptor are key players in the regulation of body weight. In an attempt to dissect the molecular mechanism of the Zucker fatty rat leptin receptor mutation (Gln(269) --> Pro) we analyzed the effects of this mutation on leptin receptor signaling and expression in three different expression systems: 1) 32D cells expressing leptin/erythropoietin receptor chimeras, 2) COS-7 cells expressing a leptin receptor short form, and 3) 293 cells expressing soluble receptor forms. To determine if the Gln(269) --> Pro mutation is critical for the observed phenotype, we made a similar Gln --> Pro mutation at a vicinal residue two amino acids upstream of the fatty mutation to see if it would have similar effects. Incorporation of either of the Gln --> Pro mutations into wild type receptor forms did not interfere with leptin binding, but it resulted in a signaling-incompetent receptor. In addition, the majority of the mutant receptor protein was localized intracellularly. Our results suggest that the obese phenotype resulting from the Gln(269) --> Pro mutation in the leptin receptor of the Zucker fatty rat may be due not only to a reduced cell surface expression of this form of the leptin receptor, but also to a post-leptin binding malfunction of the receptor that interferes with subsequent signal transduction.