Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo
Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo
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DOI：
10.1074/jbc.m205825200
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发表时间：
2002-11-29
影响因子：
4.8
通讯作者：
Li, C
中科院分区：
文献类型：
--
作者：
Ge, HF;Huang, L;Li, C
瘦素是一种脂肪细胞来源的激素，对食物摄入和体重具有强有力的影响。具有瘦素或瘦素受体突变的遗传性肥胖啮齿动物发展为病态肥胖和糖尿病。瘦素受体OB-R选择性剪接成至少五种转录物，编码受体OB-Ra、-B、-c、-d和-e。OB-Re不编码跨膜结构域并且是分泌的。在人类中，还没有发现与OB-Re相对应的转录本。然而，可溶性瘦素受体在人血浆中循环，并代表主要的瘦素结合活性。在这份报告中，我们试图确定是否可溶性瘦素受体也可能来自跨膜受体亚型的胞外域脱落。使用表达OB-Ra（最丰富的瘦素受体亚型）和OB-Rb（瘦素受体的信号传导形式）的稳定细胞系，我们证明了可溶性瘦素受体蛋白确实可以通过这两种受体亚型在体外的蛋白水解裂解产生。使用表达双重标记的OB-Ra或Ob-Rb的腺病毒的实验也证明，可溶性瘦素受体可能来源于两种受体同种型在体内的胞外域脱落。由于我们早期和其他研究表明，可溶性受体调节瘦素的水平以及活性，我们的研究结果表明，跨膜瘦素受体的胞外域的调节脱落可能代表了一种新的机制，调节瘦素的生物活性。
Leptin is an adipocyte-derived hormone with potent effects on food intake and body weight. Genetically obese rodents with mutations of leptin or leptin receptor develop morbid obesity and diabetes. The receptor for leptin, OB-R, is alternatively spliced to at least five transcripts, encoding receptors designated OB-Ra, -b, -c, -d, and -e. OB-Re does not encode a transmembrane domain and is secreted. In humans, transcripts corresponding to OB-Re have not been discovered. However, soluble leptin receptor does circulate in human plasma and represents the major leptin-binding activity. In this report, we attempted to determine whether the soluble leptin receptor may also be derived from membrane-spanning receptor isoforms by ectodomain shedding. Using stable cell lines expressing both OB-Ra, the most abundant leptin receptor isoform, and OB-Rb, the signaling form of the leptin receptor, we demonstrate that soluble leptin receptor protein can indeed be generated by proteolytic cleavage of these two receptor isoforms in vitro. Experiments using adenoviruses expressing dually tagged OB-Ra or Ob-Rb also demonstrate that soluble leptin receptor may be derived from ectodomain shedding of both receptor isoforms in vivo. Because our earlier and other studies have shown that the soluble receptors modulate the levels as well as activity of leptin, our findings suggest that regulated shedding of the ectodomain of membrane-spanning leptin receptors may represent a novel mechanism of modulating leptin's biological activity.