Localization of the human oxytocin receptor in caveolin-1 enriched domains turns the receptor-mediated inhibition of cell growth into a proliferative response
Localization of the human oxytocin receptor in caveolin-1 enriched domains turns the receptor-mediated inhibition of cell growth into a proliferative response
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DOI：
10.1038/sj.onc.1205219
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发表时间：
2002-03-07
期刊：
影响因子：
8
通讯作者：
Chini, B
中科院分区：
文献类型：
--
作者：
Guzzi, F;Zanchetta, D;Chini, B
在这项研究中，我们调查的功能作用的本地化的人OTR小窝蛋白-1丰富的膜结构域。稳定表达WT OTR-GFP的MDCK细胞的生物化学分级分离表明，仅少量的受体被分配在小窝蛋白-1富集的结构域中。然而，当与小窝蛋白-2融合时，OTR蛋白被证明仅定位于富含小窝蛋白-1的级分中，在那里它以增加的亲和力结合激动剂并有效地偶联到Ga（q/11）。有趣的是，嵌合蛋白不能进行激动剂诱导的内化，并保持局限于质膜，即使在长时间的激动剂暴露（120分钟）。当分析OT诱导的对细胞增殖的作用时，观察到受体刺激的显著差异：人WT OTR的刺激抑制细胞生长，而嵌合蛋白具有增殖作用。这些数据表明，在小窝蛋白-1富集的微结构域中的人OTR的定位从根本上改变了其对细胞生长的调节作用;因此，驻留在小窝结构中的OTR的部分可能在调节细胞增殖中起关键作用。
In this study, we investigated the functional role of the localization of human OTR in caveolin-1 enriched membrane domains. Biochemical fractionation of MDCK cells stably expressing the WT OTR-GFP indicated that only minor quantities of receptor are partitioned in caveolin-1 enriched domains. However, when fused to caveolin-2, the OTR protein proved to be exclusively localized in caveolin-1 enriched fractions, where it bound the agonist with increased affinity and efficiently coupled to Galpha(q/11). Interestingly, the chimeric protein was unable to undergo agonist-induced internalization and remained confined to the plasma membrane even after prolonged agonist exposure (120 min). A striking difference in receptor stimulation was observed when the OT-induced effect on cell proliferation was analysed: stimulation of the human WT OTR inhibited cell growth, whereas the chimeric protein had a proliferative effect. These data indicate that the localization of human OTR in caveolin-1 enriched microdomains radically alters its regulatory effects on cell growth; the fraction of OTR residing in caveolar structures may therefore play a crucial role in regulating cell proliferation.