Cho-Clark Madelaine, Larco Darwin O, Semsarzadeh Nina N, Vasta Florencia, Mani Shaila K, Wu T John
Department of Obstetrics and Gynecology (T.J.W., M.C., F.V.) and the Program in Molecular and Cellular Biology (D.O.L., T.J.W.), Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814; and Departments of Molecular and Cellular Biology and Neuroscience (S.K.M.), Baylor College of Medicine, Houston, Texas 77030.
Mol Endocrinol. 2014 Jan;28(1):80-98. doi: 10.1210/me.2013-1203. Epub 2013 Jan 1.
The decapeptide GnRH is known for its central role in the regulation of the hypothalamo-pituitary-gonadal axis. In addition, it is also known to have local effects within peripheral tissues. The zinc metalloendopeptidase, EC 3.4.24.15 (EP24.15), can cleave GnRH at the Tyr(5)-Gly(6) bond to form the pentapeptide, GnRH-(1-5). The central and peripheral effect of GnRH-(1-5) is different from its parent peptide, GnRH. In the current study, we examined the effect of GnRH-(1-5) on epidermal growth factor receptor (EGFR) phosphorylation and cellular migration. Using the Ishikawa cell line as a model of endometrial cancer, we demonstrate that GnRH-(1-5) stimulates epidermal growth factor release, increases the phosphorylation of EGFR (P < .05) at three tyrosine sites (992, 1045, 1068), and promotes cellular migration. In addition, we also demonstrate that these actions of GnRH-(1-5) are mediated by the orphan G protein-coupled receptor 101 (GPR101). Down-regulation of GPR101 expression blocked the GnRH-(1-5)-mediated release of epidermal growth factor and the subsequent phosphorylation of EGFR and cellular migration. These results suggest that GPR101 is a critical requirement for GnRH-(1-5) transactivation of EGFR in Ishikawa cells.
十肽促性腺激素释放激素（GnRH）因其在下丘脑 - 垂体 - 性腺轴调节中的核心作用而闻名。此外，它在周围组织中也具有局部作用。锌金属内肽酶，EC 3.4.24.15（EP24.15），可在Tyr(5)-Gly(6)键处切割GnRH，形成五肽GnRH-(1-5)。GnRH-(1-5)的中枢和外周作用与其母体肽GnRH不同。在本研究中，我们检测了GnRH-(1-5)对表皮生长因子受体（EGFR）磷酸化和细胞迁移的影响。以石川细胞系作为子宫内膜癌模型，我们证明GnRH-(1-5)刺激表皮生长因子释放，增加EGFR在三个酪氨酸位点（992、1045、1068）的磷酸化（P <.05），并促进细胞迁移。此外，我们还证明GnRH-(1-5)的这些作用是由孤儿G蛋白偶联受体101（GPR101）介导的。GPR101表达的下调阻断了GnRH-(1-5)介导的表皮生长因子释放以及随后的EGFR磷酸化和细胞迁移。这些结果表明，GPR101是石川细胞中GnRH-(1-5)对EGFR反式激活的关键条件。
