Department of Pharmacology and Nutritional Sciences, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky.
Department of Pharmacology and Nutritional Sciences, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky
Mol Pharmacol. 2018 Jul;94(1):665-673. doi: 10.1124/mol.117.110510. Epub 2018 Apr 19.
The insulin receptor (IR) is a ligand-activated receptor tyrosine kinase that has a key role in metabolism, cellular survival, and proliferation. Progesterone receptor membrane component 1 (PGRMC1) promotes cellular signaling via receptor trafficking and is essential for some elements of tumor growth and metastasis. In the present study, we demonstrate that PGRMC1 coprecipitates with IR. Furthermore, we show that PGRMC1 increases plasma membrane IR levels in multiple cell lines and decreases insulin binding at the cell surface. The findings have therapeutic applications because a small-molecule PGRMC1 ligand, AG205, also decreases plasma membrane IR levels. However, PGRMC1 knockdown via short hairpin RNA expression and AG205 treatment potentiated insulin-mediated phosphorylation of the IR signaling mediator AKT. Finally, PGRMC1 also increased plasma membrane levels of two key glucose transporters, GLUT-4 and GLUT-1. Our data support a role for PGRMC1 maintaining plasma membrane pools of the receptor, modulating IR signaling and function.
胰岛素受体（IR）是一种配体激活的受体酪氨酸激酶，在代谢、细胞存活和增殖中具有关键作用。孕激素受体膜成分 1（PGRMC1）通过受体运输促进细胞信号转导，是肿瘤生长和转移的某些要素所必需的。在本研究中，我们证明了 PGRMC1 与 IR 共沉淀。此外，我们还表明，PGRMC1 增加了多种细胞系的质膜 IR 水平，并减少了细胞表面的胰岛素结合。这些发现具有治疗应用价值，因为小分子 PGRMC1 配体 AG205 也降低了质膜 IR 水平。然而，通过短发夹 RNA 表达和 AG205 处理敲低 PGRMC1 会增强胰岛素介导的 IR 信号转导介质 AKT 的磷酸化。最后，PGRMC1 还增加了两种关键葡萄糖转运蛋白 GLUT-4 和 GLUT-1 的质膜水平。我们的数据支持 PGRMC1 维持受体质膜池的作用，调节 IR 信号和功能。
