Abstract
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.
Original language | English |
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Pages (from-to) | 665-673 |
Number of pages | 9 |
Journal | Molecular Pharmacology |
Volume | 94 |
Issue number | 1 |
DOIs | |
State | Published - 2018 |
Bibliographical note
Publisher Copyright:© 2018 by The American Society for Pharmacology and Experimental Therapeutics.
Funding
This work was supported by Washington University Diabetes Research Center Grant P30 DK020579-40; University of Kentucky CTSA Grant UL1 TR001998; and National Institutes of Health National Institute on Aging [Grant 5R01AG033649-08] and National Institutes of Health [Grant T32 DK007778 (to K.K.H. and H.F.)]. https://doi.org/10.1124/mol.117.110510. s This article has supplemental material available at molpharm. aspetjournals.org.
Funders | Funder number |
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National Institutes of Health National Institute on Aging | 5R01AG033649-08 |
The George Washington University | P30 DK020579-40 |
National Institutes of Health (NIH) | T32 DK007778 |
National Institute on Aging | R01AG033649 |
University of Kentucky | UL1 TR001998 |
ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology