期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2117004119
关键词
progesterone; 17OHP; GPR126; Gi; TNBC
资金
- National Key R&D Program of China [2019YFA0904200]
- National Science Fund for Excellent Young Scholars [81822008]
- National Science Fund for Distinguished Young Scholars [81773704]
- National Natural Science Foundation of China [92057121, 31870781, 31971195]
- Shandong Provincial Natural Science Fund for Excellent Young Scholars [ZR2021YQ18]
- Key Research and Development Program of Shandong Province [2021CXGC011105]
- Major Basic Research Project of Shandong Natural Science Foundation [ZR2020ZD39]
- Key Research Project of the Natural Science Foundation of Beijing, China [Z200019]
- Innovative Research Team in University [IRT_17R68]
- Shandong Provincial Natural Science Foundation [ZR2020QH057]
This study identified GPR126 as a membrane receptor for progesterone/17OHP and explored its involvement in potential tumor progression in triple-negative breast cancer.
GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001(ECL2) and F1012(ECL2) are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.
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