Progesterone activates GPR126 to promote breast cancer development via the Gi pathway.
Progesterone activates GPR126 to promote breast cancer development via the Gi pathway.
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黄体酮通过 Gi 通路激活 GPR126 促进乳腺癌发生
DOI：
10.1073/pnas.2117004119
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发表时间：
2022-04-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
类固醇激素孕酮高度参与不同的生理-病理生理过程，包括骨形成和癌症进展。了解孕激素的作用机制，特别是识别孕激素受体，具有重要的价值。在本研究中，我们发现GPR126是孕酮和17-羟孕酮的膜受体，并触发其下游的G蛋白信号转导。我们进一步鉴定了与这两种配体相互作用的GPR126残基，发现孕酮通过依赖GPR126的GI-SRC信号促进了三阴性乳腺癌模型的进展。因此，开发针对GPR126-GI的拮抗剂可能为三阴性乳腺癌患者提供另一种治疗选择。GPR126是黏附G蛋白偶联受体(AGPCRs)的一员，对多种组织的正常发育至关重要，其突变与多种病理过程有关。在这里，我们通过筛选34种类固醇激素及其衍生物来产生cAMP，我们发现孕酮(P4)和17-羟孕酮(17OHP)可以特异性地激活GPR126，并通过与GPR126 C末端片段七跨膜域的配体口袋结合来触发其下游的GI信号转导。根据计算模拟结构模型对K1001ECL2和F1012ECL2进行了详细的突变筛选，结果表明K1001ECL2和F1012ECL2是特异识别17OHP但不识别孕酮的关键残基。最后，功能分析显示，孕激素触发的GPR126激活在体外促进了细胞的生长，在体内促进了肿瘤的形成，这涉及到三阴性乳腺癌模型中的GI-SRC通路。总之，我们的工作确定了孕酮/17OHP的膜受体，并阐明了GPR126参与三阴性乳腺癌潜在肿瘤进展的机制，这将丰富我们对aGPCR成员GPR126和类固醇激素孕酮的功能和工作机制的理解。
The steroid hormone progesterone is highly involved in different physiological–pathophysiological processes, including bone formation and cancer progression. Understanding the working mechanisms, especially identifying the receptors of progesterone hormones, is of great value. In the present study, we identified GPR126 as a membrane receptor for both progesterone and 17-hydroxyprogesterone and triggered its downstream G protein signaling. We further characterized the residues of GPR126 that interact with these two ligands and found that progesterone promoted the progression of a triple-negative breast cancer model through GPR126-dependent Gi-SRC signaling. Therefore, developing antagonists targeting GPR126-Gi may provide an alternative therapeutic option for patients with 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 K1001ECL2 and F1012ECL2 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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