Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar.
Calcium Signaling Group, Weill Cornell Medicine Qatar.
PLoS Biol. 2020 Nov 2;18(11):e3000901. doi: 10.1371/journal.pbio.3000901. eCollection 2020 Nov.
The steroid hormone progesterone (P4) mediates many physiological processes through either nuclear receptors that modulate gene expression or membrane P4 receptors (mPRs) that mediate nongenomic signaling. mPR signaling remains poorly understood. Here we show that the topology of mPRβ is similar to adiponectin receptors and opposite to that of G-protein-coupled receptors (GPCRs). Using Xenopus oocyte meiosis as a well-established physiological readout of nongenomic P4 signaling, we demonstrate that mPRβ signaling requires the adaptor protein APPL1 and the kinase Akt2. We further show that P4 induces clathrin-dependent endocytosis of mPRβ into signaling endosome, where mPR interacts transiently with APPL1 and Akt2 to induce meiosis. Our findings outline the early steps involved in mPR signaling and expand the spectrum of mPR signaling through the multitude of pathways involving APPL1.
甾体激素孕酮（P4）通过调节基因表达的核受体或介导非基因组信号的膜 P4 受体（mPR）来介导许多生理过程。mPR 信号仍然知之甚少。在这里，我们表明 mPRβ 的拓扑结构类似于脂联素受体，而与 G 蛋白偶联受体（GPCR）相反。我们使用非洲爪蟾卵母细胞减数分裂作为非基因组 P4 信号的既定生理读出，证明 mPRβ 信号需要衔接蛋白 APPL1 和激酶 Akt2。我们进一步表明，P4 将 mPRβ 内吞进入信号内体，在信号内体中，mPR 与 APPL1 和 Akt2 短暂相互作用以诱导减数分裂。我们的发现概述了 mPR 信号涉及的早期步骤，并通过涉及 APPL1 的多种途径扩展了 mPR 信号的范围。
