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.

类固醇激素孕酮（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）介导许多生理过程。mPR信号仍然知之甚少。在这里，我们显示mPRβ的拓扑结构类似于脂连蛋白受体，而与G蛋白偶联受体（GPCR）相反。使用非洲爪蟾卵母细胞减数分裂作为非基因组P4信号的公认生理读数，我们证明mPRβ信号需要适配器蛋白APPL1和激酶Akt2。我们进一步显示，P4诱导网格蛋白依赖的mPRβ内吞作用进入信号内体，其中mPR与APPL1和Akt2瞬时相互作用以诱导减数分裂。我们的发现概述了参与mPR信号传递的早期步骤，并通过涉及APPL1的多种途径扩大了mPR信号传递的范围。