The classical progesterone receptor associates with p42 MAPK and is involved in phosphatidylinositol 3-kinase signaling in Xenopus oocytes

The induction of Xenopus laevis oocyte maturation by progesterone is a striking example of a steroid hormone-mediated event that does not require transcription. Here we have investigated the role of the classical progesterone receptor in this nongenomic signaling. The Xenopus progesterone receptor (XPR) was predominantly cytoplasmic; however, a significant fraction (similar to5%) of one form of the receptor (p82 XPR) was associated with the plasma membrane-containing P-10,000 fraction, compatible with the observation that membrane-impermeant derivatives of progesterone can induce maturation. XPR co-precipitated with active phosphatidylinositol 3-kinase. The phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin delayed progesterone-induced maturation and completely blocked the insulin-dependent maturation, indicating that the association of XPR with PI3-K could be functionally important. We also examined whether the nongenomic signaling properties of XPR can account for the ability of glucocorticoids and the progesterone antagonist RU486 to induce maturation. We found that none of these steroids cause XPR to become associated with active PI3-K; thus, association of XPR with active PI3-K is progesterone-specific. Finally, we showed that p42 mitogen-activated protein kinase (MAPK) associates with XPR after progesterone-induced germinal vesicle breakdown and that active recombinant MAPK is able to phosphorylate p110 XPR in vitro. These findings demonstrate that the classical progesterone receptor is involved in progesterone-induced nongenomic signaling in Xenopus oocytes and provide evidence that p42 MAPK and PI3-K activity are directly associated with the classical progesterone receptor.