The Role of EGFR Signaling in Gonadotropin-Induced Steroidogenesis
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Recent evidence has demonstrated that cross talk between G protein-coupled receptors and Epidermal Growth Factor Receptor (EGFR) is critical for steroidogenesis in all three major steroid-producing tissues. We have recently characterized the intracellular signals regulating Luteinizing Hormone (LH) -induced steroid production in Leydig cells, demonstrating a linear pathway whereby LH receptor activation stimulates cAMP production and PKA signaling. Protein Kinase A (PKA) signaling then triggers EGF receptor activation, which activates the Mitogen Activated Protein Kinase (MAPK) cascade to promote steroidogenic acute regulatory (StAR) phosphorylation and translocation to the mitochondria. Interesting, PKA-mediated transactivation of the EGF receptor occurs via both intracellular, ligand-independent signaling, as well as extracellular, ligand-dependent activation that requires Matrix Metalloproteinase (MMP)-mediated release of membrane-bound EGF receptor ligands. However, only intracellular signaling is required for LH-induced steroid production. Furthermore, the LH-EGFR pathway appears to be important only for early steroidogenesis in Leydig cells, as LHinduced steroidogenesis beyond 60 minutes no longer requires EGFR or MAPK signaling. Here we characterize the LH-induced signals that regulate steroidogenesis in the ovary. We demonstrate that, similar to Leydig cells, activation of the EGF receptor is important for gonadotropin-induced steroid production in the ovary. Trans-activation of the EGFR is mediated by an increase of cAMP and PKA signaling. However, steroidogenesis in the ovary is dependent on an extracellular ligandindependent mechanism, as MMPs were shown to be crucial for the cleavage and activation of membrane bound EGFR upon LH stimulation. EGFR signaling was shown to activate the MAPK cascade and lead to subsequent phosphorylation of the steroidogenic acute regulatory protein (StAR). Interestingly, EGFR and MAPK signaling, unlike that in Leydig cells, as necessary for short and long term gonadotropininduced steroid production in the ovary. In vivo studies further demonstrate the importance of EGFR signaling since serum progesterone levels were significantly reduced when EGFR was inhibited. These findings demonstrate physiologic importance and potential treatment options since women with endocrine disorder such as PCOS can be treated with EGFR antagonist to reduce excess steroid production in the ovary.