The ERK Signaling Cascade Inhibits Gonadotropin-stimulated Steroidogenesis

• Published in: The Journal of biological chemistry 2001-04, Vol.276 (17), p.13957-13964
• Main Authors: Seger, R, Hanoch, T, Rosenberg, R, Dantes, A, Merz, W E, Strauss, 3rd, J F, Amsterdam, A
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Chorionic Gonadotropin - metabolism; Colforsin - pharmacology; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation; Enzyme Inhibitors - pharmacology; Female; Flavonoids - pharmacology; Follicle Stimulating Hormone - metabolism; Gonadotropins - metabolism; Granulosa Cells - metabolism; Humans; Luteinizing Hormone - metabolism; MAP Kinase Signaling System; Microscopy, Fluorescence; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; Phosphoproteins - biosynthesis; Phosphorylation; Plasmids - metabolism; Progesterone - biosynthesis; Progesterone - metabolism; Protein Binding; Rats; Signal Transduction; Steroids - biosynthesis; Time Factors; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M006852200

The response of granulosa cells to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is mediated mainly by cAMP/protein kinase A (PKA) signaling. Notably, the activity of the extracellular signal-regulated kinase (ERK) signaling cascade is elevated in response to these stimuli as well. We studied the involvement of the ERK cascade in LH- and FSH-induced steroidogenesis in two granulosa-derived cell lines, rLHR-4 and rFSHR-17, respectively. We found that stimulation of these cells with the appropriate gonadotropin induced ERK activation as well as progesterone production downstream of PKA. Inhibition of ERK activity enhanced gonadotropin-stimulated progesterone production, which was correlated with increased expression of the steroidogenic acute regulatory protein (StAR), a key regulator of progesterone synthesis. Therefore, it is likely that gonadotropin-stimulated progesterone formation is regulated by a pathway that includes PKA and StAR, and this process is down-regulated by ERK, due to attenuation of StAR expression. Our results suggest that activation of PKA signaling by gonadotropins not only induces steroidogenesis but also activates down-regulation machinery involving the ERK cascade. The activation of ERK by gonadotropins as well as by other agents may be a key mechanism for the modulation of gonadotropin-induced steroidogenesis.