Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation

• Published in: The Journal of biological chemistry Vol. 291; no. 9; pp. 4547 - 4560
• Main Authors: Law, Nathan C., Hunzicker-Dunn, Mary E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.02.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Enzyme Activation; Female; Follicle Stimulating Hormone - metabolism; follicle-stimulating hormone (FSH); G-protein coupled receptor (GPCR); Granulosa Cells - cytology; Granulosa Cells - metabolism; Humans; insulin receptor substrate 1 (IRS-1); Insulin Receptor Substrate Proteins - agonists; Insulin Receptor Substrate Proteins - antagonists & inhibitors; Insulin Receptor Substrate Proteins - metabolism; insulin-like growth factor (IGF); Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Mutation; Phosphatidylinositol 3-Kinase - chemistry; Phosphatidylinositol 3-Kinase - metabolism; phosphoprotein phosphatase 1 (PP1); Phosphorylation; protein kinase A (PKA); Protein Phosphatase 1 - antagonists & inhibitors; Protein Phosphatase 1 - chemistry; Protein Phosphatase 1 - genetics; Protein Phosphatase 1 - metabolism; Protein Processing, Post-Translational; Rats, Sprague-Dawley; Receptor, IGF Type 1 - agonists; Receptor, IGF Type 1 - metabolism; Recombinant Proteins - metabolism; RNA Interference; Signal Transduction; Tyrosine - metabolism; phosphoprotein phosphatase 1 (PP1); protein kinase A (PKA); insulin receptor substrate 1 (IRS-1); G-protein coupled receptor (GPCR); insulin-like growth factor (IGF); follicle-stimulating hormone (FSH)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.698761

The ubiquitous phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many cellular functions. However, the mechanism by which G protein-coupled receptors (GPCRs) signal to activate PI3K is poorly understood. We have used ovarian granulosa cells as a model to investigate this pathway, based on evidence that the GPCR agonist follicle-stimulating hormone (FSH) promotes the protein kinase A (PKA)-dependent phosphorylation of insulin receptor substrate 1 (IRS1) on tyrosine residues that activate PI3K. We report that in the absence of FSH, granulosa cells secrete a subthreshold concentration of insulin-like growth factor-1 (IGF-1) that primes the IGF-1 receptor (IGF-1R) but fails to promote tyrosine phosphorylation of IRS1. FSH via PKA acts to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R by activating protein phosphatase 1 (PP1) to promote dephosphorylation of inhibitory Ser/Thr residues on IRS1, including Ser789. Knockdown of PP1β blocks the ability of FSH to activate PI3K in the presence of endogenous IGF-1. Activation of PI3K thus requires both PKA-mediated relief of IRS1 inhibition and IGF-1R-dependent tyrosine phosphorylation of IRS1. Treatment with FSH and increasing concentrations of exogenous IGF-1 triggers synergistic IRS1 tyrosine phosphorylation at PI3K-activating residues that persists downstream through protein kinase B (AKT) and FOXO1 (forkhead box protein O1) to drive synergistic expression of genes that underlies follicle maturation. Based on the ability of GPCR agonists to synergize with IGFs to enhance gene expression in other cell types, PP1 activation to relieve IRS1 inhibition may be a more general mechanism by which GPCRs act with the IGF-1R to activate PI3K/AKT.