Understanding the Molecular Link Between FSH and IGF-1 Signaling in Rat Granulosa Cells
Law, Nathan Christopher
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Mouse knockout models define follicle-stimulating hormone (FSH) and insulin-like growth factor-1 (IGF-1) as pivotal co-regulators of ovarian follicle maturation and hence, female fertility. Moreover, numerous studies report that FSH and IGF-1 synergistically regulate the expression of genes necessary to promote follicle maturation. Statistical synergy identifies a physical intersection between two signaling pathways, producing a greater-than-additive response. However, the mechanism underlying FSH and IGF-1 cross-talk remains a major unresolved aspect of ovarian physiology. We report the unexpected convergence of FSH and IGF-1 pathways at insulin receptor substrate 1 (IRS1) in rat granulosa cells (GCs). GCs secrete a subthreshold concentration of IGF-1 in the absence of FSH that primes the IGF-1R, but fails to stimulate IGF-1R-dependent IRS1 YMXM phosphorylation that activates the phosphoinositide-3 kinase (PI3K)/AKT pathway. Thus, IRS1 YMXM phosphorylation is the rate-determining step in FSH-dependent PI3K/AKT activation. Data herein support the notion that IRS1 is restrained to YMXM phosphorylation by the IGF-1R due to inhibitory Ser/Thr phosphorylation on IRS1. FSH signals via its G protein-coupled receptor (GPCR) and the downstream effector protein kinase A (PKA) to activate protein phosphatase 1 (PP1). PP1 facilitates dephosphorylation of four IRS1 Ser/Thr residues, Ser789, Ser612, Ser346, and Ser318, to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R and promote IGF-1R-dependent IRS1 YMXM phosphorylation and PI3K/ATK activation. By this mechanism, FSH-stimulated IRS1/PI3K/AKT activation is triggered in the presence of endogenous IGF-1 or synergistically enhanced in the presence of exogenous IGF-1. Synergistic IRS1 YMXM phosphorylation persists downstream through the transcription factor forkhead box O1 to drive the synergistic expression of genes that promote follicle maturation. With IGF expression nearly ubiquitous in mammal, we also show that GPCR- mediated PP1 activation to relieve IRS1 inhibition is a more universal mechanism by which GPCRs act in conjunction with the IGF-1R to activate the PI3K/AKT pathway. The PI3K/AKT pathway is known to regulate numerous cell functions, including apoptosis, proliferation, metabolism, and differentiation. Based on the widespread expression of GPCRs in nearly every tissue, the ability of GPCRs to activate the PI3K/AKT is important in for a wide range of cell types beyond preantral GCs.