Fertility in females requires controlled maturation of the oocyte, supporting granulosa cells (GCs), and thecal cells that comprise the ovarian follicle. Follicle growth is a dynamic process that demands exquisite regulation. Follicles are restrained at the preantral stage until they are stimulated by the pituitary hormone follicle stimulating hormone (FSH). In response to FSH GCs produce steroid and protein hormones and growth factors that regulate the hypothalamic/pituitary axis and uterine receptivity, and promote oocyte maturation and development of the follicle to a preovulatory phenotype. All of the documented responses to FSH are mediated via cAMP and it's predominate intracellular target, cAMP-dependent protein kinase (PKA). Indeed, GCs offer one of the best examples of a cellular model whose responses are orchestrated by PKA. Signaling by PKA is confined to specific locations in cells by virtue of a family of A-kinase anchoring proteins (AKAPs) that localize pools of PKA, their substrates, and interconnected signaling enzymes. This application focuses on the mechanisms by which PKA integrates transcriptional networks to imitate maturation of GCs. PKA accomplishes this integrating function by phosphorylating substrates that directly regulate transcription or by regulating pathways whose targets regulate transcription. The co-activator beta-catenin is emerging as one potential PKA substrate necessary for activation of a subset of FSH target genes. PKA also phosphorylates an unidentified substrate that directs activation of the phosphatidylinositol-3 kinase (PI-3K) pathway fundamental to GC survival, proliferation, and differentiation. Among the many PI-3K pathway targets, the transcriptional factor FOXO1 (forkhead box O factor 1) requires phosphorylation/inactivation to permit induction of at least a subset of FSH target genes. We postulate that PKA phosphorylates both beta-catenin to activate its co- activator activity and a substrate to direct activation of the PI-3K pathway to activate and inactivate a network of FOXO1-regulated target genes.
Aims test the following hypotheses: that a specific AKAP targets a pool of PKA to a multi-enzyme complex that directs activation of PI-3K;that induction of FSH target genes like Lhcgr requires activation of beta-catenin;and that the PI-3K pathway target FOXO1 regulates a network of direct target genes that maintain GCs in an immature stage. Understanding how FSH signals to direct follicular maturation can translate into safer and more effective treatments of infertility and early pregnancy loss as well as new approaches for contraceptive drugs.
FSH signaling to mature follicles to the preovulatory phenotype is required for fertility. Understanding how FSH signals to direct follicular maturation can translate into safer and more effective treatments of infertility and early pregnancy loss as well as new approaches for contraceptive drugs.
|Law, Nathan C; Donaubauer, Elyse M; Zeleznik, Anthony J et al. (2017) How Protein Kinase A Activates Canonical Tyrosine Kinase Signaling Pathways To Promote Granulosa Cell Differentiation. Endocrinology 158:2043-2051|
|Puri, Pawan; Little-Ihrig, Lynda; Chandran, Uma et al. (2016) Protein Kinase A: A Master Kinase of Granulosa Cell Differentiation. Sci Rep 6:28132|
|Ponder, Kathryn L; Bárcena, Alicia; Bos, Frank L et al. (2016) Preeclampsia and Inflammatory Preterm Labor Alter the Human Placental Hematopoietic Niche. Reprod Sci 23:1179-92|
|Donaubauer, Elyse M; Hunzicker-Dunn, Mary E (2016) Extracellular Signal-regulated Kinase (ERK)-dependent Phosphorylation of Y-Box-binding Protein 1 (YB-1) Enhances Gene Expression in Granulosa Cells in Response to Follicle-stimulating Hormone (FSH). J Biol Chem 291:12145-60|
|Herndon, Maria K; Law, Nathan C; Donaubauer, Elyse M et al. (2016) Forkhead box O member FOXO1 regulates the majority of follicle-stimulating hormone responsive genes in ovarian granulosa cells. Mol Cell Endocrinol 434:116-26|
|Law, Nathan C; White, Morris F; Hunzicker-Dunn, Mary E (2016) G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway. J Biol Chem 291:27160-27169|
|Law, Nathan C; Hunzicker-Dunn, Mary E (2016) Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation. J Biol Chem 291:4547-60|
|Law, Nathan C; Weck, Jennifer; Kyriss, Brandon et al. (2013) Lhcgr expression in granulosa cells: roles for PKA-phosphorylated ?-catenin, TCF3, and FOXO1. Mol Endocrinol 27:1295-310|
|Hunzicker-Dunn, Mary E; Lopez-Biladeau, Blanca; Law, Nathan C et al. (2012) PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells. Proc Natl Acad Sci U S A 109:E2979-88|