Convergence of Wnt and PKA Signaling Research

Secretion of progesterone is a primary function of the corpus luteum (CL) and a prerequisite for normal maintenance of pregnancy in all mammals. The single most important factor involved in regulating the secretion of progesterone in the CL, irrespective of species, is luteinizing hormone (LH). This pituitary gonadotropin induces luteinization of follicular cells, formation of the CL, and is capable of extending the functional life span of the CL. The exact mechanism of action of LH is unknown. The phosphorylation of GSK3B (Ser9) is a point of convergence for multiple signaling pathways, including protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K)/Akt, and Wnt. GSK3B is regulated by phosphorylation of the N-terminal serine residue (Ser9) which inactivates GSK3B and prevents the destruction of b-catenin allowing it to translocate to the nucleus and regulate gene expression. Recent studies indicate synergy of b-catenin with Liver receptor homologue-1 (LRH-1 also known as NR5A2) in the regulation of steroidogenic tissues.

Our work indicates that signals stimulated by LH converge with the Wnt signaling pathway. LH increases cAMP and PKA activity in luteal cells which contribute to the inactivation of GSK3B and accumulation of b-catenin. Our data suggest that the actions of LH to elevate b-catenin correlates with increased expression of genes in the steroidogenic pathway and increased progesterone secretion. Current studies are focused on the ability of PKA to phosphorylate b-catenin on novel C-terminal sites and the role these PKA-phospho-sites in the stabilization and cellular localization of b-catenin, and the role of these sites in transcriptional activation.