Signal Transduction Laboratory 

Director
John S. Davis, Ph.D.

Convergence of Wnt and PKA Signaling 

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 gonadotrophin 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 potential point of convergence for multiple signaling pathways, including protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3-K)/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) in the regulation of steroidogenic tissues.  Experiments are underway to dertermine the utility of using adenoviruses to express b-catenin, LRH-1 and green fluorescent protein (GFP), in primary cultures of bovine luteal cells. 

Recent work in our laboratory indicates that signals stimulated by LH may converge with the Wnt signaling pathway. LH increases cAMP and PKA activity in luteal cells which contribute to the phosphorylation and inactivation of GSK-3b. This leads to a reduction in the phosphorylation and accumulation of b-catenin.  Our data suggest that the actions of LH to elevate the transcriptional co-regulator b-catenin correlates with increased expression of genes in the steroidogenic pathway and increased progesterone secretion.  Pharmacologic inhibition of GSK-3b also elevated b-catenin and progesterone synthesis.

Back to main page, Signal Transduction Laboratory