Crosstalk between Ras/Raf and Tcf signaling following stimulation of the FP prostanoid receptor by prostaglandin‐F2alpha (PGF2a)

Abstract

PGF2α is an autocrine/paracrine hormone that mediates its effects through the G‐protein‐coupled FP prostanoid receptor. We have previously shown that FP receptors can increase T‐cell factor (Tcf) transcriptional activation by stabilization of cytosolic β–catenin. Using HEK 293 cells stably expressing recombinant human FP receptor, and astrocytoma cells expressing endogenous FP receptors, we now show that stimulation with PGF2α activates a novel cell signaling mechanism involving the activation of Ras and B‐Raf followed by Tcf transcriptional activation. We further show by immunoblot analysis, that the activitation of this signaling pathway induces the expression of CYR61 (cysteine‐rich angiogenic protein 61) and CTGF (Connective Tissue Growth Factor). CYR61 and CTGF are members of the CCN family, which have important roles in the regulation of cell adhesion, proliferation, and survival. Both the Ras/Raf and β‐catenin‐Tcf pathways are dysregulated in cancers and suggest that the FP receptor may be an overlooked therapeutic target in the treatment of cancer. Supported by EY11291.