| The F prostanoid receptor (FP receptor) is a GPCR that, upon binding of prostaglandin F2alpha (PGF2alpha), mediates IP3 production and PKC-dependent MAPK activation. We report that AL-8810, a characterized antagonist for PGF2alpha-dependent IP3 production, potently activates ERK1/2 in a PKC-independent manner, since PGF2alpha induced PKCbeta1-GFP translocation, while AL-8810 did not. AL-8810, though, induced EGFR phosphorylation, and the resultant ERK1/2 activation was inhibited by an EGFR antagonist, which suggested a transactivation signalling pathway. Batimastat, a matrix metalloprotease (MMP) inhibitor abolished both AL-8810- and PGF2alpha-induced ERK1/2, and therefore PGF2alpha may also signal through EGFR-independent transactivation. In osteoblasts, both PGF2alpha and AL-8810 activated MAPK in an EGFR-dependent manner, though PKC remained essential for PGF2alpha, as IL-6 and cell proliferation (known PKC effects) were induced by PGF2alpha but not AL-8810. Here, we highlight the biased signalling of AL-8810 on FP receptor produced MAPK through EGFR-MMP-mediated transactivation and also suggest a novel PGF2alpha-induced PKC-MMP, EGFR-independent, pathway. |
