Cellular conditioning and activation of β-catenin signaling by the FP_B prostanoid receptor

FP prostanoid receptors have been identified as two isoforms named FP_A and FP_B. We have shown that the FP_B isoform, but not the FP_A, activates β-catenin-mediated transcription. We now report that the mechanism of this FP_B-specific activation of β-catenin signaling occurs in two steps. The first is a conditioning step that involves an agonist-independent association of the FP_B receptor with phosphatidylinositol 3-kinase followed by constitutive internalization of a receptor complex containing E-cadherin and β-catenin. This constitutive internalization conditions the cell for subsequent β-catenin signaling by increasing the cellular content of cytosolic β-catenin. The second step involves agonist-dependent activation of Rho followed by cell rounding. Because of the conditioning step, this agonist-dependent step results in a stabilization of β-catenin and activation of transcription. Although stimulation of the FP_A isoform activates Rho and induces cellular shape change, it does not activate β-catenin signaling, because the FP_A does not undergo constitutive internalization and does not condition the cell for β-catenin signaling. The cellular conditioning described here for the FP_B illustrates the potential of the receptor to alter the signaling environment of a cell even in the absence of agonist and has general significance for understanding G-protein-coupled receptor signaling.