The RNA-Binding Protein KSRP Promotes Decay of β-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling

Abstract

β-catenin plays an essential role in several biological events including cell fate determination, cell proliferation, and transformation. Here we report that β-catenin is encoded by a labile transcript whose half-life is prolonged by Wnt and phosphatidylinositol 3-kinase–AKT signaling. AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP's ability to promote rapid mRNA decay. Our results uncover an unanticipated level of control of β-catenin expression pointing to KSRP as a required factor to ensure rapid degradation of β-catenin in unstimulated cells. We propose KSRP phosphorylation as a link between phosphatidylinositol 3-kinase–AKT signaling and β-catenin accumulation. During mammalian development and adulthood, β-catenin regulates the transcription of a family of genes with multiple essential roles in cell proliferation and differentiation. β-catenin also plays a role in cancer when it carries mutations that result in uncontrolled β-catenin function. Here, we report that the lifetime of the β-catenin–encoding transcript is under regulatory control. We show that specific cellular signals relevant to proper mammalian development and implicated in tumor formation can prolong β-catenin transcript half-life, leading to the accumulation of β-catenin protein. We identify a molecular mechanism for this prolongation by showing that a protein factor responsible for β-catenin transcript instability (and thus degradation) is impaired by phosphorylation, a chemical modification. When this factor is impaired, β-catenin mRNA and protein accumulate. Our results point to an unanticipated control of β-catenin levels through regulation of its transcript half-life in response to signals related to proliferation and differentiation.