Mechanism of Phosphorylation-Dependent Binding of APC to β-Catenin and Its Role in β-Catenin Degradation

Abstract The transcriptional coactivator β-catenin mediates Wnt growth factor signaling. In the absence of a Wnt signal, casein kinase 1 (CK1) and glycogen synthase kinase-3β (GSK-3β) phosphorylate cytosolic β-catenin, thereby flagging it for recognition and destruction by the ubiquitin/proteosome machinery. Phosphorylation occurs in a multiprotein complex that includes the kinases, β-catenin, axin, and the Adenomatous Polyposis Coli (APC) protein. The role of APC in this process is poorly understood. CK1ϵ and GSK-3β phosphorylate APC, which increases its affinity for β-catenin. Crystal structures of phosphorylated and nonphosphoryated APC bound to β-catenin reveal a phosphorylation-dependent binding motif generated by mutual priming of CK1 and GSK-3β substrate sequences. Axin is shown to act as a scaffold for substrate phosphorylation by these kinases. Phosphorylated APC and axin bind to the same surface of, and compete directly for, β-catenin. The structural and biochemical data suggest a novel model for how APC functions in β-catenin degradation.

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