Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation.

The transcriptional coactivator beta-catenin mediates Wnt growth factor signaling. In the absence of a Wnt signal, casein kinase 1 (CK1) and glycogen synthase kinase-3beta (GSK-3beta) phosphorylate cytosolic beta-catenin, thereby flagging it for recognition and destruction by the ubiquitin/proteosome machinery. Phosphorylation occurs in a multiprotein complex that includes the kinases, beta-catenin, ...
axin, and the Adenomatous Polyposis Coli (APC) protein. The role of APC in this process is poorly understood. CK1epsilon and GSK-3beta phosphorylate APC, which increases its affinity for beta-catenin. Crystal structures of phosphorylated and nonphosphorylated APC bound to beta-catenin reveal a phosphorylation-dependent binding motif generated by mutual priming of CK1 and GSK-3beta 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, beta-catenin. The structural and biochemical data suggest a novel model for how APC functions in beta-catenin degradation.
Mesh Terms:
Adenomatous Polyposis Coli Protein, Amino Acid Sequence, Animals, Casein Kinases, Crystallography, X-Ray, Cytoskeletal Proteins, Glycogen Synthase Kinase 3, Humans, Mice, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Kinases, Protein Structure, Tertiary, Proto-Oncogene Proteins, Repressor Proteins, Signal Transduction, Trans-Activators, Wnt Proteins, beta Catenin
Mol. Cell
Date: Aug. 27, 2004
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