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.
Pubmed ID: 15327768 RIS Download
Adenomatous Polyposis Coli Protein | Amino Acid Sequence | Animals | Axin Protein | 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