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

• Published in: Molecular cell 2004-08, Vol.15 (4), p.511-521
• Main Authors: Ha, Nam-Chul, Tonozuka, Takashi, Stamos, Jennifer L., Choi, Hee-Jung, Weis, William I.
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - chemistry; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Amino Acid Sequence; Animals; Axin Protein; beta Catenin; Casein Kinases; Crystallography, X-Ray; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Humans; Mice; Models, Molecular; Molecular Sequence Data; Phosphorylation; Protein Binding; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Structure, Tertiary; Proto-Oncogene Proteins - metabolism; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; Wnt Proteins
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2004.08.010

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.