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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

Authors

  • Ha NC
  • Tonozuka T
  • Stamos JL
  • Choi HJ
  • Weis WI

Journal

Molecular cell

Publication Data

August 27, 2004

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM56169

Mesh Terms

  • 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