Hot spots in beta-catenin for interactions with LEF-1, conductin and APC.
Interactions between beta-catenin and LEF-1/TCF, APC and conductin/axin are essential for wnt-controlled stabilization of beta-catenin and transcriptional activation. The wnt signal transduction pathway is important in both embryonic development and tumor progression. We identify here amino acid residues in beta-catenin that distinctly affect its binding to LEF-1/TCF, APC and conductin. These residues form separate surface clusters, termed hot spots, along the armadillo superhelix of beta-catenin. We also show that complementary charged and hydrophobic amino acids are required for formation of the bipartite beta-catenin-LEF-1 transcription factor. Moreover, we demonstrate that conductin/axin binding to beta-catenin is essential for beta-catenin degradation, and that APC acts as a cofactor of conductin/axin in this process. Binding of APC to conductin/axin activates the latter and occurs between their SAMP and RGS domains, respectively.
von Kries
J P
JP
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13093 Berlin, Germany.
Winbeck
G
G
Asbrand
C
C
Schwarz-Romond
T
T
Sochnikova
N
N
Dell'Oro
A
A
Behrens
J
J
Birchmeier
W
W
D025601:Adenomatous Polyposis Coli Protein; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008024:Ligands; D051821:Lymphoid Enhancer-Binding Factor 1; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques; D051176:beta Catenin
C491761:AXIN2 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; D008024:Ligands; D051821:Lymphoid Enhancer-Binding Factor 1; D009363:Neoplasm Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin