Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex.
Degradation of cytosolic β-catenin by the APC/Axin1 destruction complex represents the key regulated step of the Wnt pathway. It is incompletely understood how the Axin1 complex exerts its Wnt-regulated function. Here, we examine the mechanism of Wnt signaling under endogenous levels of the Axin1 complex. Our results demonstrate that β-catenin is not only phosphorylated inside the Axin1 complex, but also ubiquinated and degraded via the proteasome, all within an intact Axin1 complex. In disagreement with current views, we find neither a disassembly of the complex nor an inhibition of phosphorylation of Axin1-bound β-catenin upon Wnt signaling. Similar observations are made in primary intestinal epithelium and in colorectal cancer cell lines carrying activating Wnt pathway mutations. Wnt signaling suppresses β-catenin ubiquitination normally occurring within the complex, leading to complex saturation by accumulated phospho-β-catenin. Subsequently, newly synthesized β-catenin can accumulate in a free cytosolic form and engage nuclear TCF transcription factors.
Hubrecht Institute, KNAW and University Medical Centre Utrecht, The Netherlands.
Vivian S W
VS
Li
Ser Sue
SS
Ng
Paul J
PJ
Boersema
Teck Y
TY
Low
Wouter R
WR
Karthaus
Jan P
JP
Gerlach
Shabaz
S
Mohammed
Albert J R
AJ
Heck
Madelon M
MM
Maurice
Tokameh
T
Mahmoudi
Hans
H
Clevers
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D060466:Axin Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000032:analysis / Q000737:chemistry; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C555337:APC protein, human; C555451:AXIN1 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D010455:Peptides; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex