Induction of Gsk3β-β-TrCP interaction is required for late phase stabilization of β-catenin in canonical Wnt signaling.
A pivotal step in canonical Wnt signaling is Wnt-induced β-catenin stabilization. In the absence of Wnt, β-catenin is targeted for β-transducin repeats-containing proteins (β-TrCP)-mediated degradation due to phosphorylation by glycogen synthase kinase 3 (Gsk3). How canonical Wnt signaling regulates Gsk3 to inhibit β-catenin proteolysis remains largely elusive. This study reveals novel key molecular events in Wnt signaling: induction of Gsk3β ubiquitination and Gsk3β-β-TrCP binding. We found that Wnt stimulation induced prolonged monoubiquitination of Gsk3β and Gsk3β-β-TrCP interaction. Monoubiquitination did not cause Gsk3β degradation nor affects its enzymatic activity. Rather, increased monoubiquitination of Gsk3β/Gsk3β-β-TrCP association suppressed β-catenin recruitment of β-TrCP, leading to long-term inhibition of β-catenin ubiquitination and degradation.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Chenxi
C
Gao
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Guangming
G
Chen
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Guillermo
G
Romero
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Stergios
S
Moschos
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Xiang
X
Xu
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213. Electronic address: huj3@upmc.edu.
Jing
J
Hu
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004795:Enzyme Stability; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
C471644:BTRC protein, human; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
Beta-catenin; Glycogen Synthase Kinase 3; Ubiquitin Ligase; Ubiquitination; Wnt Signaling