Neddylation is essential for β-catenin degradation in Wnt signaling pathway

Cell Rep. 2022 Mar 22;38(12):110538. doi: 10.1016/j.celrep.2022.110538.

Abstract

β-Catenin is a central component in the Wnt signaling pathway; its degradation has been tightly connected to ubiquitylation, but it is rarely examined by loss-of-function assays. Here we observe that endogenous β-catenin is not stabilized upon ubiquitylation depletion by a ubiquitylation inhibitor, TAK-243. We demonstrate that N-terminal phosphorylated β-catenin is quickly and strongly stabilized by a specific neddylation inhibitor, MLN4924, in all examined cell types, and that β-catenin and TCF4 interaction is strongly enhanced by inhibition of neddylation but not ubiquitylation. We also confirm that the E3 ligase β-TrCP2, but not β-TrCP1, is associated with neddylation and destruction of β-catenin. GSK3β and adenomatous polyposis coli (APC) are not required for β-catenin neddylation but essential for its subsequent degradation. Our findings not only clarify the process of β-catenin modification and degradation in the Wnt signaling pathway but also highlight the importance of reassessing previously identified ubiquitylation substrates.

Keywords: CP; CP: Molecular Biology; Molecular Biology; Wnt signaling pathway; neddylation; stabilization; ubiquitylation; β-TrCP2; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli* / metabolism
  • Humans
  • Ubiquitination
  • Wnt Signaling Pathway / physiology
  • beta Catenin* / metabolism

Substances

  • Adenomatous Polyposis Coli Protein
  • beta Catenin