90K Glycoprotein Promotes Degradation of Mutant β-Catenin Lacking the ISGylation or Phosphorylation Sites in the N-terminus

Neoplasia. 2016 Oct;18(10):618-625. doi: 10.1016/j.neo.2016.08.006. Epub 2016 Sep 23.

Abstract

β-Catenin is a major transducer of the Wnt signaling pathway, which is aberrantly expressed in colorectal and other cancers. Previously, we showed that β-catenin is downregulated by the 90K glycoprotein via ISGylation-dependent degradation. However, the further mechanisms of β-catenin degradation by 90K-mediated ISGylation pathway were not investigated. This study aimed to identify the β-catenin domain responsible for the action of 90K and to compare the mechanism of 90K on β-catenin degradation with phosphorylation-dependent ubiquitinational degradation of β-catenin. The deletion mutants of β-catenin lacking N- or C-terminal domain or mutating the N-terminal lysine or nonlysine residue were employed to delineate the characteristics of β-catenin degradation by 90K-mediated ISGylation pathway. 90K induced Herc5 and ISG15 expression and reduced β-catenin levels in HeLa and CSC221 cells. The N-terminus of β-catenin is required for 90K-induced β-catenin degradation, but the N-terminus of β-catenin is not essential for interaction with Herc5. However, substituting lysine residues in the N-terminus of β-catenin with arginine or deleting serine or threonine residue containing domains from the N-terminus does not affect 90K-induced β-catenin degradation, indicating that the N-terminal 86 amino acids of β-catenin are crucial for 90K-mediated ISGylation/degradation of β-catenin in which the responsible lysine or nonlysine residues were not identified. Our present results highlight the action of 90K on promoting degradation of mutant β-catenin lacking the phosphorylation sites in the N-terminus. It provides further insights into the discrete pathway downregulating the stabilized β-catenin via acquiring mutations at the serine/threonine residues in the N-terminus.

MeSH terms

  • Antigens, Neoplasm / metabolism*
  • Biomarkers, Tumor / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Gene Deletion
  • Glycoproteins / metabolism*
  • Glycosylation
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mutant Proteins*
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs*
  • Proteolysis
  • Signal Transduction
  • beta Catenin / chemistry
  • beta Catenin / deficiency
  • beta Catenin / metabolism*

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Carrier Proteins
  • Glycoproteins
  • HERC5 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LGALS3BP protein, human
  • Mutant Proteins
  • beta Catenin