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

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2016-10, Vol.18 (10), p.618-625
• Main Authors: Park, So-Yeon, Yoon, Somy, Kim, Hangun, Kim, Kyung Keun
• Format: Article
• Language: English
• ISSN: 1522-8002
• DOI: 10.1016/j.neo.2016.08.006

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