90K Glycoprotein Promotes Degradation of Mutant β-Catenin Lacking the ISGylation or Phosphorylation Sites in the N-terminus.
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.
College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, South Korea.
So-Yeon
SY
Park
Medical Research Center for Gene Regulation, The Brain Korea 21 Project, Chonnam National University Medical School, Kwangju, South Korea.
Somy
S
Yoon
College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, South Korea. Electronic address: hangunkim@sunchon.ac.kr.
Hangun
H
Kim
Medical Research Center for Gene Regulation, The Brain Korea 21 Project, Chonnam National University Medical School, Kwangju, South Korea. Electronic address: kimkk@chonnam.ac.kr.
Kyung Keun
KK
Kim
D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D017353:Gene Deletion; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050505:Mutant Proteins; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D015398:Signal Transduction; D051176:beta Catenin / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D016326:Extracellular Matrix Proteins
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D051176:beta Catenin; C402395:HERC5 protein, human; C081856:LGALS3BP protein, human; D016326:Extracellular Matrix Proteins
Cancer Res. 1995 Aug 1;55(15):3223-7
7542166
Chem Rev. 2011 Dec 14;111(12):7923-40
22004258
Biochim Biophys Acta. 2003 Jun 5;1653(1):1-24
12781368
J Cell Sci. 2012 Feb 1;125(Pt 3):539-48
22389393
Mol Cell. 2001 May;7(5):915-26
11389839
Cell Signal. 2014 Mar;26(3):570-9
24308963
Genes Dev. 2000 Aug 1;14 (15):1837-51
10921899
J Biol Chem. 2005 Jun 10;280(23):22462-72
15797863
Cell Cycle. 2014;13(14):2200-10
24844324
Nucleic Acids Res. 2011 Jan;39(Database issue):D945-50
20952405
Clin Cancer Res. 2013 Nov 1;19(21):5927-39
24056783
J Cell Biochem. 2006 Aug 1;98(5):1351-66
16518858
Prostate. 2006 Feb 15;66(3):283-93
16245278
Cancer Res. 2002 May 1;62(9):2535-9
11980646
Mol Biol Cell. 2000 Oct;11(10):3509-23
11029052
Genes Dev. 2005 Apr 15;19(8):877-90
15833914
Structure. 2008 Mar;16(3):478-87
18334222
Br J Cancer. 1994 Jan;69(1):172-6
8286203
Mol Cell. 2001 May;7(5):927-36
11389840
PLoS One. 2012;7(6):e38294
22693631
J Interferon Cytokine Res. 2011 Jan;31(1):119-30
21190487
Biochim Biophys Acta. 2014 Jan;1843(1):86-96
23872423
Glycoconj J. 2004;19(7-9):551-6
14758079
Oncogene. 2006 Dec 4;25(57):7482-91
17143292
Gut. 2010 Jul;59(7):907-17
20581239