Neddylation is essential for β-catenin degradation in Wnt signaling pathway. 2022

Bojun Wang, and Tiantian Wang, and Huimin Zhu, and Rong Yan, and Xinru Li, and Chengqian Zhang, and Wanyu Tao, and Xisong Ke, and Piliang Hao, and Yi Qu
Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200, Cailun Road, Shanghai 201203, P.R. China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

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.

UI MeSH Term Description Entries
D011125 Adenomatous Polyposis Coli A polyposis syndrome due to an autosomal dominant mutation of the APC genes (GENES, APC) on CHROMOSOME 5. The syndrome is characterized by the development of hundreds of ADENOMATOUS POLYPS in the COLON and RECTUM of affected individuals by early adulthood. Polyposis Coli, Familial,Polyposis Syndrome, Familial,Adenomatous Polyposis Coli, Familial,Adenomatous Polyposis of the Colon,Familial Adenomatous Polyposis,Familial Adenomatous Polyposis Coli,Familial Adenomatous Polyposis of the Colon,Familial Intestinal Polyposis,Familial Multiple Polyposi,Familial Multiple Polyposis,Familial Multiple Polyposis Syndrome,Familial Polyposis Coli,Familial Polyposis Syndrome,Familial Polyposis of the Colon,Hereditary Polyposis Coli,Myh-Associated Polyposis,Polyposis Coli,Polyposis, Adenomatous Intestinal,Adenomatous Intestinal Polyposes,Adenomatous Intestinal Polyposis,Adenomatous Polyposes, Familial,Adenomatous Polyposis Colus,Adenomatous Polyposis, Familial,Coli, Adenomatous Polyposis,Coli, Familial Polyposis,Coli, Hereditary Polyposis,Coli, Polyposis,Colus, Adenomatous Polyposis,Colus, Familial Polyposis,Colus, Hereditary Polyposis,Colus, Polyposis,Familial Adenomatous Polyposes,Familial Intestinal Polyposes,Familial Multiple Polyposes,Familial Multiple Polyposus,Familial Polyposis Colus,Familial Polyposis Syndromes,Hereditary Polyposis Colus,Intestinal Polyposes, Familial,Intestinal Polyposis, Adenomatous,Intestinal Polyposis, Familial,Multiple Polyposes, Familial,Multiple Polyposi, Familial,Multiple Polyposis, Familial,Multiple Polyposus, Familial,Myh Associated Polyposis,Myh-Associated Polyposes,Polyposes, Familial Adenomatous,Polyposes, Familial Multiple,Polyposes, Myh-Associated,Polyposi, Familial Multiple,Polyposis Coli, Adenomatous,Polyposis Coli, Hereditary,Polyposis Colus,Polyposis Colus, Adenomatous,Polyposis Colus, Familial,Polyposis Colus, Hereditary,Polyposis, Familial Adenomatous,Polyposis, Familial Multiple,Polyposis, Myh-Associated,Polyposus, Familial Multiple
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D051176 beta Catenin A multi-functional catenin that participates in CELL ADHESION and nuclear signaling. Beta catenin binds CADHERINS and helps link their cytoplasmic tails to the ACTIN in the CYTOSKELETON via ALPHA CATENIN. It also serves as a transcriptional co-activator and downstream component of WNT PROTEIN-mediated SIGNAL TRANSDUCTION PATHWAYS. beta-Catenin,Catenin, beta
D054875 Ubiquitination The act of ligating UBIQUITINS to PROTEINS to form ubiquitin-protein ligase complexes to label proteins for transport to the PROTEASOME ENDOPEPTIDASE COMPLEX where proteolysis occurs. Ubiquitylation
D060449 Wnt Signaling Pathway A complex signaling pathway whose name is derived from the DROSOPHILA Wg gene, and the vertebrate INT gene. The signaling pathway is initiated by the binding of WNT PROTEINS to cell surface WNT RECEPTORS which interact with the AXIN SIGNALING COMPLEX and an array of second messengers that influence the actions of BETA CATENIN. Wnt Signaling,Wnt Pathway,Wnt Pathway, Canonical,Wnt beta-Catenin Signaling Pathway,Canonical Wnt Pathway,Canonical Wnt Pathways,Pathway, Canonical Wnt,Pathway, Wnt,Pathway, Wnt Signaling,Signaling Pathway, Wnt,Signaling, Wnt,Wnt Signaling Pathways,Wnt Signalings,Wnt beta Catenin Signaling Pathway
D025601 Adenomatous Polyposis Coli Protein A negative regulator of beta-catenin signaling which is mutant in ADENOMATOUS POLYPOSIS COLI and GARDNER SYNDROME.

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