Reversible modification of adenomatous polyposis coli (APC) with K63-linked polyubiquitin regulates the assembly and activity of the β-catenin destruction complex.

Abstract	The adenomatous polyposis coli (APC) tumor suppressor forms a complex with Axin and GSK3β to promote the phosphorylation and degradation of β-catenin, a key co-activator of Wnt-induced transcription. Here, we establish that APC is modified predominantly with K63-linked ubiquitin chains when it is bound to Axin in unstimulated HEK293 cells. Wnt3a stimulation induced a time-dependent loss of K63-polyubiquitin adducts from APC, an effect synchronous with the dissociation of Axin from APC and the stabilization of cytosolic β-catenin. RNAi-mediated depletion of Axin or β-catenin, which negated the association between APC and Axin, resulted in the absence of K63-adducts on APC. Overexpression of wild-type and phosphodegron-mutant β-catenin, combined with analysis of thirteen human cancer cell lines that harbor oncogenic mutations in APC, Axin, or β-catenin, support the hypothesis that a fully assembled APC-Axin-GSK3β-phospho-β-catenin complex is necessary for the K63-polyubiquitylation of APC. Intriguingly, the degree of this modification on APC appears to correlate inversely with the levels of β-catenin in cells. Together, our results indicate that K63-linked polyubiquitin adducts on APC regulate the assembly and/or efficiency of the β-catenin destruction complex.
Authors	Hoanh Tran, Paul Polakis
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 34 Pg. 28552-63 (Aug 17 2012) ISSN: 1083-351X [Electronic] United States
PMID	22761442 (Publication Type: Journal Article)
Chemical References	APC protein, human Adenomatous Polyposis Coli Protein Axin Protein Multiprotein Complexes WNT3A protein, human Wnt3A Protein beta Catenin GSK3B protein, human Glycogen Synthase Kinase 3 beta Glycogen Synthase Kinase 3
Topics	Adenomatous Polyposis Coli Protein (genetics, metabolism) Axin Protein (genetics, metabolism) Cell Line, Tumor Glycogen Synthase Kinase 3 (genetics, metabolism) Glycogen Synthase Kinase 3 beta HEK293 Cells Humans Multiprotein Complexes (genetics, metabolism) Mutation Proteolysis Ubiquitination Wnt3A Protein (genetics, metabolism) beta Catenin (genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!