title: E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling.
abstract: Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to fine-tune the Wnt pathway and provides multiple safeguards against tumorigenesis.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Dominguez-Brauer
authors.affiliation: Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Rahima
authors.initials: R
authors.lastname: Khatun
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Elia
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Ramachandran
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Shakiba P
authors.initials: SP
authors.lastname: Baniasadi
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Jones
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.affiliation: Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada tmak@uhnresearch.ca yisheng@yorku.ca.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada; tmak@uhnresearch.ca yisheng@yorku.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency; D000818:Animals; D060466:Axin Protein / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D003110:Colonic Neoplasms / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000502:physiology; D009940:Organoids / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C111729:Axin2 protein, mouse; C495267:CTNNB1 protein, mouse; C530105:Ccnd1 protein, mouse; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; C000613192:adenomatous polyposis coli protein, mouse; D051176:beta Catenin; D019938:Cyclin D1; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Mule; Wnt signaling; colorectal cancer; stem cells; β-catenin