title: Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation.
abstract: The E3 ubiquitin ligase Mule is often overexpressed in human colorectal cancers, but its role in gut tumorigenesis is unknown. Here, we show in vivo that Mule controls murine intestinal stem and progenitor cell proliferation by modulating Wnt signaling via c-Myc. Mule also regulates protein levels of the receptor tyrosine kinase EphB3 by targeting it for proteasomal and lysosomal degradation. In the intestine, EphB/ephrinB interactions position cells along the crypt-villus axis and compartmentalize incipient colorectal tumors. Our study thus unveils an important new avenue by which Mule acts as an intestinal tumor suppressor by regulation of the intestinal stem cell niche.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Dominguez-Brauer
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON 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, ON 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, ON M5G 2C1, Canada.
authors.forename: Jérôme M
authors.initials: JM
authors.lastname: Fortin
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Nechanitzky
authors.affiliation: Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Brauer
authors.affiliation: Department of Biology, York University, Toronto, ON M3J 1P3, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: The David H. Koch Institute of Integrative Cancer Research at MIT, Department of Biology, Cambridge, MA 02139, USA.
authors.forename: Miyeko D
authors.initials: MD
authors.lastname: Mana
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Iok In Christine
authors.initials: IIC
authors.lastname: Chio
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Cairns
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Leanne
authors.initials: L
authors.lastname: Tworzyanski
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Reardon
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Marques
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Silvester
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Cox
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: The David H. Koch Institute of Integrative Cancer Research at MIT, Department of Biology, Cambridge, MA 02139, USA.
authors.forename: Omer H
authors.initials: OH
authors.lastname: Yilmaz
authors.affiliation: The David H. Koch Institute of Integrative Cancer Research at MIT, Department of Biology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, Broad Institute, and Howard Hughes Medical Institute, Cambridge, MA 02142, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Department of Gastroenterology, School of Medicine, Keio University, 35 Shinanomachi, Shinnjukuku, Tokyo 160-8582, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada. Electronic address: tmak@uhnresearch.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000473:pathology; D000483:Alleles; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004705:Endocytosis; D036389:Ephrin-B3 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007422:Intestines / Q000166:cytology*; D008247:Lysosomes / Q000378:metabolism*; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D019879:Paneth Cells / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D055153:Stem Cell Niche; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D036389:Ephrin-B3; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex