Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation

Carmen Dominguez-Brauer; Zhenyue Hao; Andrew J Elia; Jérôme M Fortin; Robert Nechanitzky; Patrick M Brauer; Yi Sheng; Miyeko D Mana; Iok In Christine Chio; Jillian Haight; Aaron Pollett; Robert Cairns; Leanne Tworzyanski; Satoshi Inoue; Colin Reardon; Ana Marques; Jennifer Silvester; Maureen A Cox; Andrew Wakeham; Omer H Yilmaz; David M Sabatini; Johan H van Es; Hans Clevers; Toshiro Sato; Tak W Mak

doi:10.1016/j.stem.2016.04.002

Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation

Cell Stem Cell. 2016 Aug 4;19(2):205-216. doi: 10.1016/j.stem.2016.04.002. Epub 2016 May 12.

Authors

Carmen Dominguez-Brauer¹, Zhenyue Hao¹, Andrew J Elia¹, Jérôme M Fortin¹, Robert Nechanitzky¹, Patrick M Brauer², Yi Sheng³, Miyeko D Mana⁴, Iok In Christine Chio⁵, Jillian Haight¹, Aaron Pollett⁶, Robert Cairns¹, Leanne Tworzyanski¹, Satoshi Inoue¹, Colin Reardon⁷, Ana Marques¹, Jennifer Silvester¹, Maureen A Cox¹, Andrew Wakeham¹, Omer H Yilmaz⁴, David M Sabatini⁸, Johan H van Es⁹, Hans Clevers⁹, Toshiro Sato¹⁰, Tak W Mak¹¹

Affiliations

¹ The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
² Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
³ Department of Biology, York University, Toronto, ON M3J 1P3, Canada.
⁴ The David H. Koch Institute of Integrative Cancer Research at MIT, Department of Biology, Cambridge, MA 02139, USA.
⁵ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
⁶ Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
⁷ Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA 95616, USA.
⁸ 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.
⁹ Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
¹⁰ Department of Gastroenterology, School of Medicine, Keio University, 35 Shinanomachi, Shinnjukuku, Tokyo 160-8582, Japan.
¹¹ The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada. Electronic address: tmak@uhnresearch.ca.

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.

MeSH terms

Adenomatous Polyposis Coli / pathology
Alleles
Animals
Carcinogenesis / metabolism
Carcinogenesis / pathology
Cell Proliferation
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology
Endocytosis
Ephrin-B3 / metabolism*
HEK293 Cells
Humans
Intestines / cytology*
Lysosomes / metabolism*
Mice, Knockout
Models, Biological
Mutation / genetics
Paneth Cells / pathology
Proteasome Endopeptidase Complex / metabolism*
Proteolysis*
Proto-Oncogene Proteins c-myc / metabolism
Stem Cell Niche*
Tumor Suppressor Proteins
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / deficiency
Ubiquitin-Protein Ligases / metabolism*
Wnt Signaling Pathway*

Substances

Ephrin-B3
Proto-Oncogene Proteins c-myc
Tumor Suppressor Proteins
Ubiquitin
Huwe1 protein, mouse
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex

Abstract

MeSH terms

Substances

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