1. Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation
- Author
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Dominguez-Brauer, Carmen, Hao, Zhenyue, Elia, Andrew J, Fortin, Jérôme M, Nechanitzky, Robert, Brauer, Patrick M, Sheng, Yi, Mana, Miyeko D, Chio, Iok In Christine, Haight, Jillian, Pollett, Aaron, Cairns, Robert, Tworzyanski, Leanne, Inoue, Satoshi, Reardon, Colin, Marques, Ana, Silvester, Jennifer, Cox, Maureen A, Wakeham, Andrew, Yilmaz, Omer H, Sabatini, David M, van Es, Johan H, Clevers, Hans, Sato, Toshiro, and Mak, Tak W
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Cancer ,Regenerative Medicine ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research ,Biotechnology ,Digestive Diseases ,Colo-Rectal Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Oral and gastrointestinal ,Adenomatous Polyposis Coli ,Alleles ,Animals ,Carcinogenesis ,Cell Proliferation ,Colonic Neoplasms ,Endocytosis ,Ephrin-B3 ,HEK293 Cells ,Humans ,Intestines ,Lysosomes ,Mice ,Knockout ,Models ,Biological ,Mutation ,Paneth Cells ,Proteasome Endopeptidase Complex ,Proteolysis ,Proto-Oncogene Proteins c-myc ,Stem Cell Niche ,Tumor Suppressor Proteins ,Ubiquitin ,Ubiquitin-Protein Ligases ,Wnt Signaling Pathway ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2016