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. YilmazDavid M. Sabatini, Johan H. van Es, Hans Clevers, Toshiro Sato, Tak W. Mak

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)205-216
Number of pages12
JournalCell Stem Cell
Volume19
Issue number2
DOIs
StatePublished - Aug 4 2016

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ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Dominguez-Brauer, C., Hao, Z., Elia, A. J., Fortin, J. M., Nechanitzky, R., Brauer, P. M., Sheng, Y., Mana, M. D., Chio, I. I. C., Haight, J., Pollett, A., Cairns, R., Tworzyanski, L., Inoue, S., Reardon, C., Marques, A., Silvester, J., Cox, M. A., Wakeham, A., ... Mak, T. W. (2016). Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation. Cell Stem Cell, 19(2), 205-216. https://doi.org/10.1016/j.stem.2016.04.002