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

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

18 Citations (Scopus)

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 language	English
Journal	Cell Stem Cell
Early online date	12 May 2016
DOIs	https://doi.org/10.1016/j.stem.2016.04.002
Publication status	Published - 04 Aug 2016

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10.1016/j.stem.2016.04.002

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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. https://doi.org/10.1016/j.stem.2016.04.002

@article{6e8146721ebb4d50b980b5a1e6684318,

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.",

author = "Carmen Dominguez-Brauer and Zhenyue Hao and Elia, {Andrew J} and Fortin, {J{\'e}r{\^o}me M} and Robert Nechanitzky and Brauer, {Patrick M} and Yi Sheng and Mana, {Miyeko D} and Chio, {Iok In Christine} and Jillian Haight and Aaron Pollett and Robert Cairns and Leanne Tworzyanski and Satoshi Inoue and Colin Reardon and Ana Marques and Jennifer Silvester and Cox, {Maureen A} and Andrew Wakeham and Yilmaz, {Omer H} and Sabatini, {David M} and {van Es}, {Johan H} and Hans Clevers and Toshiro Sato and Mak, {Tak W}",

year = "2016",

month = aug,

day = "4",

doi = "10.1016/j.stem.2016.04.002",

language = "English",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

}

Dominguez-Brauer, C, Hao, Z, Elia, AJ, Fortin, JM, Nechanitzky, R, Brauer, PM, Sheng, Y, Mana, MD, Chio, IIC, Haight, J, Pollett, A, Cairns, R, Tworzyanski, L, Inoue, S, Reardon, C, Marques, A, Silvester, J, Cox, MA, Wakeham, A, Yilmaz, OH, Sabatini, DM, van Es, JH , Clevers, H, Sato, T & Mak, TW 2016, 'Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation', Cell Stem Cell. https://doi.org/10.1016/j.stem.2016.04.002

TY - JOUR

T1 - Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation

AU - Dominguez-Brauer, Carmen

AU - Hao, Zhenyue

AU - Elia, Andrew J

AU - Fortin, Jérôme M

AU - Nechanitzky, Robert

AU - Brauer, Patrick M

AU - Sheng, Yi

AU - Mana, Miyeko D

AU - Chio, Iok In Christine

AU - Haight, Jillian

AU - Pollett, Aaron

AU - Cairns, Robert

AU - Tworzyanski, Leanne

AU - Inoue, Satoshi

AU - Reardon, Colin

AU - Marques, Ana

AU - Silvester, Jennifer

AU - Cox, Maureen A

AU - Wakeham, Andrew

AU - Yilmaz, Omer H

AU - Sabatini, David M

AU - van Es, Johan H

AU - Clevers, Hans

AU - Sato, Toshiro

AU - Mak, Tak W

PY - 2016/8/4

Y1 - 2016/8/4

N2 - 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.

AB - 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.

U2 - 10.1016/j.stem.2016.04.002

DO - 10.1016/j.stem.2016.04.002

M3 - Article

C2 - 27184401

SN - 1934-5909

JO - Cell Stem Cell

JF - Cell Stem Cell

ER -

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

Abstract

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