SH3BP4 Regulates Intestinal Stem Cells and Tumorigenesis by Modulating β-Catenin Nuclear Localization.

Cell Reports
Pedro AntasVivian S W Li

Abstract

Wnt signals at the base of mammalian crypts play a pivotal role in intestinal stem cell (ISC) homeostasis, whereas aberrant Wnt activation causes colon cancer. Precise control of Wnt signal strength is governed by a number of negative inhibitory mechanisms acting at distinct levels of the cascade. Here, we identify the Wnt negative regulatory role of Sh3bp4 in the intestinal crypt. We show that the loss of Sh3bp4 increases ISC and Paneth cell numbers in murine intestine and accelerates adenoma development in Apcmin mice. Mechanistically, human SH3BP4 inhibits Wnt signaling downstream of β-catenin phosphorylation and ubiquitination. This Wnt inhibitory role is dependent on the ZU5 domain of SH3BP4. We further demonstrate that SH3BP4 is expressed at the perinuclear region to restrict nuclear localization of β-catenin. Our data uncover the tumor-suppressive role of SH3BP4 that functions as a negative feedback regulator of Wnt signaling through modulating β-catenin's subcellular localization.

Citations

Sep 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Marjoke F DebetsBenjamin Schumann
Jan 22, 2021·Nature Communications·Natalie C ButterfieldJ H Duncan Bassett
Mar 25, 2021·Developmental Cell·Christoph J BurckhardtGaudenz Danuser
Apr 27, 2021·Frontiers in Physiology·María Daniella CarrettaRafael Agustín Burgos

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Methods Mentioned

BETA
immunoprecipitation
ubiquitination
Nuclear Translocation
GTPase
GTPases
transfection
flow cytometry
PCR

Software Mentioned

GraphPad Prism8
ImageJ
Fiji
RNAScope

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