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

被引：20

作者：

Antas, Pedro ^{[1
]}

Novellasdemunt, Laura ^{[1
]}

Kucharska, Anna ^{[1
]}

Massie, Isobel ^{[1
]}

Carvalho, Joana ^{[1
]}

Oukrif, Dahmane ^{[2
]}

Nye, Emma ^{[1
]}

Novelli, Marco ^{[2
]}

Li, Vivian S. W. ^{[1
]}

机构：

[1] Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England

[2] Univ Coll London Hosp NHS Fdn Trust, Histopathol Dept, London, England

来源：

CELL REPORTS | 2019年 / 26卷 / 09期

基金：

欧盟地平线“2020”; 英国惠康基金; 英国医学研究理事会;

关键词：

NEGATIVE REGULATOR; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; COLON; ACTIVATION; MUTATION; DOMAIN; RNF43;

D O I：

10.1016/j.celrep.2019.01.110

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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 Apc(min) mice. Mechanistically, human SH3BP4 inhibits Wnt signaling downstream of beta-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 beta-catenin. Our data uncover the tumor-suppressive role of SH3BP4 that functions as a negative feedback regulator of Wnt signaling through modulating beta-catenin's subcellular localization.

引用

页码：2266 / +

页数：12

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