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

Cell Rep. 2019 Feb 26;26(9):2266-2273.e4. doi: 10.1016/j.celrep.2019.01.110.


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.

Keywords: Sh3bp4; Wnt; colorectal cancer; intestinal stem cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Carcinogenesis*
  • Cell Line, Tumor
  • Cell Nucleus
  • HEK293 Cells
  • Humans
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism*
  • Mice
  • Mice, Knockout
  • Paneth Cells / cytology
  • Protein Domains
  • Stem Cells / metabolism*
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • SH3BP4 protein, human
  • Wnt Proteins
  • beta Catenin