SUMMARY
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 b-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 b-catenin. Our data uncover the tumor-suppressive role of SH3BP4 that
functions as a negative feedback regulator of Wnt
signaling through modulating b-catenin’s subcellular
localization
