An MST4‐pβ‐Catenin(Thr40) Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis

Elevated Wnt/β‐catenin signaling has been commonly associated with tumorigenesis especially colorectal cancer (CRC). Here, an MST4‐pβ‐catenin(Thr40) signaling axis essential for intestinal stem cell (ISC) homeostasis and CRC development is uncovered. In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates β‐catenin at Thr40 to block its Ser33 phosphorylation by GSK3β. Thus, MST4 mediates an active process that prevents β‐catenin from binding to and being degraded by β‐TrCP, leading to accumulation and full activation of β‐catenin. Depletion of MST4 causes loss of ISCs and inhibits CRC growth. Mice bearing either MST4(T178E) mutation with constitutive kinase activity or β‐catenin(T40D) mutation mimicking MST4‐mediated phosphorylation show overly increased ISCs/CSCs and exacerbates CRC. Furthermore, the MST4‐pβ‐catenin(Thr40) axis is upregulated and correlated with poor prognosis of human CRC. Collectively, this work establishes a previously undefined machinery for β‐catenin activation, and further reveals its function in stem cell and tumor biology, opening new opportunities for targeted therapy of CRC.