| First Author | Zhang H | Year | 2021 |
| Journal | Adv Sci (Weinh) | Volume | 8 |
| Issue | 17 | Pages | e2004850 |
| PubMed ID | 34240584 | Mgi Jnum | J:322311 |
| Mgi Id | MGI:7258192 | Doi | 10.1002/advs.202004850 |
| Citation | Zhang H, et al. (2021) An MST4-pbeta-Catenin(Thr40) Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis. Adv Sci (Weinh) 8(17):e2004850 |
| abstractText | Elevated Wnt/beta-catenin signaling has been commonly associated with tumorigenesis especially colorectal cancer (CRC). Here, an MST4-pbeta-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 beta-catenin at Thr40 to block its Ser33 phosphorylation by GSK3beta. Thus, MST4 mediates an active process that prevents beta-catenin from binding to and being degraded by beta-TrCP, leading to accumulation and full activation of beta-catenin. Depletion of MST4 causes loss of ISCs and inhibits CRC growth. Mice bearing either MST4(T178E) mutation with constitutive kinase activity or beta-catenin(T40D) mutation mimicking MST4-mediated phosphorylation show overly increased ISCs/CSCs and exacerbates CRC. Furthermore, the MST4-pbeta-catenin(Thr40) axis is upregulated and correlated with poor prognosis of human CRC. Collectively, this work establishes a previously undefined machinery for beta-catenin activation, and further reveals its function in stem cell and tumor biology, opening new opportunities for targeted therapy of CRC. |
