An MST4‐pβ‐CateninThr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis

• Main Authors: Hui Zhang, Moubin Lin, Chao Dong, Yang Tang, Liwei An, Junyi Ju, Fuping Wen, Fan Chen, Meng Wang, Wenjia Wang, Min Chen, Yun Zhao, Jixi Li, Steven X. Hou, Xinhua Lin, Lulu Hu, Wenbo Bu, Dianqing Wu, Lin Li, Shi Jiao, Zhaocai Zhou
• Format: Article
• Language: English
• Published: Wiley 2021-09-01
• Series: Advanced Science
• Subjects: cancer stem cells; colorectal cancer; intestinal stem cells; MST4‐pβ‐cateninThr40 signaling axis; targeted therapy
• Online Access: https://doi.org/10.1002/advs.202004850

Abstract Elevated Wnt/β‐catenin signaling has been commonly associated with tumorigenesis especially colorectal cancer (CRC). Here, an MST4‐pβ‐cateninThr40 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 MST4T178E mutation with constitutive kinase activity or β‐cateninT40D mutation mimicking MST4‐mediated phosphorylation show overly increased ISCs/CSCs and exacerbates CRC. Furthermore, the MST4‐pβ‐cateninThr40 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.