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

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.

• 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
• Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 8 Issue 17 Pg. e2004850 (09 2021) ISSN: 2198-3844 [Electronic] Germany
• PMID: 34240584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.

Chemical References

• beta Catenin
• STK26 protein, human
• Stk26 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Carcinogenesis (genetics)
• Colorectal Neoplasms (genetics, metabolism)
• Disease Models, Animal
• Female
• Humans
• Intestines (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Stem Cells (metabolism)
• Wnt Signaling Pathway (genetics)
• beta Catenin (genetics, metabolism)