An MST4-pβ-CateninThr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis,Advanced Science

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An MST4-pβ-CateninThr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis
Advanced Science ( IF 14.3 ) Pub Date : 2021-07-08 , DOI: 10.1002/advs.202004850
Hui Zhang _{1,

2} , Moubin Lin ₃ , Chao Dong ₄ , Yang Tang ₅ , Liwei An ₅ , Junyi Ju ₅ , Fuping Wen ₁ , Fan Chen ₁ , Meng Wang ₂ , Wenjia Wang ₂ , Min Chen ₁ , Yun Zhao ₁ , Jixi Li ₂ , Steven X Hou ₂ , Xinhua Lin ₂ , Lulu Hu ₆ , Wenbo Bu ₇ , Dianqing Wu ₈ , Lin Li ₁ , Shi Jiao ₂ , Zhaocai Zhou ₂

Affiliation

State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
State Key Laboratory of Genetic Engineering, Department of Cell and Developmental Biology, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, China.
Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, 650118, China.
Department of Medical Ultrasound, Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
Department of Materials Science, Fudan University, Shanghai, 200433, China.
Department of Pharmacology, Yale School of Medicine, New Haven, CT, 06520, USA.

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.

中文翻译：

MST4-pβ-CateninThr40 信号轴控制肠干细胞和肿瘤发生

Wnt/ β-连环蛋白信号传导升高通常与肿瘤发生尤其是结直肠癌 (CRC) 相关。在此，揭示了肠道干细胞 (ISC) 稳态和 CRC 发育所必需的 MST4-p β-连环蛋白^Thr40信号轴。响应 Wnt3a 刺激，激酶 MST4 直接磷酸化β -catenin Thr40，以阻断 GSK3 β对其 Ser33 的磷酸化。因此，MST4 介导一个主动过程，防止β-连环蛋白与 β-TrCP 结合并被β -TrCP 降解，从而导致β-连环蛋白的积累和完全激活。 MST4 的耗尽会导致 ISC 损失并抑制 CRC 生长。携带具有组成型激酶活性的 MST4 ^T178E突变或模仿 MST4 介导的磷酸化的β-连环蛋白^T40D突变的小鼠表现出过度增加的 ISC/CSC 并加剧 CRC。此外，MST4-p β-连环蛋白^Thr40轴上调并与人类 CRC 不良预后相关。总的来说，这项工作建立了一种先前未定义的β-连环蛋白激活机制，并进一步揭示了其在干细胞和肿瘤生物学中的功能，为结直肠癌的靶向治疗开辟了新的机会。

更新日期：2021-09-09

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