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Nat Cell Biol. 2019 Feb;21(2):179-189. doi: 10.1038/s41556-018-0264-3. Epub 2019 Jan 21.

ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions.

Zhang Q1, Xiao M1, Gu S1, Xu Y1, Liu T1, Li H1, Yu Y1, Qin L2,3, Zhu Y1, Chen F1, Wang Y4, Ding C5,6, Wu H1, Ji H7, Chen Z8, Zu Y9, Malkoski S10, Li Y3,11, Liang T12, Ji J1, Qin J3,5,13, Xu P1, Zhao B1, Shen L1, Lin X2, Feng XH14,15,16.

Author information

1
MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
2
DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
3
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
4
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
5
Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, China.
6
College of Life Sciences, Fudan University, Shanghai, China.
7
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
8
Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
9
The Methodist Hospital Research Institute, Houston, TX, USA.
10
Department of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado, USA.
11
Breast Center, Baylor College of Medicine, Houston, TX, USA.
12
Department of Hepatobiliary and Pancreatic Surgery and the Key Laboratory of Cancer Prevention and Intervention, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
13
Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
14
MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. fenglab@zju.edu.cn.
15
DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA. fenglab@zju.edu.cn.
16
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA. fenglab@zju.edu.cn.

Abstract

Loss of TGF-β tumour suppressive response is a hallmark of human cancers. As a central player in TGF-β signal transduction, SMAD4 (also known as DPC4) is frequently mutated or deleted in gastrointestinal and pancreatic cancer. However, such genetic alterations are rare in most cancer types and the underlying mechanism for TGF-β resistance is not understood. Here we describe a mechanism of TGF-β resistance in ALK-positive tumours, including lymphoma, lung cancer and neuroblastoma. We demonstrate that, in ALK-positive tumours, ALK directly phosphorylates SMAD4 at Tyr 95. Phosphorylated SMAD4 is unable to bind to DNA and fails to elicit TGF-β gene responses and tumour suppressing responses. Chemical or genetic interference of the oncogenic ALK restores TGF-β responses in ALK-positive tumour cells. These findings reveal that SMAD4 is tyrosine-phosphorylated by an oncogenic tyrosine kinase during tumorigenesis. This suggests a mechanism by which SMAD4 is inactivated in cancers and provides guidance for targeted therapies in ALK-positive cancers.

PMID:
30664791
DOI:
10.1038/s41556-018-0264-3
[Indexed for MEDLINE]

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