@article{392249b4743d407581f3534f5a7bde33,
title = "ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions",
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.",
author = "Qianting Zhang and Mu Xiao and Shuchen Gu and Yongxian Xu and Ting Liu and Hao Li and Yi Yu and Lan Qin and Yezhang Zhu and Fenfang Chen and Yulong Wang and Chen Ding and Hongxing Wu and Hongbin Ji and Zhe Chen and Youli Zu and Stephen Malkoski and Yi Li and Tingbo Liang and Junfang Ji and Jun Qin and Pinglong Xu and Bin Zhao and Li Shen and Xia Lin and Feng, {Xin Hua}",
note = "Funding Information: We thank R. Chiarle for NPM–ALK and kinase-dead NPM–ALK(K210R), N. Fusenig for the HaCaT cell line, D. Luskutoff for p800(PAI-1)–Luc, Y. P. Moss{\'e} for the NB-1643 cell line, M. Vigny for the full-length ALK complementary DNA, B. Vogelstein for WWP1(p21)–Luc and SBE–Luc and X.-F. Wang for p15–Luc. We are indebted to L. Ding and Y. Ma at Betta Pharmaceutical for sharing the ALK inhibitor X396. We thank colleagues at Beijing Proteome Research Center and National Center for Protein Sciences (The PHOENIX Center, Beijing) for assistance with mass spectrometry analysis. We are grateful to K. Yu for sharing reagents, and J. Peng, Y. Zhu, N. Xu, H. Xia and members of the Feng laboratory for helpful discussion and technical assistance. We also thank K. Wrighton for editing the manuscript. We are grateful to L. Su for her contribution. This research was partly supported by grants from the NSFC (91540205, 31090360, 31571447), the NIH (R21CA209007) and the DoD (DAMD W81XWH-15–1–0650/0651), and the Fundamental Research Funds for the Central Universities. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = feb,
day = "1",
doi = "10.1038/s41556-018-0264-3",
language = "English (US)",
volume = "21",
pages = "179--189",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "2",
}