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

Qianting Zhang, Mu Xiao, Shuchen Gu, Yongxian Xu, Ting Liu, Hao Li, Yi Yu, Lan Qin, Yezhang Zhu, Fenfang Chen, Yulong Wang, Chen Ding, Hongxing Wu, Hongbin Ji, Zhe Chen, Youli Zu, Stephen Malkoski, Yi Li, Tingbo Liang, Junfang JiJun Qin, Pinglong Xu, Bin Zhao, Li Shen, Xia Lin, Xin Hua Feng

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)179-189
Number of pages11
JournalNature Cell Biology
Volume21
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Cell Biology

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