| Literature DB >> 30664791 |
Mu Xiao1, Shuchen Gu1, Yongxian Xu1, Qianting Zhang1, Ting Liu1, Hao Li1, Yi Yu1, Lan Qin2,3, Yezhang Zhu1, Fenfang Chen1, Yulong Wang4, Chen Ding5,6, Hongxing Wu1, Hongbin Ji7, Zhe Chen8, Youli Zu9, Stephen Malkoski10, Yi Li3,11, Tingbo Liang12, Junfang Ji1, Jun Qin3,5,13, Pinglong Xu1, Bin Zhao1, Li Shen1, Xia Lin2, Xin-Hua Feng14,15,16.
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.Entities:
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Year: 2019 PMID： 30664791 DOI： 10.1038/s41556-018-0264-3
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824