ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions.
Qianting ZhangMu XiaoShuchen GuYongxian XuTing LiuHao LiYi YuLan QinYezhang ZhuFenfang ChenYulong WangChen DingHongxing WuHongbin JiZhe ChenYouli ZuStephen MalkoskiYi LiTingbo LiangJunfang JiJun QinPing-Long XuBin ZhaoLi ShenXia LinXin-Hua FengPublished in: Nature cell biology (2019)
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.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- advanced non small cell lung cancer
- tyrosine kinase
- genome wide
- epidermal growth factor receptor
- signaling pathway
- endothelial cells
- induced apoptosis
- transcription factor
- oxidative stress
- single molecule
- dna methylation
- single cell
- young adults
- cell proliferation
- cell cycle arrest
- nucleic acid