ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions
ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions
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ALK 磷酸化 SMAD4 酪氨酸以禁用 TGF-β 肿瘤抑制功能
DOI：
10.1038/s41556-018-0264-3
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发表时间：
2019-02-01
影响因子：
21.3
通讯作者：
Feng, Xin-Hua
中科院分区：
文献类型：
--
作者：
Zhang, Qianting;Xiao, Mu;Feng, Xin-Hua
TGF-β肿瘤抑制反应的丧失是人类癌症的标志。作为TGF-β信号转导的核心参与者，SMAD 4（也称为DPC 4）在胃肠道和胰腺癌中经常突变或缺失。然而，这种遗传改变在大多数癌症类型中是罕见的，并且TGF-β抗性的潜在机制尚不清楚。在这里，我们描述了ALK阳性肿瘤（包括淋巴瘤、肺癌和神经母细胞瘤）中TGF-β抵抗的机制。我们证明，在ALK阳性肿瘤中，ALK直接磷酸化SMAD 4的Tyr 95。磷酸化SMAD 4不能与DNA结合，不能引发TGF-β基因应答和肿瘤抑制应答。致癌ALK的化学或遗传干扰可恢复ALK阳性肿瘤细胞中的TGF-β反应。这些发现表明SMAD 4在肿瘤发生过程中被致癌酪氨酸激酶酪氨酸磷酸化。这表明SMAD 4在癌症中失活的机制，并为ALK阳性癌症的靶向治疗提供指导。
Loss of TGF-beta tumour suppressive response is a hallmark of human cancers. As a central player in TGF-beta 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-beta resistance is not understood. Here we describe a mechanism of TGF-beta 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-beta gene responses and tumour suppressing responses. Chemical or genetic interference of the oncogenic ALK restores TGF-beta 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.