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

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.