ArticleNature cell biology2019
ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions.
Article in Nature cell biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 114 citations in OpenAlex.
- SHP2 negatively regulates TGF-β signaling by destabilizing the TGF-β type I receptor.Cell communication and signaling : CCS · 2026Article
- Ex vivo drug sensitivity profiling to complement molecular profiling in pediatric precision oncology.NPJ precision oncology · 2026Article
- SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence.Nature cancer · 2025Article
- Focal adhesion kinase/Src family kinase axis-mediated tyrosine phosphorylation of metabolic enzymes facilitates tumor metastasis.Signal transduction and targeted therapy · 2025Article
- Proteomics in pancreatic cancer.Biomarker research · 2025Review
- Mechanisms of GPM6A in Malignant Tumors.Cancer reports (Hoboken, N.J.) · 2025Review
- Implication of protein post translational modifications in gastric cancer.Frontiers in cell and developmental biology · 2025Review
- SMAD4 Limits PARP1 dependent DNA Repair to Render Pancreatic Cancer Cells Sensitive to Radiotherapy.Cell death & disease · 2024Article
- The LRG-TGF-β-Alk-1/TGFßRII-Smads as Predictive Biomarkers of Chronic Hydrocephalus after Aneurysmal Subarachnoid Hemorrhage.Journal of neurological surgery. Part A, Central European neurosurgery · 2024Article
- SNHG17 alters anaerobic glycolysis by resetting phosphorylation modification of PGK1 to foster pro-tumor macrophage formation in pancreatic ductal adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2023Article
- Integrated circulating tumour DNA and cytokine analysis for therapy monitoring of ALK-rearranged lung adenocarcinoma.British journal of cancer · 2023Article
- Imatinib blocks tyrosine phosphorylation of Smad4 and restores TGF-β growth-suppressive signaling in BCR-ABL1-positive leukemia.Signal transduction and targeted therapy · 2023Article
- HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity.The EMBO journal · 2023Article
- Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-β/Smad2 signaling in chondrocytes.JCI insight · 2023Article
- Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC.Cell death & disease · 2022Article
- Spatiotemporal modulation of SMAD4 by HBx is required for cellular proliferation in hepatitis B-related liver cancer.Cellular oncology (Dordrecht, Netherlands) · 2022Article
- Systematic identification of ALK substrates by integrated phosphoproteome and interactome analysis.Life science alliance · 2022Article
- SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8Science advances · 2022Article
- PTBP3 mediates TGF-β-induced EMT and metastasis of lung adenocarcinoma.Cell cycle (Georgetown, Tex.) · 2022Article
- Targeting TGF-β signal transduction for fibrosis and cancer therapy.Molecular cancer · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
26 authors at 9 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.