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

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 u...

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Published inNature cell biology Vol. 21; no. 2; pp. 179 - 189
Main Authors Zhang, Qianting, Xiao, Mu, Gu, Shuchen, Xu, Yongxian, Liu, Ting, Li, Hao, Yu, Yi, Qin, Lan, Zhu, Yezhang, Chen, Fenfang, Wang, Yulong, Ding, Chen, Wu, Hongxing, Ji, Hongbin, Chen, Zhe, Zu, Youli, Malkoski, Stephen, Li, Yi, Liang, Tingbo, Ji, Junfang, Qin, Jun, Xu, Pinglong, Zhao, Bin, Shen, Li, Lin, Xia, Feng, Xin-Hua
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.02.2019
Nature Publishing Group
Subjects
631/67
631/80/458/1733
631/80/86
Anaplastic Lymphoma Kinase - genetics
Anaplastic Lymphoma Kinase - metabolism
Animals
Biomedical and Life Sciences
Blocking
Cancer
Cancer Research
Cell Biology
Cell Line
Cell Line, Tumor
Deoxyribonucleic acid
Developmental Biology
DNA
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic - drug effects
HEK293 Cells
Humans
Kinases
Life Sciences
Lung cancer
Lymphoma
Mice, Inbred BALB C
Mice, Nude
Mutation
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
Neuroblastoma
Organic chemistry
Pancreatic cancer
Phosphorylation
Protein-tyrosine kinase
Signal transduction
Smad4 protein
Smad4 Protein - genetics
Smad4 Protein - metabolism
Stem Cells
Transduction
Transforming Growth Factor beta - pharmacology
Transplantation, Heterologous
Tumor suppressor genes
Tumorigenesis
Tumors
Tyrosine
Tyrosine - genetics
Tyrosine - metabolism
Online AccessGet full text

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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. Zhang et al. show that ALK phosphorylates SMAD4 at Tyr 95 to block its binding to DNA, representing a mutation-independent mechanism for blocking the tumour suppressor function of TGF-β in ALK-positive cancers.
AbstractList 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.Zhang et al. show that ALK phosphorylates SMAD4 at Tyr 95 to block its binding to DNA, representing a mutation-independent mechanism for blocking the tumour suppressor function of TGF-β in ALK-positive cancers.
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.
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.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.
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. Zhang et al. show that ALK phosphorylates SMAD4 at Tyr 95 to block its binding to DNA, representing a mutation-independent mechanism for blocking the tumour suppressor function of TGF-β in ALK-positive cancers.
Author Yu, Yi
Li, Hao
Zu, Youli
Li, Yi
Gu, Shuchen
Qin, Lan
Wang, Yulong
Lin, Xia
Chen, Zhe
Zhao, Bin
Liu, Ting
Feng, Xin-Hua
Liang, Tingbo
Xu, Yongxian
Zhu, Yezhang
Qin, Jun
Shen, Li
Malkoski, Stephen
Ding, Chen
Wu, Hongxing
Ji, Junfang
Zhang, Qianting
Chen, Fenfang
Xiao, Mu
Ji, Hongbin
Xu, Pinglong
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/30664791$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
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The Author(s), under exclusive licence to Springer Nature Limited 2019. corrected publication 2021.
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Snippet 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...
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SubjectTerms 631/67
631/80/458/1733
631/80/86
Anaplastic Lymphoma Kinase - genetics
Anaplastic Lymphoma Kinase - metabolism
Animals
Biomedical and Life Sciences
Blocking
Cancer
Cancer Research
Cell Biology
Cell Line
Cell Line, Tumor
Deoxyribonucleic acid
Developmental Biology
DNA
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic - drug effects
HEK293 Cells
Humans
Kinases
Life Sciences
Lung cancer
Lymphoma
Mice, Inbred BALB C
Mice, Nude
Mutation
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
Neuroblastoma
Organic chemistry
Pancreatic cancer
Phosphorylation
Protein-tyrosine kinase
Signal transduction
Smad4 protein
Smad4 Protein - genetics
Smad4 Protein - metabolism
Stem Cells
Transduction
Transforming Growth Factor beta - pharmacology
Transplantation, Heterologous
Tumor suppressor genes
Tumorigenesis
Tumors
Tyrosine
Tyrosine - genetics
Tyrosine - metabolism
Title ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions
URI https://link.springer.com/article/10.1038/s41556-018-0264-3
https://www.ncbi.nlm.nih.gov/pubmed/30664791
https://www.proquest.com/docview/2174744408
https://www.proquest.com/docview/2485324860
https://www.proquest.com/docview/2179429875
Volume 21
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