Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics
Increasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA‐damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated...
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Online Access: | https://doi.org/10.1002/1878-0261.12696 |
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doaj-a11e365e276f480ca20d636cb70182c82020-11-25T03:35:30ZengWileyMolecular Oncology1574-78911878-02612020-06-011461185120610.1002/1878-0261.12696Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomicsAriel Bensimon0Jonas P. Koch1Paola Francica2Selina M. Roth3Rahel Riedo4Astrid A. Glück5Eleonora Orlando6Andree Blaukat7Daniel M. Aebersold8Yitzhak Zimmer9Ruedi Aebersold10Michaela Medová11Department of Biology Institute of Molecular Systems Biology ETH Zürich SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandGlobal Research & Development Merck KGaA Darmstadt GermanyDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandDepartment of Biology Institute of Molecular Systems Biology ETH Zürich SwitzerlandDepartment of Radiation Oncology, Inselspital Bern University HospitalUniversity of Bern SwitzerlandIncreasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA‐damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity‐based phosphoproteomic discovery survey, we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using invivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene‐driven proliferation and genomic stability.https://doi.org/10.1002/1878-0261.12696ATMDNA damage responseionizing radiationmass spectrometryMETreceptor tyrosine kinase |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ariel Bensimon Jonas P. Koch Paola Francica Selina M. Roth Rahel Riedo Astrid A. Glück Eleonora Orlando Andree Blaukat Daniel M. Aebersold Yitzhak Zimmer Ruedi Aebersold Michaela Medová |
spellingShingle |
Ariel Bensimon Jonas P. Koch Paola Francica Selina M. Roth Rahel Riedo Astrid A. Glück Eleonora Orlando Andree Blaukat Daniel M. Aebersold Yitzhak Zimmer Ruedi Aebersold Michaela Medová Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics Molecular Oncology ATM DNA damage response ionizing radiation mass spectrometry MET receptor tyrosine kinase |
author_facet |
Ariel Bensimon Jonas P. Koch Paola Francica Selina M. Roth Rahel Riedo Astrid A. Glück Eleonora Orlando Andree Blaukat Daniel M. Aebersold Yitzhak Zimmer Ruedi Aebersold Michaela Medová |
author_sort |
Ariel Bensimon |
title |
Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics |
title_short |
Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics |
title_full |
Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics |
title_fullStr |
Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics |
title_full_unstemmed |
Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics |
title_sort |
deciphering met‐dependent modulation of global cellular responses to dna damage by quantitative phosphoproteomics |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2020-06-01 |
description |
Increasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA‐damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity‐based phosphoproteomic discovery survey, we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using invivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene‐driven proliferation and genomic stability. |
topic |
ATM DNA damage response ionizing radiation mass spectrometry MET receptor tyrosine kinase |
url |
https://doi.org/10.1002/1878-0261.12696 |
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