Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics
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Date
2020-06
Publication Type
Journal Article
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yes
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Abstract
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.
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published
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Journal / series
Volume
14 (6)
Pages / Article No.
1185 - 1206
Publisher
Wiley
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Subject
ATM; DNA damage response; ionizing radiation; mass spectrometry; MET; receptor tyrosine kinase
Organisational unit
03663 - Aebersold, Rudolf (emeritus) / Aebersold, Rudolf (emeritus)
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Funding
147086 - A Technology and Platform for Plasma Protein Biomarker Validation with Applications to Cancer (SNF)
166435 - MitoModules: Biomarkers in context (SNF)
166435 - MitoModules: Biomarkers in context (SNF)