Deciphering MET-dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics.

Bensimon, Ariel; Koch, Jonas P.; Francica, Paola; Roth, Selina M.; Riedo, Rahel; Glück, Astrid A.; Orlando, Eleonora; Blaukat, Andree; Aebersold, Daniel M.; Zimmer, Yitzhak; Aebersold, Ruedi; Medová, Michaela (2020). Deciphering MET-dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics. Molecular oncology, 14(6), pp. 1185-1206. Elsevier 10.1002/1878-0261.12696

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Increasing evidence suggests that interference with growth factor receptor tyrosine kinases (RTKs) 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 in vivo 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Koch, Jonas Paul; Francica, Paola; Roth, Selina Moara; Riedo, Rahel; Glück, Astrid Andreina; Orlando, Eleonora; Aebersold, Daniel; Zimmer, Yitzhak and Medova, Michaela

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1878-0261

Publisher:

Elsevier

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

13 May 2020 10:12

Last Modified:

04 Jun 2020 01:34

Publisher DOI:

10.1002/1878-0261.12696

PubMed ID:

32336009

Uncontrolled Keywords:

ATM CHEK1 DNA damage response MET NUMA1 ionizing radiation mass spectrometry oncogene phosphoproteomics receptor tyrosine kinase selected reaction monitoring (SRM) targeted inhibition targeted proteomics

URI:

https://boris.unibe.ch/id/eprint/143964

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