A DNA-PK phosphorylation site on MET regulates its signaling interface with the DNA damage response.

Autor: Koch JP; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010, Bern, Switzerland., Roth SM; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010, Bern, Switzerland., Quintin A; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland., Gavini J; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010, Bern, Switzerland.; Department for BioMedical Research, Visceral Surgery, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland., Orlando E; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010, Bern, Switzerland., Riedo R; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland., Pozzato C; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland., Hayrapetyan L; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010, Bern, Switzerland., Aebersold R; Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, 8093, Zürich, Switzerland.; Faculty of Science, University of Zürich, 8057, Zürich, Switzerland., Stroka DM; Department for BioMedical Research, Visceral Surgery, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland., Aebersold DM; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland., Medo M; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland., Zimmer Y; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland., Medová M; Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland. michaela.medova@unibe.ch.; Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland. michaela.medova@unibe.ch.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2023 Jun; Vol. 42 (26), pp. 2113-2125. Date of Electronic Publication: 2023 May 15.
DOI: 10.1038/s41388-023-02714-6
Abstrakt: The DNA damage response (DDR) is intertwined with signaling pathways downstream of oncogenic receptor tyrosine kinases (RTKs). To drive research into the application of targeted therapies as radiosensitizers, a better understanding of this molecular crosstalk is necessary. We present here the characterization of a previously unreported MET RTK phosphosite, Serine 1016 (S1016) that represents a potential DDR-MET interface. MET S1016 phosphorylation increases in response to irradiation and is mainly targeted by DNA-dependent protein kinase (DNA-PK). Phosphoproteomics unveils an impact of the S1016A substitution on the overall long-term cell cycle regulation following DNA damage. Accordingly, the abrogation of this phosphosite strongly perturbs the phosphorylation of proteins involved in the cell cycle and formation of the mitotic spindle, enabling cells to bypass a G2 arrest upon irradiation and leading to the entry into mitosis despite compromised genome integrity. This results in the formation of abnormal mitotic spindles and a lower proliferation rate. Altogether, the current data uncover a novel signaling mechanism through which the DDR uses a growth factor receptor system for regulating and maintaining genome stability.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: