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

Koch, Jonas P; Roth, Selina M; Quintin, Aurélie; Gavini, Jacopo; Orlando, Eleonora; Riedo, Rahel; Pozzato, Chiara; Hayrapetyan, Liana; Aebersold, Ruedi; Stroka, Deborah M; Aebersold, Daniel M; Medo, Matúš; Zimmer, Yitzhak; Medova, Michaela (2023). A DNA-PK phosphorylation site on MET regulates its signaling interface with the DNA damage response. Oncogene, 42(26), pp. 2113-2125. Nature Publishing Group 10.1038/s41388-023-02714-6

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

09 Interdisciplinary Units > Microscopy Imaging Center (MIC)
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
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

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Koch, Jonas Paul, Roth, Selina Moara, Quintin, Aurelie, Gavini, Jacopo, Orlando, Eleonora, Riedo, Rahel, Pozzato, Chiara, Hayrapetyan, Liana, Stroka, Deborah, Aebersold, Daniel Matthias, Medo, Matúš, Zimmer, Yitzhak, Medova, Michaela

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0950-9232

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Pubmed Import

Date Deposited:

16 May 2023 10:33

Last Modified:

17 Sep 2024 16:06

Publisher DOI:

10.1038/s41388-023-02714-6

PubMed ID:

37188738

BORIS DOI:

10.48350/182609

URI:

https://boris.unibe.ch/id/eprint/182609

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