Abstract There is emerging evidence that DNA damage response (DDR) intertwines with signaling pathways downstream of oncogenic receptor tyrosine kinases (RTKs). Two complementary phosphoproteomic approaches revealed global networks and identified and validated core phosphosites that participate in a crosstalk between the MET RTK and the DDR, including a newly discovered phosphosite on MET itself, Ser1016. DNA-PK phosphorylates Ser1016, and this phosphorylation is increased following irradiation. Cell lines as well as animal models expressing Ser1016Ala phosphodeficient receptor exhibit greater sensitivity to irradiation. MET Ser1016Ala mutants fail to undergo proper radiation-induced cell cycle arrest by bypassing the G2 checkpoint with a premature entry into mitosis and abnormal mitotic spindles, leading to a lower proliferation rate of Ser1016-deficient cells. Regulation of MET activity through Ser1016 phosphorylation by a DDR core kinase represents a critical event involved in DNA repair signaling through a growth factor receptor that frequently functions as a tumor driver. Citation Format: Jonas P. Koch, Ariel Bensimon, Selina M. Roth, Matúš Medo, Paola Francica, Eleonora Orlando, Rahel Riedo, Jacopo Gavini, Aurélie Quintin, Astrid A. Glück, Deborah M. Stroka, 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 reveals Ser1016 as a novel MET phosphosite that regulates cellular response to irradiation [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A52.