title: Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response.
abstract: Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA.
authors.forename: Hong-Jen
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: 1] Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA [2] Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.affiliation: 1] Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung 404 [2] The Genomics Research Center, Academia Sinica, Taipei 115.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ming-Chuan
authors.initials: MC
authors.lastname: Hsu
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung 404.
authors.forename: Ying-Nai
authors.initials: YN
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chien-Chia
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: 1] Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA [2] Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Leizhen
authors.initials: L
authors.lastname: Wei
authors.affiliation: 1] Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA [2] Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA.
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Chang
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA.
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Liao
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei 115.
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.affiliation: University of Queensland Centre for Clinical Research, Royal Brisbane Hospital Campus, Herston, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Lavin
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shiaw-Yih
authors.initials: SY
authors.lastname: Lin
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA [3] Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung 404 [4] Department of Biotechnology, Asia University, Taichung 404.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D011799:Quinazolines; D034741:RNA, Small Interfering; D014443:Tyrosine; D064447:Checkpoint Kinase 2; D066246:ErbB Receptors; D064007:Ataxia Telangiectasia Mutated Proteins; D000077156:Gefitinib