Serine 207 phosphorylated lysyl-tRNA synthetase predicts disease-free survival of non-small-cell lung carcinoma
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Suliman Boulos1,*, Min Chul Park2,*, Marian Zeibak3, Shen Yun Foo4, Yoon Kyung Jeon5, Young Tae Kim6, Alex Motzik3, Sagi Tshori7, Tamar Hamburger8, Sunghoon Kim2, Hovav Nechushtan1 and Ehud Razin3,4
1Department of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
2Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea
3Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
4NUS-HUJ-CREATE Cellular & Molecular Mechanisms of Inflammation Program, Department of Microbiology and Immunology, National University of Singapore, Singapore
5Department of Pathology, Seoul National University Hospital, Seoul, Korea
6Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Korea
7Kaplan Medical Center, Rehovot, Israel
8Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
*These authors have contributed equally to this work
Ehud Razin, email: [email protected]
Hovav Nechushtan, email: [email protected]
Keywords: LysRS, P-s207 LysRS, multi-synthetase complex, EGFR, non-small-cell lung cancer
Received: January 23, 2017 Accepted: April 25, 2017 Published: May 22, 2017
It has been shown that various tRNA synthetases exhibit non-canonical activities unrelated to their original role in translation. We have previously described a signal transduction pathway in which serine 207 phosphorylated lysyl-tRNA synthetase (P-s207 LysRS) is released from the cytoplasmic multi-tRNA synthetase complex (MSC) into the nucleus, where it activates the transcription factor MITF in stimulated cultured mast cells and cardiomyocytes. Here we describe a similar transformation of LysRS due to EGFR signaling activation in human lung cancer. Our data shows that activation of the EGFR results in phosphorylation of LysRS at position serine 207, its release from the MSC and translocation to the nucleus. We then generated a P-s207 LysRS rabbit polyclonalantibody and tested 242 tissue micro-array samples derived from non-small-cell lung cancer patients. Highly positive nuclear staining for P-s207 LysRS was noted in patients with EGFR mutations as compared to WT EGFR patients and was associated with improved mean disease-free survival (DFS). In addition, patients with mutated EGFR and negative lymph node metastases had better DFS when P-s207 LysRS was present in the nucleus. The data presented strongly suggests functional and prognostic significance of P-s207 LysRS in non-small-cell lung cancer.
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