Abstract
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.
Highlights
Lysyl-tRNA synthetase (LysRS) is an enzyme which catalyzes the ligation of lysine to its cognate transfer RNA during protein synthesis
As phosphorylation on Serine 207 (P-s207) LysRS has been shown to translocate to the nucleus [4], a nuclear/cytoplasmic fractionation assay was carried out following EGF activation of Epidermal Growth Factor Receptor (EGFR)
In order to determine whether EGFR/ERK pathway is required for phosphorylation of LysRS, A549 cells were exposed to the ERK inhibitor U0126 prior to their exposure to EGF (Figure 1D)
Summary
Lysyl-tRNA synthetase (LysRS) is an enzyme which catalyzes the ligation of lysine to its cognate transfer RNA (tRNA) during protein synthesis. It belongs to a family of 20 enzymes known as aminoacyltRNA synthetases (AARSs). The primary function of this group of enzymes is the aminoacylation of tRNAs. LysRS is part of the intracellular multi-tRNA synthetase complex (MSC) that consists of three non-enzymatic www.impactjournals.com/oncotarget proteins and 8 AARSs [1]. Numerous aminoacyl-tRNA synthetase (AARS) have obtained a non-canonical role in signal transduction in both normal and cancerous tissues [2]. In many instances the alternative role was a result either of a post translational modification, different localization or fragmentation of the original molecule
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