Lysyl trna synthetase ap4a pathway in cancer

We described a novel transcriptional regulatory pathway in which Lysyl tRNA synthetase (KARS)which is a critical enzyme in translation is phosphorylated at serine 207 , leaves the tRNA multisynthetase complex undergoes a conformational transformation , translocates to the nucleus where it binds and activates a transcription factor . KARS may also produce ap4a which may act as a second messenger releasing the inhibitor HINT from transcription factors .The same KARS specific phosphorylation seems to occur in KARS found in the HIV virion and is has a role for full HIV infectivity. We recently produced an antibody to pKARS . We used this antibody and contstructs containing modified KARS plasmids for analysis of tissue culture extracts and tissue arrays to obtain insitghts as to the role pKARS in cancer. EGFR activated the phosphorylation of KARS and its release from the multisynthetase complex. In patients with Lung tumors in which pKARS was highly expressed in the nucleus seem to survive shorter time if they did not have a mutation in EGFR. Overexpression of pseudo phospohorylated KARS in such lung cancer cell lines increased their proliferation. In lung cancer with mutations in EGFR such expression seem to induce partial resistance to EGFR inhibitors. In contrast to that progression free survival of lung cancer patients with EGFR mutations was better if pKARS was highly expressed in the tumor cells . The evidence we provide support the notion Lysyl trna synthetase ap4a pathway is activated in cancer and may have an important role in tumor progression.