Although adaptive systems of immunity against tumor initiation and destruction are well investigated, less understood is the role, if any, of endogenous factors that have conventional functions. Here we show that glycyl-tRNA synthetase (GRS), an essential component of the translation apparatus, circulates in serum and can be secreted from macrophages in response to Fas ligand that is released from tumor cells. Through cadherin (CDH)6 (K-cadherin), GRS bound to different ERK-activated tumor cells, and released phosphatase 2A (PP2A) from CDH6. The activated PP2A then suppressed ERK signaling through dephosphorylation of ERK and induced apoptosis. These activities were inhibited by blocking GRS with a soluble fragment of CDH6. With in vivo administration of GRS, growth of tumors with a high level of CDH6 and ERK activation were strongly suppressed. Our results implicate a conventional cytoplasmic enzyme in translation as an intrinsic component of the defense against ERK-activated tumor formation.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2012 Mar 13|
Bibliographical noteFunding Information:
Prof Sandosh Padmanabhan is the Professor of Cardiovascular Genomics and Therapeutics at the University of Glasgow. He completed his MBBS and MD at JIPMER, Pondicherry, India. He was awarded the Gold Medal for MD General Medicine in 1995 by Pondicherry University, the Bellahouston Medal by the University of Glasgow in 2004 for his PhD thesis on G-protein signalling in hypertension. His research combines epidemiology and randomised clinical trials incorporating high-throughput genomics and metabolomics in the dissection of cardiovascular traits and drug response. His research is funded by the British Heart Foundation and the Medical Research Council. Sandosh Padmanabhan is supported through funds from the Medical Research Council and the British Heart Foundation. Email: Sandosh.Padmanabhan@glasgow.ac.uk Dr Rhian Touyz, MBBCh, MSc(Med), PhD, is Professor and Director of the Institute of Cardiovascular and Medical Sciences, and BHF Chair of Cardiovascular Medicine, University of Glasgow. She was the Canada Research Chair in Hypertension in Ottawa, Canada. She is a clinician-scientist with a focus on molecular and cellular mechanisms of hypertension. Dr Touyz is President of the International Society of Hypertension. She is Editor-in-Chief of Clinical Science, Deputy Editor of Hypertension, and Associate Editor of Pharmacological Reviews. Her lab is trainee-oriented and she has supervised over 50 graduate/post-doctoral students. She has published 350 peer-reviewed papers. Her interests include signal transduction, oxidative stress, ion transport and vascular biology. Rhian Touyz is supported through a British Heart Foundation Chair. E-mail: Rhian.Touyz@glasgow.ac.uk
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