Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis

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.

[1]  P. Krammer,et al.  Immune escape of tumors: apoptosis resistance and tumor counterattack , 2002, Journal of leukocyte biology.

[2]  S. Keyse,et al.  Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. , 2000, Current opinion in cell biology.

[3]  Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. , 2001 .

[4]  Ping-yuan Wang,et al.  A cholesterol‐regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity , 2003, The EMBO journal.

[5]  P. Schimmel,et al.  Two distinct cytokines released from a human aminoacyl-tRNA synthetase. , 1999, Science.

[6]  J. Thevelein,et al.  Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy , 2006, Nature Genetics.

[7]  G. Trinchieri.  Natural killer cells wear different hats: effector cells of innate resistance and regulatory cells of adaptive immunity and of hematopoiesis. , 1995, Seminars in immunology.

[8]  A. Ashkenazi,et al.  Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. , 2003, Cytokine & growth factor reviews.

[9]  J. Chen,et al.  Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. , 1992, Science.

[10]  R. Juliano,et al.  Adhesion Regulation of Stromal Cell-derived Factor-1 Activation of ERK in Lymphocytes by Phosphatases* , 2003, Journal of Biological Chemistry.

[11]  M. Kapoor,et al.  Functional and crystal structure analysis of active site adaptations of a potent anti-angiogenic human tRNA synthetase. , 2007, Structure.

[12]  Christopher Haslett,et al.  Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo , 1999, Nature Medicine.

[13]  G. Carruba,et al.  Estrogen regulates cytokine production and apoptosis in PMA‐differentiated, macrophage‐like U937 cells , 2003, Journal of cellular biochemistry.

[14]  Sunghoon Kim,et al.  Noncanonical Function of Glutamyl-Prolyl-tRNA Synthetase Gene-Specific Silencing of Translation , 2004, Cell.

[15]  F. Castellino,et al.  Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. , 2007, Blood.

[16]  J. Aisner.  Extensive-disease small-cell lung cancer: the thrill of victory; the agony of defeat. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  J. Pettitt.  The cadherin superfamily. , 2005, WormBook : the online review of C. elegans biology.

[18]  R. Burgess,et al.  An Active Dominant Mutation of Glycyl-tRNA Synthetase Causes Neuropathy in a Charcot-Marie-Tooth 2D Mouse Model , 2006, Neuron.

[19]  K. Fischbeck,et al.  GARS axonopathy: not every neuron's cup of tRNA , 2010, Trends in Neurosciences.

[20]  S. Hirohashi,et al.  Isolation and sequence analysis of human cadherin-6 complementary DNA for the full coding sequence and its expression in human carcinoma cells. , 1995, Cancer research.

[21]  D. Noh,et al.  A proteomic approach based on multiple parallel separation for the unambiguous identification of an antibody cognate antigen , 2010, Electrophoresis.

[22]  N. Raben,et al.  A motif in human histidyl-tRNA synthetase which is shared among several aminoacyl-tRNA synthetases is a coiled-coil that is essential for enzymatic activity and contains the major autoantigenic epitope. , 1994, The Journal of biological chemistry.

[23]  P. Schimmel,et al.  New functions of aminoacyl-tRNA synthetases beyond translation , 2010, Nature Reviews Molecular Cell Biology.

[24]  Xiang-Lei Yang,et al.  Charcot–Marie–Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect , 2007, Proceedings of the National Academy of Sciences.

[25]  M. Mathews,et al.  Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity , 1983, Nature.

[26]  M. Kapoor,et al.  Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality , 2010, Nature Structural &Molecular Biology.

[27]  M. Smyth,et al.  Immune surveillance of tumors. , 2007, The Journal of clinical investigation.

[28]  D. Söll,et al.  Aminoacyl-tRNA synthesis. , 2000, Annual review of biochemistry.

[29]  A. Cherniack,et al.  The mitochondrial tyrosyl-tRNA synthetase of Podospora anserina is a bifunctional enzyme active in protein synthesis and RNA splicing , 1992, Molecular and cellular biology.

[30]  J. Alam,et al.  Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells. , 2001, International journal of oncology.

[31]  P. Schimmel,et al.  A human aminoacyl-tRNA synthetase as a regulator of angiogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  David C. H. Yang,et al.  Histidyl–tRNA Synthetase and Asparaginyl–tRNA Synthetase, Autoantigens in Myositis, Activate Chemokine Receptors on T Lymphocytes and Immature Dendritic Cells , 2002, The Journal of experimental medicine.

[33]  S. Pomer,et al.  Concomitant overexpression of the EGFR and erbB‐2 genes in renal cell carcinoma (RCC) is correlated with dedifferentiation and metastasis , 1996, International journal of cancer.

[34]  J. Schalken,et al.  Expression of cadherin-6 as a novel diagnostic tool to predict prognosis of patients with E-cadherin-absent renal cell carcinoma. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  Sunghoon Kim,et al.  Aminoacyl tRNA synthetases and their connections to disease , 2008, Proceedings of the National Academy of Sciences.

[36]  C Chothia,et al.  Cadherin superfamily proteins in Caenorhabditis elegans and Drosophila melanogaster. , 2001, Journal of molecular biology.

[37]  J. Blenis,et al.  The RSK family of kinases: emerging roles in cellular signalling , 2008, Nature Reviews Molecular Cell Biology.

[38]  Masaru Mitsushima,et al.  Involvement of phosphatases in the anchorage-dependent regulation of ERK2 activation. , 2007, Experimental cell research.

[39]  G. Johnson,et al.  Ras-dependent growth factor regulation of MEK kinase in PC12 cells. , 1994, Science.

[40]  C. Der,et al.  Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer , 2007, Oncogene.

[41]  R. Weichselbaum,et al.  Tumour-endothelium interactions in co-culture: coordinated changes of gene expression profiles and phenotypic properties of endothelial cells , 2003, Journal of Cell Science.

[42]  J. Rhim,et al.  Activated H-ras oncogenes in human kidney tumors. , 1988, Cancer research.

[43]  Gerhard Christofori,et al.  Cell adhesion and signalling by cadherins and Ig-CAMs in cancer , 2004, Nature Reviews Cancer.

[44]  Sunghoon Kim,et al.  Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers. , 2005, Trends in biochemical sciences.

[45]  L B Schook,et al.  Tumor necrosis factor alpha is an autocrine growth regulator during macrophage differentiation. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[46]  P. Schimmel,et al.  Functional expansion of human tRNA synthetases achieved by structural inventions , 2010, FEBS letters.

[47]  M. Karin,et al.  Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. , 2004, Cancer cell.

[48]  V. Janssens,et al.  Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. , 2001, The Biochemical journal.

[49]  M. Karin,et al.  Inhibition of NF-κB in cancer cells converts inflammation- induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression , 2004 .

[50]  M. Karno,et al.  Renal cell carcinoma. , 1956, Bulletin. Tufts-New England Medical Center.

[51]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.