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

Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):E640-7. doi: 10.1073/pnas.1200194109. Epub 2012 Feb 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / immunology*
  • Cell Transformation, Neoplastic / pathology*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fas Ligand Protein / metabolism
  • Glycine-tRNA Ligase / metabolism*
  • Humans
  • Macrophages / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Binding
  • Receptors, Cell Surface / metabolism
  • Stress, Physiological
  • Xenograft Model Antitumor Assays


  • Cadherins
  • Fas Ligand Protein
  • Receptors, Cell Surface
  • Extracellular Signal-Regulated MAP Kinases
  • Glycine-tRNA Ligase
  • K cadherin