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

Min Chul Park1, Taehee Kang, Da Jin

  • 1Medicinal Bioconvergence Research Center, and World Class University Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Technology, Seoul National University, Seoul 151-742, Korea.

Proceedings of the National Academy of Sciences of the United States of America
|February 21, 2012
PubMed

Insights

Glycyl-tRNA synthetase (GRS), a translation enzyme, circulates in serum and combats tumor growth. It binds to tumor cells, activating pathways that induce apoptosis and suppress tumor progression, highlighting its role in cancer defense.

Area of Science:

  • Biochemistry
  • Immunology
  • Cancer Biology

Background:

  • Adaptive immunity in cancer is well-studied, but the role of endogenous factors with conventional functions remains less understood.
  • Tumor cells release Fas ligand, which can trigger responses in other cells.
  • ERK signaling is a key pathway implicated in tumor cell proliferation and survival.

Purpose of the Study:

  • To investigate the role of glycyl-tRNA synthetase (GRS) as an endogenous factor in anti-tumor defense.
  • To elucidate the mechanism by which GRS interacts with tumor cells and affects signaling pathways.
  • To evaluate the therapeutic potential of GRS in suppressing tumor growth.

Main Methods:

  • Detection of circulating GRS in serum.
  • Investigation of GRS secretion from macrophages stimulated by Fas ligand.
  • Analysis of GRS binding to tumor cells via cadherin-6 (CDH6).
  • Assessment of phosphatase 2A (PP2A) activation and its effect on ERK signaling.
  • In vivo studies using GRS administration to assess tumor suppression.

Main Results:

  • Glycyl-tRNA synthetase (GRS) circulates in serum and is secreted by macrophages upon stimulation.
  • GRS binds to ERK-activated tumor cells through cadherin-6 (CDH6), releasing active phosphatase 2A (PP2A).
  • Activated PP2A dephosphorylates ERK, suppressing signaling and inducing tumor cell apoptosis.
  • Blocking GRS with soluble CDH6 inhibited these anti-tumor effects.
  • In vivo administration of GRS significantly suppressed the growth of tumors with high CDH6 and ERK activation.

Conclusions:

  • Conventional cytoplasmic translation factors, like GRS, can function as endogenous anti-tumor agents.
  • GRS represents a novel mechanism of cancer defense by targeting ERK signaling through PP2A activation.
  • GRS holds potential as a therapeutic agent for tumors characterized by high CDH6 expression and ERK pathway activation.

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