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RasGRP links T-cell receptor signaling to Ras

J O Ebinu1, S L Stang, C Teixeira

  • 1Departments of Biochemistry and Immunobiology, University of Alberta, Edmonton, Canada.

Blood
|May 16, 2000
PubMed

Insights

RasGRP links T-cell receptor (TCR) stimulation to Ras-Erk signaling via phospholipase C-gamma1 (PLC-gamma1). This pathway, involving RasGRP, enhances interleukin-2 secretion and is a target for drug development.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • T-cell receptor (TCR) stimulation activates intracellular pathways involving protein tyrosine kinases, phospholipase C-gamma1 (PLC-gamma1), diacylglycerol (DAG), and calcium.
  • TCR-stimulated protein tyrosine kinase activity is also thought to independently recruit the Ras activator Sos to the plasma membrane, leading to Ras activation.

Purpose of the Study:

  • To investigate the role of RasGRP, a novel Ras activator, in T-cell signaling pathways.
  • To determine if RasGRP links TCR stimulation and PLC-gamma1 to Ras-Erk signaling.

Main Methods:

  • Investigated RasGRP expression in T cells.
  • Utilized a PLC-gamma1 inhibitor to assess Ras activation.
  • Examined RasGRP and Ras-guanyl nucleotide association activity in TCR-stimulated Jurkat T cells.
  • Assessed the effects of RasGRP overexpression on TCR-Ras-Erk signaling and interleukin-2 secretion.

Main Results:

  • RasGRP is expressed in T cells and contains calcium-binding EF hands and a DAG-binding domain.
  • Inhibition of PLC-gamma1 diminished Ras activation following TCR stimulation.
  • TCR-stimulated Jurkat T cells showed increased RasGRP and Ras-guanyl nucleotide association activity, which was blocked by anti-RasGRP antibodies.
  • Overexpression of RasGRP enhanced TCR-Ras-Erk signaling and augmented interleukin-2 secretion.

Conclusions:

  • RasGRP acts as a crucial link between TCR and PLC-gamma1, connecting them to the Ras-Erk signaling pathway.
  • The RasGRP-mediated pathway is a potential target for pharmacologic manipulation in T-cell related conditions.

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