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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3199-3203
RasGRP links T-cell receptor signaling to Ras
Julius O. Ebinu,
Stacey L. Stang,
Christine Teixeira,
Drell A. Bottorff,
Jonathan Hooton,
Peter M. Blumberg,
Michele Barry,
R. Chris Bleakley,
Hanne L. Ostergaard, and
James C. Stone
From the Departments of Biochemistry and Immunobiology, University
of Alberta, Edmonton, Alberta, Canada; and the Laboratory of
Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute,
Bethesda, MD.
Stimulation of the T-cell receptor (TCR) alters a number of
intracellular signaling pathways including one that involves protein tyrosine kinases, phospholipase C- 1 (PLC-1), diacylglycerol (DAG), and calcium messengers. By a divergent pathway, TCR-stimulated protein tyrosine kinase activity is thought to result independently in
recruitment of the Ras activator Sos to the plasma membrane, leading to
Ras activation. Here we show that RasGRP, a Ras activator that contains
calcium-binding EF hands and a DAG-binding domain, is expressed in T
cells. A PLC-1 inhibitor diminished activation of Ras following TCR
stimulation. Membranes from TCR-stimulated Jurkat T cells exhibited
increased RasGRP and increased Ras-guanyl nucleotide association
activity that was inhibited by antibodies directed against RasGRP.
Overexpression of RasGRP in T cells enhanced TCR-Ras-Erk signaling and
augmented interleukin-2 secretion in response to calcium ionophore plus
DAG analogues phorbol ester myristate or bryostatin-1. Thus, RasGRP
links TCR and PLC-1 to Ras-Erk signaling, a pathway amenable to
pharmacologic manipulation.
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