RasGRP links T-cell receptor signaling to Ras.
Stimulation of the T-cell receptor (TCR) alters a number of intracellular signaling pathways including one that involves protein tyrosine kinases, phospholipase C-gamma1 (PLC-gamma1), 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-gamma1 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-gamma1 to Ras-Erk signaling, a pathway amenable to pharmacologic manipulation.
Ebinu
J O
JO
Departments of Biochemistry and Immunobiology, University of Alberta, Edmonton, Canada.
Stang
S L
SL
Teixeira
C
C
Bottorff
D A
DA
Hooton
J
J
Blumberg
P M
PM
Barry
M
M
Bleakley
R C
RC
Ostergaard
H L
HL
Stone
J C
JC
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D018631:ras Proteins / Q000276:immunology*
D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D018631:ras Proteins