RasGRP links T-cell receptor signaling to Ras

• Published in: Blood 2000-05, Vol.95 (10), p.3199-3203
• Main Authors: EBINU, J. O, STANG, S. L, TEIXEIRA, C, BOTTORFF, D. A, HOOTON, J, BLUMBERG, P. M, BARRY, M, BLEAKLEY, R. C, OSTERGAARD, H. L, STONE, J. C
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line; DNA-Binding Proteins - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Guanine Nucleotide Exchange Factors; Immunobiology; Lymphocyte Activation - immunology; Mice; Modulation of the immune response (stimulation, suppression); ras Proteins - immunology; Receptors, Antigen, T-Cell - immunology; Signal Transduction - immunology; T-Lymphocytes - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v95.10.3199

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.