title: RasGRP links T-cell receptor signaling to Ras.
abstract: 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.
authors.affiliation: Departments of Biochemistry and Immunobiology, University of Alberta, Edmonton, Canada.
authors.forename: J O
authors.initials: JO
authors.lastname: Ebinu
authors.forename: S L
authors.initials: SL
authors.lastname: Stang
authors.forename: C
authors.initials: C
authors.lastname: Teixeira
authors.forename: D A
authors.initials: DA
authors.lastname: Bottorff
authors.forename: J
authors.initials: J
authors.lastname: Hooton
authors.forename: P M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: M
authors.initials: M
authors.lastname: Barry
authors.forename: R C
authors.initials: RC
authors.lastname: Bleakley
authors.forename: H L
authors.initials: HL
authors.lastname: Ostergaard
authors.forename: J C
authors.initials: JC
authors.lastname: Stone
mesh_terms: 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*
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D018631:ras Proteins