SLP-76 and Vav function in separate, but overlapping pathways to augment interleukin-2 promoter activity.
SLP-76 and Vav, two hematopoietic cell specific molecules, are critical for T cell development and activation. Following T cell antigen receptor stimulation, SLP-76 and Vav both undergo tyrosine phosphorylation and associate with each other via the SH2 domain of Vav and phosphorylated tyrosines of SLP-76. Furthermore, SLP-76 and Vav have a synergistic effect on interleukin (IL)-2 promoter activity in T cells. In this report, we show that two tyrosines, Tyr-113 and Tyr-128, of SLP-76 are required for its binding to Vav, both in vitro and in intact cells. Surprisingly, we find also that the interaction between SLP-76 and Vav is not required for their cooperation in augmenting IL-2 promoter activity, as the two molecules appear to function in different signaling pathways upstream of IL-2 gene expression. Overexpression of SLP-76 in the Jurkat T cell line potentiates the activities of both nuclear factor of activated T cells and AP-1 transcription factors. In contrast, overexpression of Vav leads to enhanced nuclear factor of activated T cells activity without affecting AP-1. Additionally, overexpression of Vav, but not SLP-76, augments CD28-induced IL-2 promoter activity. These findings suggest that the synergy between SLP-76 and Vav in regulating IL-2 gene expression reflects the cooperation between different signaling pathways.
Fang
N
N
Graduate Program in Immunology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Koretzky
G A
GA
D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D019169:Jurkat Cells; D019950:Mitogen-Activated Protein Kinase 1; D015513:Oncogene Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; D007376:Interleukin-2; D015513:Oncogene Proteins; D010750:Phosphoproteins; D051567:Proto-Oncogene Proteins c-vav; C092947:SLP-76 signal Transducing adaptor proteins; D018808:Transcription Factor AP-1; C496618:VAV1 protein, human; D014443:Tyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1