1. CD45 and Src-related protein tyrosine kinases regulate the T cell response to phorbol esters.
- Author
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Czyzyk JK, Fernsten PD, Brtva TR, Der CJ, and Winfield JB
- Subjects
- Antibodies, Monoclonal pharmacology, Benzoquinones, Enzyme Inhibitors pharmacology, Gene Expression Regulation genetics, Genes, ras physiology, Humans, Jurkat Cells, Lactams, Macrocyclic, Promoter Regions, Genetic genetics, Quinones pharmacology, Rifabutin analogs & derivatives, Signal Transduction drug effects, Signal Transduction physiology, Transcription Factor AP-1 metabolism, Transcriptional Activation physiology, src-Family Kinases antagonists & inhibitors, Leukocyte Common Antigens physiology, T-Lymphocytes drug effects, Tetradecanoylphorbol Acetate pharmacology, src-Family Kinases physiology
- Abstract
Protein kinase C (PKC)-dependent activation of the Ras signal transduction cascade is essential for induction of the IL-2 promoter during stimulation of T lymphocytes via the T cell receptor (TCR). In this study, the effects of PKC-activating phorbol myristate acetate (PMA) on Ras-dependent activation of transcription from the ets/AP-1 Ras-responsive promoter element were examined in human T cells. Pretreatment of Jurkat cells with the Src-family PTK inhibitor herbimycin A resulted in a 50% inhibition of transactivation of the reporter following incubation with PMA. Evidence was also obtained to suggest the participation of the leukocyte-specific protein tyrosine phosphatase CD45, a regulator of Src-like PTKs, in the PMA-induced activation of the Ras/Raf pathway. First, PMA-induced transactivation of ets/AP-1 is diminished 75% in CD45-negative variants, compared with CD45-positive cells. Second, engagement of CD45 by monoclonal antibodies suppresses the PMA response from the reporter construct. Taken together, these data suggest that Src-related proteins mediate PKC-dependent activation of the Ras/Raf pathway and implicate CD45 in the TCR-independent activation of T lymphocytes induced by agents such as PMA.
- Published
- 1998
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