Stimulation of the T-cell antigen receptor-CD3 complex signaling pathway by the tyrosine phosphatase inhibitor pervanadate is mediated by inhibition of CD45: evidence for two interconnected Lck/Fyn- or zap-70-dependent signaling pathways.
The tyrosine phosphatase specific inhibitor pervanadate is a potent activator of T lymphocytes through induction of tyrosine phosphorylation and downstream events of the activation cascade. Using CD45- or CD3-negative variants of the Jurkat leukemic T-cell line we show that the different biochemical events induced by pervanadate appeared to be dependent on the presence at the cell surface of either CD45 or CD3. CD45-dependent events such as tyrosine phosphorylation of Shc, activation of nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1), transcription factors, and stimulation of interleukin-2 (IL-2) promoter and of CD69 and CD25 surface expression paralleled activation of the tyrosine kinases lck and fyn. By contrast, stimulation of calcium influx, a CD3-dependent event, paralleled zap-70 activation. The data demonstrate that the T-cell antigen receptor-CD3 (TcR-CD3) complex is functionally linked to two different protein tyrosine kinase (PTK) modules with separate specific functions and that CD45 may be an important regulator of this coupling.
Imbert
V
V
INSERM Unité 364, Faculté de Médecine Pasteur, Nice, France.
Farahifar
D
D
Auberger
P
P
Mary
D
D
Rossi
B
B
Peyron
J F
JF
D001483:Base Sequence; D001665:Binding Sites; D017252:CD3 Complex / Q000276:immunology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology*; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000378:metabolism
D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C076715:pervanadate; D014638:Vanadates; D004247:DNA; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases