Pervanadate simulates the effects of interleukin-2 (IL-2) in human T cells and provides evidence for the activation of two distinct tyrosine kinase pathways by IL-2.
Pervanadate has been shown to rapidly increase the level of tyrosine phosphorylation in intact cells. Because one of the most rapidly detectable events following treatment of human T cells with interleukin-2 (IL-2) is tyrosine kinase activation, we were interested to determine whether pervanadate could act to induce IL-2-associated events. We show here that pervanadate does act to induce IL-2 signal transduction pathways as determined by induction of mitogenesis and interferon gamma production in normal human T cells and the factor independent T cell line YT. Analysis of signal transduction events shows that pervanadate induces the activity of the src family of tyrosine kinases lck and fyn and the tyrosine phosphorylation of a major IL-2 responsive protein of 97 kDa. Pervanadate does not, however, induce the activity of tyrosine kinases associated with the IL-2 receptor or the phosphorylation of a major IL-2 responsive protein of 116 kDa (Jak-3). Together these data suggest that src family kinase activation is a down stream event following IL-2 stimulation and is not directly associated with the activation of the IL-2 receptor-associated tyrosine kinase. The data also imply that tyrosine phosphorylation of p116/Jak-3 is strictly associated with activation of tyrosine kinases associated with the IL-2 receptor. With the use of pervanadate as a tool, we have established a dissociation of src family kinases with IL-2 receptor activation and imply the involvement of two distinct tyrosine kinase pathways, a receptor-associated pathway closely coupled with Jak-3 phosphorylation and a downstream pathway involving src family kinase activation.
Evans
G A
GA
Biological Carcinogenesis and Development Program, Program Resources Inc./DynCorp, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702-1201.
Garcia
G G
GG
Erwin
R
R
Howard
O M
OM
Farrar
W L
WL
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage*; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008970:Molecular Weight; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects*; D014638:Vanadates / Q000008:administration & dosage*
D007376:Interleukin-2; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C076715:pervanadate; D014638:Vanadates; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C494957:FYN protein, human; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn