Complex effects of phenylarsine oxide in T cells. Induction of tyrosine phosphorylation and calcium mobilization independent of CD45 expression.
The effects of phenylarsine oxide, a phosphotyrosine phosphatase inhibitor, on early signal transduction events in human T cells were studied. Simultaneous stimulation of T cells with anti-CD3 monoclonal antibody and phenylarsine oxide prevented increased tyrosine phosphorylation of phospholipase C gamma 1. In contrast, treatment of resting T cells with phenylarsine oxide alone resulted in increased tyrosine phosphorylation of a number of other intracellular substrates. Further, phenylarsine oxide was able to cause an immediate disruption of signal transduction in T cells after anti-CD3 stimulation, as measured by a return of intracellular calcium concentration and inositol 1,4,5-trisphosphate production to base-line levels. Surprisingly, in view of the inhibitory effects of phenylarsine oxide on T cell receptor signal transduction, treatment of T cells with phenylarsine oxide alone caused a dose-dependent increase in intracellular-free calcium concentration that was not accompanied with detectable increases in inositol 1,4,5-trisphosphate production. The phenylarsine oxide-induced increase in free calcium had distinct kinetics from antigen receptor-activated calcium mobilization and was derived from both intracellular sources and increased plasma membrane calcium permeability. This effect was independent of the CD45 transmembrane tyrosine phosphatase. Phenylarsine oxide thus has complex effects on signal transduction in T cells that suggests multiple intracellular targets, and these should be considered in the interpretation of experiments using this agent to study cellular kinase and phosphatase interactions. Finally, the effects of phenylarsine oxide on cellular calcium homeostasis may provide a mechanism of action for the therapeutic and/or toxic effects of arsenicals used for various forms of chemotherapy.
Fletcher
M C
MC
Immune Cell Biology Program, Naval Medical Research Institute, Bethesda, Maryland 20889.
Samelson
L E
LE
June
C H
CH
D001152:Arsenicals / Q000494:pharmacology*; D017252:CD3 Complex / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D004112:Dimercaprol / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008970:Molecular Weight; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D019000:Phosphotyrosine; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D001152:Arsenicals; D017252:CD3 Complex; D010750:Phosphoproteins; D004112:Dimercaprol; C029341:oxophenylarsine; D019000:Phosphotyrosine; D014443:Tyrosine; D015544:Inositol 1,4,5-Trisphosphate; D017493:Leukocyte Common Antigens; D002118:Calcium