T-cell receptor signaling is mediated by transient Lck activity, which is inhibited by inorganic mercury.
Genetically susceptible rodents exposed to low nontoxic levels of inorganic mercury (Hg(2+)) develop idiosyncratic autoimmune disease associated with defective T-cell function. However, the molecular mechanisms underlying this phenomenon remain mostly unexplained. Brief exposure of T cells to micromolar concentrations of Hg(2+) leads to physiologically relevant nontoxic cellular mercury burdens, and as we have previously reported, attenuates T-cell receptor (TCR) signal strength by approximately 50%. We have found this to be the result of an inadequate activation of the tyrosine kinase ZAP-70, which is hypophosphorylated following TCR stimulation in Hg(2+) burdened cells when compared to untreated controls. In T cells, ZAP-70 phosphorylation is dependent on lymphocyte-specific protein tyrosine kinase (Lck) activity, which in turn is either positively or negatively regulated by the phosphorylation of specific Lck tyrosine residues. In particular, the general belief is that Lck is negatively regulated by phosphorylation of tyrosine 192 (Y192). We now demonstrate by Western blotting that, in Jurkat T cells, TCR signal transduction (and ZAP-70 phosphorylation) was positively associated with a rapid transient phosphorylation of Y192, which was inhibited in cells that were briefly (5 min) exposed to 5 microM Hg(2+). Thus, Hg(2+) inhibits a critical activating role played by Lck Y192 during the most proximal events of the TCR-induced cell signaling.
Ziemba
Stamatina E
SE
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Menard
Sherri L
SL
McCabe
Michael J
MJ
Rosenspire
Allen J
AJ
D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000502:physiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D008628:Mercury / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; D008628:Mercury