REDOX MECHANISM AS ALTERNATIVE TO LIGAND-BINDING FOR RECEPTOR ACTIVATION DELIVERING DISREGULATED CELLULAR SIGNALS

Cross-linking with specific ligand is a general requirement for ordere d activation of cell surface receptors. In this study we demonstrated a novel pathway for disregulated receptor activation through a redox m echanism. Treatment of murine thymocytes or spleen cells with thiol-re active HgCl2, a known inducer of autoimmune proliferative lymphocyte d isorders in rodents, was found to induce tyrosine phosphorylation of s everal cellular proteins, which was up to 100 times as extensive as th at triggered by stimulation with antireceptor antibody or mitogen. Thr ough the cross-linkage by thiol-reactive bivalent mercury, transmembra ne CD4, CD3, and CD45 and glycosylphosphatidylinositol-anchored Thy-1 were aggregated together on thymocytes or T lymphocytes. Along with th e aggregation of Thy-1 and CD4, nonreceptor protein tyrosine kinase p5 6lck was aggregated and activated. These events were linked to extensi ve protein tyrosine phosphorylation, which was visualized as a well lo calized spot beneath the membrane. Under appropriate conditions, this novel pathway of multiple receptor aggregation delivered a disregulate d signal into T lymphocytes, which cross-talked to the antireceptor an tibody-induced signal, for prolonged cell proliferation and IL-2 produ ction. These results suggest a novel mechanism of disregulation of the ligand-dependent receptor function.