Redox mechanism as alternative to ligand binding for receptor activation delivering disregulated cellular signals.
Cross-linking with specific ligand is a general requirement for ordered activation of cell surface receptors. In this study we demonstrated a novel pathway for disregulated receptor activation through a redox mechanism. Treatment of murine thymocytes or spleen cells with thiol-reactive HgCl2, a known inducer of autoimmune proliferative lymphocyte disorders in rodents, was found to induce tyrosine phosphorylation of several cellular proteins, which was up to 100 times as extensive as that triggered by stimulation with antireceptor antibody or mitogen. Through the cross-linkage by thiol-reactive bivalent mercury, transmembrane CD4, CD3, and CD45 and glycosylphosphatidylinositol-anchored Thy-1 were aggregated together on thymocytes or T lymphocytes. Along with the aggregation of Thy-1 and CD4, nonreceptor protein tyrosine kinase p56lck was aggregated and activated. These events were linked to extensive protein tyrosine phosphorylation, which was visualized as a well localized spot beneath the membrane. Under appropriate conditions, this novel pathway of multiple receptor aggregation delivered a disregulated signal into T lymphocytes, which cross-talked to the antireceptor antibody-induced signal, for prolonged cell proliferation and IL-2 production. These results suggest a novel mechanism of disregulation of the ligand-dependent receptor function.
Nakashima
I
I
Department of Immunology, Nagoya University School of Medicine, Japan.
Pu
M Y
MY
Nishizaki
A
A
Rosila
I
I
Ma
L
L
Katano
Y
Y
Ohkusu
K
K
Rahman
S M
SM
Isobe
K
K
Hamaguchi
M
M
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D017493:Leukocyte Common Antigens / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008562:Membrane Glycoproteins / Q000502:physiology; D008627:Mercuric Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011940:Receptor Aggregation / Q000187:drug effects; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D018800:Thy-1 Antigens; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000954:Antigens, Surface; D017252:CD3 Complex; D015704:CD4 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D018800:Thy-1 Antigens; D019000:Phosphotyrosine; D014443:Tyrosine; D008627:Mercuric Chloride; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens