Rapid desensitization of B-cell receptor by a dithiol-reactive protein tyrosine phosphatase inhibitor: uncoupling of membrane IgM from syk inhibits signals leading to Ca2+ mobilization.
B-cell antigen receptor (BCR)-mediated calcium response can be blocked by phenylarsine oxide (PAO), a dithiol group-reactive protein tyrosine phosphatase inhibitor. We have examined the mechanism of this inhibition in BL41 Burkitt lymphoma cells. PAO-dependent inhibition is not restricted to the BCR-mediated functions, as evidenced by the failure of the same cells to mobilize Ca2+ in response to CD19 cross-linking. In contrast, calcium response induced by a putative syk activator, H2O2, exhibited only a moderate sensitivity to PAO, demonstrating that PAO did not cause general suppression of all the functions leading to Ca2+ mobilization. BCR cross-linking or H2O2 treatment leads to the induction of almost complete non-responsiveness for the reciprocal stimulation. Since BCR cross-linking did not generate non-responsiveness to H2O2 in the presence of PAO, and PAO-treated cells remained responsive to syk activation by H2O2, we suppose that PAO may inhibit BCR-mediated signal transduction events upstream of syk activation. This assumption was supported by additional data, indicating that PAO was able to modulate functions of at least 2 different protein tyrosine kinase enzymes involved in BCR-mediated signaling. PAO induced rapid and dose-dependent tyrosine phosphorylation of lyn and selectively inhibited BCR-mediated tyrosine phosphorylation of syk. The results presented in this paper demonstrate that PAO may provoke cellular desensitization process by alteration of the signal transducer functions of lyn and syk tyrosine kinase enzymes.
Rozsnyay
Z
Z
Laboratory of Immunoregulation, VIRCC, Sandoz Research Institute, Vienna, Austria.
Sarmay
G
G
Gergely
J
J
D015703:Antigens, CD / Q000378:metabolism; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D001152:Arsenicals / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D004220:Disulfides; D015536:Down-Regulation; D004347:Drug Interactions; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007075:Immunoglobulin M / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases
D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D001152:Arsenicals; D004220:Disulfides; D004792:Enzyme Precursors; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; C036987:protein p80; C029341:oxophenylarsine; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases; D002118:Calcium