Surface immunoglobulin crosslinking activates a tyrosine kinase pathway in B cells that is independent of protein kinase C.
It has been found that the principal biochemical pathway activated in B cells stimulated by antigen- or anti-immunoglobulin-mediated crosslinking of surface immunoglobulin is that resulting in hydrolysis of phosphatidylinositol bisphosphate with generation of diacylglycerol and inositol trisphosphate. Recent evidence suggests that surface immunoglobulin-mediated B-cell activation can proceed without detectable increases in the concentration of either diacylglycerol or intracellular Ca2+ concentration, implicating involvement of other non-protein-kinase-C/Ca2(+)-dependent signal-transduction pathways. Therefore, we sought evidence for activation of a signaling pathway that is associated with growth regulation in other cell types--i.e., the protein-tyrosine kinases. We now show that crosslinking of membrane immunoglobulin by mitogenic antibodies leads to rapid tyrosine phosphorylation of several cellular substrates, consistent with the induction of a tyrosine kinase activity. This increase in tyrosine phosphorylation is weakly (if at all) stimulated by other B-cell mitogens, including phorbol esters and ionophores, and does not require the presence of detectable protein kinase C. Furthermore, inhibition of anti-immunoglobulin-stimulated phosphatidylinositol bisphosphate hydrolysis does not inhibit activation of this tyrosine kinase-dependent pathway. These findings suggest that occupancy of the membrane immunoglobulin receptor may induce multiple pathways of activation.
Brunswick
M
M
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
Samelson
L E
LE
Mond
J J
JJ
D000818:Animals; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D015153:Blotting, Western; D003432:Cross-Linking Reagents; D015759:Ionomycin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010750:Phosphoproteins / Q000302:isolation & purification; D019000:Phosphotyrosine; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D013154:Spleen / Q000276:immunology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D019000:Phosphotyrosine; D015240:Phorbol 12,13-Dibutyrate; D014443:Tyrosine; D015759:Ionomycin; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C