Major histocompatibility class II-mediated signal transduction is regulated by the protein-tyrosine phosphatase CD45.
Major histocompatibility complex class II molecules and the B cell antigen receptor (BCR) transduce similar signals when cross-linked by ligand. Therefore, studies were conducted to determine whether the protein tyrosine phosphatase CD45 regulates signaling via these transmembrane receptors in an analogous manner. Cross-linking of either class II molecules or the BCR on CD45-positive K46-17micromlambda B lymphoma cells was observed to induce activation of the Src family protein- tyrosine kinase Lyn, tyrosine phosphorylation of Syk and phospholipase Cgamma, and the production of inositol 1,4,5-trisphosphate leading to intracellular mobilization as well as extracellular influx of Ca2+. In the absence of CD45, cross-linking of either class II molecules or the BCR failed to induce activation of Lyn. Syk was inducibly phosphorylated on tyrosine in a normal manner, whereas phospholipase Cgamma exhibited a high basal level of tyrosine phosphorylation that was not significantly increased upon stimulation. Nevertheless, phospholipase Cgamma appeared to be functional because CD45-negative cells produced elevated levels of inositol 1,4,5-trisphosphate following stimulation through class II or the BCR. Regardless of this, CD45-negative cells exhibited Ca2+ mobilization responses that were greatly diminished and transient in nature. Whereas little or no mobilization of Ca2+ was observed in response to class II cross-linking, CD45-deficient cells mobilized Ca2+ from intracellular stores but not the extracellular environment in response to BCR cross-linking. These results demonstrate that CD45 regulates both Src family kinase activation and Ca2+ mobilization associated with class II- and BCR-mediated signal transduction.
Greer
S F
SF
Division of Developmental and Clinical Immunology, and Department of Microbiology, University of Alabama, Birmingham, Alabama 35294, USA.
Lin
J
J
Clarke
C H
CH
Justement
L B
LB
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000502:physiology*; D016393:Lymphoma, B-Cell; D051379:Mice; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011940:Receptor Aggregation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D004792:Enzyme Precursors; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium