Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes.
BACKGROUND
To elucidate the role of the Src family kinase Lyn in B cell receptor (BCR) signaling, we and others previously generated lyn-/- mice and analyzed their B cell responses. Although the initiation of BCR signaling in lyn-/- B cells is delayed, BCR-induced ERK2 activation and proliferation are enhanced. As the co-receptors Fc gamma RIIb1 and CD22 have been shown to be negative regulators of BCR signaling, we have now examined their functional roles in lyn-/- B cells.


RESULTS
B cells from lyn-/- mice have increased expression of the protein product of the early response gene egr-1, enhanced activation of Jun N-terminal kinase (JNK), and elevated calcium responses upon BCR cross-linking. Tyrosine phosphorylation of Fc gamma RIIb1 in lyn-/- B cells was reduced but negative regulation of the BCR signal by Fc gamma RIIb1 was only modestly impaired. In contrast, tyrosine phosphorylation of CD22 was greatly decreased in lyn-/- B cells, correlating with the inability of CD22 to downregulate the BCR-induced calcium response in these cells. Surprisingly, CD22 remains capable of regulating the ERK2 and JNK pathways in lyn-/- B cells, which may relate to the small residual increase in BCR-induced CD22 phosphorylation.


CONCLUSIONS
BCR signal initiation and negative regulation by Fc gamma RIIb1 is not critically dependent on Lyn. In contrast, Lyn plays a particularly important role in the tyrosine phosphorylation of CD22 and in the consequent inhibition of BCR-induced calcium influx. The net result of the Lyn deficiency in B cells is hyperresponsiveness to antigen stimulation, which may explain the autoimmunity observed in lyn-/- mice.
Chan
V W
VW
George Williams Hooper Foundation, University of California, San Francisco 94143, USA.
Lowell
C A
CA
DeFranco
A L
AL
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D004789:Enzyme Activation; D017353:Gene Deletion; D048031:JNK Mitogen-Activated Protein Kinases; D037102:Lectins; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000378:metabolism; D011817:Rabbits; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000502:physiology*; D017452:Receptors, IgG / Q000096:biosynthesis; D051918:Sialic Acid Binding Ig-like Lectin 2; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; C080571:Fc gamma receptor IIB; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D051918:Sialic Acid Binding Ig-like Lectin 2; D014443:Tyrosine; D011494:Protein Kinases; D048056:Mitogen-Activated Protein Kinase 9; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium