Fc gammaRIIB1 inhibition of BCR-mediated phosphoinositide hydrolysis and Ca2+ mobilization is integrated by CD19 dephosphorylation.
The B cell receptor for immunoglobulin G, Fc gammaRIIB1, is a potent transducer of signals that block antigen-induced B cell activation. Coligation of Fc gammaRIIB1 with B lymphocyte antigen receptors (BCR) causes premature termination of phosphoinositide hydrolysis and Ca2+ mobilization and inhibits proliferation. This inhibitory signal is mediated in part by phosphorylation of Fc gammaRIIB1 and recruitment of phosphatases; however, the molecular target(s) of effectors is unknown. Here we report that Fc gammaRIIB1 inhibition of BCR signaling is mediated in part by selective dephosphorylation of CD19, a BCR accessory molecule and coreceptor. CD19 dephosphorylation leads to failed CD19 association with phosphatidylinositol 3-kinase, and this in turn leads to termination of inositol-1,4,5-trisphosphate production, intracellular Ca2+ release, and Ca2+ influx. The results define a molecular circuit by which Fc gammaRIIB signals block phosphoinositide hydrolysis.
Hippen
K L
KL
Department of Pediatrics, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver 80206, USA.
Buhl
A M
AM
D'Ambrosio
D
D
Nakamura
K
K
Persin
C
C
Cambier
J C
JC
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D018941:Antigens, CD19 / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D005434:Flow Cytometry; D006868:Hydrolysis; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D018941:Antigens, CD19; C080571:Fc gamma receptor IIB; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D002118:Calcium