A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling.
The Fc receptor on B lymphocytes, Fc gamma RIIB (beta 1 isoform), helps to modulate B-cell activation triggered by the surface immunoglobulin complex. Crosslinking of membrane immunoglobulin by antigen or anti-Ig F(ab')2 antibody induces a transient increase in cytosolic free Ca2+, a rise in inositol-3-phosphate, activation of protein kinase C, and enhanced protein tyrosine phosphorylation. Crosslinking Fc gamma RIIB with the surface immunoglobulin complex confers a dominant signal that prevents or aborts lymphocyte activation triggered through the ARH-1 motifs of the signal transduction subunits Ig-alpha and Ig-beta. Here we show that Fc gamma RIIB modulates membrane immunoglobulin-induced Ca2+ mobilization by inhibiting Ca2+ influx, without changing the pattern of tyrosine phosphorylation. A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB is both necessary and sufficient for this effect. Tyrosine at residue 309 in this motif is phosphorylated upon co-crosslinking with surface immunoglobulin; mutation of this residue aborts the inhibitory effect of Fc gamma RIIB. This inhibition is directly coupled to signalling mediated through Ig-alpha and Ig-beta as evidenced by chimaeric IgM/alpha and IgM/beta molecules. The 13-residue motif in Fc gamma RIIB controls lymphocyte activation by inhibiting a Ca2+ signalling pathway triggered through ARH-1 motifs as a result of recruitment of novel SH2-containing proteins that interact with this Fc gamma RIIB cytoplasmic motif.
Muta
T
T
DeWitt Wallace Research Laboratory, Sloan-Kettering Institute, New York, New York 10021.
Kurosaki
T
T
Misulovin
Z
Z
Sanchez
M
M
Nussenzweig
M C
MC
Ravetch
J V
JV
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D003593:Cytoplasm / Q000276:immunology; D008213:Lymphocyte Activation; D008223:Lymphoma; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017354:Point Mutation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D014443:Tyrosine; D002118:Calcium