Distinct mechanisms mediate SHC association with the activated and resting B cell antigen receptor.
Ligation of the B cell antigen receptor (BCR) complex initiates tyrosine phosphorylation of the receptor's transducer components, Ig-alpha and Ig-beta and tyrosine kinase-dependent accumulation of GTP-bound, activated p21ras. The mechanism of receptor coupling to p21ras activation and the roles of Ig-alpha and Ig-beta are unknown. The results reported here indicate that the resting, nonphosphorylated BCR associates with the Grb-2/Sos-linker SHC via the Ig-alpha immunoreceptor-based tyrosine activation motif (ITAM). Ig-alpha specificity of this interaction is determined by the sequence DCSM found in Ig-alpha, but not Ig-beta. Tyrosine phosphorylation of Ig-alpha and Ig-beta ITAM allows recruitment of SHC, which now binds directly to both Ig-alpha and Ig-beta via a phosphotyrosine/SH2 interaction. In confirmation of recent studies by Saxton et al. (J. Immunol. 1994. 153: 623) receptor ligation leads to tyrosine phosphorylation of SHC and to the formation of a phospho-SHC/Grb2/Sos complex. In view of previous studies which demonstrated p21ras co-capping with ligated BCR, the data presented here suggest that Ig-alpha/beta- and SHC tyrosine phosphorylation-dependent recruitment of the Grb2/Sos complex to the receptor can occur and may provide a mechanism by which the nucleotide exchange activity of Sos could mediate activation of BCR-localized p21ras.
D'Ambrosio
D
D
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA.
Hippen
K L
KL
Cambier
J C
JC
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D007399:Interphase / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases