DISTINCT MECHANISMS MEDIATE SHC ASSOCIATION WITH THE ACTIVATED AND RESTING B-CELL ANTIGEN RECEPTOR

Ligation of the B cell antigen receptor (BCR) complex initiates tyrosi ne phosphorylation of the receptor's transducer components, Ig-alpha a nd Ig-beta and tyrosine kinase-dependent accumulation of GTP-bound, ac tivated p21(ras). The mechanism of receptor coupling to p21(ras) activ ation and the roles of Ig-alpha and Ig-beta are unknown. The results r eported here indicate that the resting, nonphosphorylated BCR associat es with the Grb-2/Sos-linker SHC via the Ig-alpha immunoreceptor-based tyrosine activation motif (ITAM). Ig-alpha specificity of this intera ction is determined by the sequence DCSM found in Ig-alpha, but not Ig -beta. Tyrosine phosphorylation of Ig-alpha and Ig-beta ITAM allows re cruitment of SHC, which now binds directly to both Ig-alpha and Ig-bet a via a phosphotyrosine/SH2 interaction. In confirmation of recent stu dies by Saxton et al. (J. Immunol. 1994. 153: 623) receptor ligation l eads to tyrosine phosphorylation of SHC and to the formation of a phos pho-SHC/Grb2/Sos complex. In view of previous studies which demonstrat ed p21(ras) co-capping with ligated BCR, the data presented here sugge st that Ig-alpha/beta- ard SHC tyrosine phosphorylation-dependent recr uitment of the Grb2/Sos complex to the receptor can occur and may prov ide a mechanism by which the nucleotide exchange activity of Sos could mediate activation of BCR-localized p21(ras).