B-CELL ANTIGEN RECEPTOR CROSS-LINKING INDUCES TYROSINE PHOSPHORYLATION AND MEMBRANE TRANSLOCATION OF A MULTIMERIC SHC COMPLEX THAT IS AUGMENTED BY CD19 CO-LIGATION

The SH2 domain-containing transforming Shc protein has been implicated in mitogenic signaling via several surface receptors through p21(ras) . Following tyrosine phosphorylation by either receptor or non-recepto r tyrosine kinases, She may interact with the adaptor protein Grb2, wh ich is linked to Sos1, a guanine nucleotide exchange factor for human ras. Ligation of the antigen receptor complex on B cells (BCR) is know n to activate various intracellular signaling pathways, which may accu mulate in mitogenic responses. With respect to the initial steps, the activation of BCR-associated non-receptor tyrosine kinases appears to be indispensible. In this report we show that She proteins become tyro sine phosphorylated after BCR ligation on both transformed and normal human B cells. This is accompanied by the association of She with Grb2 proteins and a yet unidentified 145-kDa tyrosine phosphorylated prote in. Subcellular fractionation revealed that this activation-induced mu ltimeric Shc complex rapidly translocates towards the plasma membrane. Co-ligation of the BCR with the CD19 molecule results in a marked inc rease of these events, whereas CD19 cross-linking alone does not induc e Shc tyrosine phosphorylation or translocation. Thus, in B cells the Shc complex may represent a molecular junction between the BCR and the mitogenic p21(ras) cascade.