EFFICIENT COUPLING WITH PHOSPHATIDYLINOSITOL 3-KINASE, BUT NOT PHOSPHOLIPASE C-GAMMA OR GTPASE-ACTIVATING PROTEIN, DISTINGUISHES ERBB-3 SIGNALING FROM THAT OF OTHER ERBB EGFR FAMILY MEMBERS

Recombinant expression of a chimeric EGFR/ErbB-3 receptor in NIH 3T3 f ibroblasts allowed us to investigate cytoplasmic events associated wit h ErbB-3 signal transduction upon ligand activation. An EGFR/ErbB-3 ch imera was expressed on the surface of NIH 3T3 transfectants as two cla sses of receptors possessing epidermal growth factor (EGF) binding aff inities comparable to those of the wild-type EGF receptor (EGFR). EGF induced autophosphorylation in vivo of the chimeric receptor and DNA s ynthesis of EGFR/ErbB-3 transfectants with a dose response similar to that of EGFR transfectants. However, the ErbB-3 and EGFR cytoplasmic d omains exhibited striking differences in their interactions with sever al known tyrosine kinase substrates. We demonstrated strong associatio n of phosphatidylinositol 3-kinase activity with the chimeric receptor upon ligand activation comparable in efficiency with that of the plat elet-derived growth factor receptor, while the EGFR exhibited a 10- to 20-fold-lower efficiency in phosphatidylinositol 3-kinase recruitment . By contrast, both phospholipase Cgamma and GTPase-activating protein failed to associate with or be phosphorylated by the ErbB-3 cytoplasm ic domain under conditions in which they coupled with the EGFR. In add ition, though certain signal transmitters, including Shc and GRB2, wer e recruited by both kinases, EGFR and ErbB-3 elicited tyrosine phospho rylation of distinct sets of intracellular substrates. Thus, our findi ngs show that ligand activation of the ErbB-3 kinase triggers a cytopl asmic signaling pathway that hitherto is unique within this receptor s ubfamily.