Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase Cγ or GTPase-activating protein, distinguishes ErbB-3 signaling from that of other ErbB/EGFR family members

P. Fedi, J. H. Pierce, P. P. Di Fiore, M. H. Kraus

Research output: Contribution to journalArticle

Abstract

Recombinant expression of a chimeric EGFR/ErbB-3 receptor in NIH 3T3 fibroblasts allowed us to investigate cytoplasmic events associated with ErbB-3 signal transduction upon ligand activation. An EGFR/ErbB-3 chimera was expressed on the surface of NIH 3T3 transfectants as two classes of receptors possessing epidermal growth factor (EGF) binding affinities comparable to those of the wild-type EGF receptor (EGFR). EGF induced autophosphorylation in vivo of the chimeric receptor and DNA synthesis of EGFR/ErbB-3 transfectants with a dose response similar to that of EGFR transfectants. However, the ErbB-3 and EGFR cytoplasmic domains exhibited striking differences in their interactions with several known tyrosine kinase substrates. We demonstrated strong association of phosphatidylinositol 3- kinase activity with the chimeric receptor upon ligand activation comparable in efficiency with that of the platelet-derived growth factor receptor, while the EGFR exhibited a 10- to 20-fold-lower efficiency in phosphatidylinositol 3-kinase recruitment. By contrast, both phospholipase Cγ and GTPase- activating protein failed to associate with or be phosphorylated by the ErbB- 3 cytoplasmic domain under conditions in which they coupled with the EGFR. In addition, though certain signal transmitters, including Shc and GRB2, were recruited by both kinases, EGFR and ErbB-3 elicited tyrosine phosphorylation of distinct sets of intracellular substrates. Thus, our findings show that ligand activation of the ErbB-3 kinase triggers a cytoplasmic signaling pathway that hitherto is unique within this receptor subfamily.

Original languageEnglish
Pages (from-to)492-500
Number of pages9
JournalMolecular and Cellular Biology
Volume14
Issue number1
Publication statusPublished - 1994

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

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