Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase

A. Ricci, L. Lanfrancone, R. Chiari, G. Belardo, C. Pertica, P. G. Natali, P. G. Pelicci, O. Segatto

Research output: Contribution to journalArticle

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Abstract

In murine fibroblasts activation of the Shc/Grb-2 pathway by the ErbB-2 kinase involves tyrosine phosphorylation of Shc products and the formation of Shc/ErbB-2, Shc/Grb-2 and Grb-2/ErbB-2 complexes. Tyr 1139 of ErbB-2 bound to the Grb-2 SH2 domain in vitro as well as in intact cells. Tyr 1221 and 1248 are binding sites of gp185ErbB-2 for Shc SH2 domain in vitro whereas Tyr 1196 and 1248 are major binding sites of ErbB-2 for She PTB domain. Inhibition of Shc/ErbB-2 complex formation in intact cells was obtained by simultaneous mutational inactivation of Shc SH2 and Shc PTB binding sites of gp185ErbB-2. Shc/ErbB-2 complexes are formed upon activation of the ErbB-2 kinase and tyrosine phosphorylation of Shc proteins; they are located in both cytosol and cellular membranes. ErbB-2 activation induces also translocation of Grb-2 from cytosol to membranes. This network of protein-protein interactions may reflect the ability of the Shc/ Grb-2 pathway to act as a molecular switch controlling different cellular functions regulated by RTK activation. In fact the Ras GDP exchanger mSOS was recruited in Grb-2/ErbB-2 complexes; furthermore besides mSOS, other polypeptides present in either cytosolic or membrane preparations were able to complex in vitro with Grb-2 SH3 domains.

Original languageEnglish
Pages (from-to)1518-1529
Number of pages12
JournalOncogene
Volume11
Issue number8
Publication statusPublished - Oct 19 1995

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src Homology Domains
TYK2 Kinase
Phosphotransferases
Binding Sites
Cytosol
Membranes
Phosphorylation
Proteins
Fibroblasts
Peptides
In Vitro Techniques

Keywords

  • ErbB-2
  • GrbB-2
  • Shc
  • Signal transduction

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase. / Ricci, A.; Lanfrancone, L.; Chiari, R.; Belardo, G.; Pertica, C.; Natali, P. G.; Pelicci, P. G.; Segatto, O.

In: Oncogene, Vol. 11, No. 8, 19.10.1995, p. 1518-1529.

Research output: Contribution to journalArticle

Ricci, A. ; Lanfrancone, L. ; Chiari, R. ; Belardo, G. ; Pertica, C. ; Natali, P. G. ; Pelicci, P. G. ; Segatto, O. / Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase. In: Oncogene. 1995 ; Vol. 11, No. 8. pp. 1518-1529.
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AU - Ricci, A.

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AU - Belardo, G.

AU - Pertica, C.

AU - Natali, P. G.

AU - Pelicci, P. G.

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