The RIα subunit of protein kinase A (PKA) binds to Grb2 and allows PKA interaction with the activated EGF-Receptor

Giampaolo Tortora, Vincenzo Damiano, Caterina Bianco, Gustavo Baldassarre, A. Raffaele Bianco, Luisa Lanfrancone, Pier Giuseppe Pelicci, Fortunato Ciardiello

Research output: Contribution to journalArticle

Abstract

Functional interactions between protein kinase A (PKA) and epidermal growth factor receptor (EGF-R) signalling pathways have been suggested. Unlike the type II isoform of PKA (PKAII), the type I (PKAI) and/or its regulatory subunit RIα are generally overexpressed in cancer cells and are induced following transforming growth factor α (TGFα)/EGF-R-dependent transformation. Downregulation of RIα/PKAI inhibits TGFα expression and EGF-R-dependent signalling. We have previously shown that addition of EGF to quiescent human normal epithelial MCF-10A cells determines PKAI expression and cell membrane translocation before cells enter S phase, while PKAI inhibition prevents S phase entry. Constitutive overexpression of PKAI confers the ability to grow in serum free medium, bypassing EGF requirement. Here we demonstrate a direct interaction of PKAI, but not of PKAII, with the activated EGF-R, that occurs within 5 min following EGF treatment of MCF-10A cells. Moreover, induction of mitogen-activated protein kinase (MAPK) activity following EGF-R activation is mimicked by PKAI overexpression and inhibited by downregulators of PKAI. Finally, the PKAI-EGF-R association occurs through the binding of RIα to the SH3 domain(s) of Grb2 adaptor protein, thus allowing the recruitment of the PKAI holoenzyme to the activated EGF-R. This is the first demonstration of a direct interaction of PKAI with the activated EGF-R macromolecular signalling complex.

Original languageEnglish
Pages (from-to)923-928
Number of pages6
JournalOncogene
Volume14
Issue number8
Publication statusPublished - 1997

Keywords

  • Breast cells
  • Growth factors
  • Signal transduction

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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