Overexpression of Shc proteins potentiates the proliferative response to the granulocyte-macrophage colony-stimulating factor and recruitment of Grb2/S0S and Grb2/p140 complexes to the β receptor subunit

Luisa Lanfrancone, Giuliana Pelicci, Maria Felice Brizzi, Maria Grezia Arouica, Cristina Casciari, Sergio Giuli, Luigi Pegoraro, Tony Pawson, Pier Giuseppe Pelicci

Research output: Contribution to journalArticlepeer-review

Abstract

The high affinity receptor for GM-CSF consists of a unique α subunit and a β subunit that is shared with receptors for IL-3 and IL-5. Activation of GM-CSF receptor (GMR) triggers two distinct cytoplasmic signalling pathways, JAK2 and Ras, and is sufficient to maintain proliferation of growth factor-dependent cell lines. She proteins are phosphorylated upon activation of GMR and may be involved in the transmission of GM-CSF signals to Ras. To define the role of She proteins in cells stimulated with GM-CSF, we investigated both the network of interactions that involve She after GM-CSF stimulation and the effects of overexpressing She proteins on the proliferative response to GM-CSF. Two cytoplasmic complexes, Grb2/Sos and Grb2/p140 bind through the Grb2 SH2 domain to phosphorylated She, and are thereby recruited to the β subunit. Both complexes are stable, even in the absence of ligand, and depend on the direct association of p140 and Sos respectively with the SH3 domains of Grb2. p140 is an uncharacterized protein constitutively phosphorylated on tyrosine and, in its Grb2-bound form, expressed only in hematopoietic cells, the oligomeric complex formed by phosphorylated β subunit-phosphorylated Shc-Grb2-S0S-p140 is also induced by IL-3 and L-S stimulation of growth-factor dependent cell lines. Overexpression of wild-type She proteins in growth factor-dependent cells increases both MAP kinase activation and proliferation in response to GM-CSF. These effects require the association of She with Grb2. Taken together these results indicate that phosphorylation of She proteins is a crucial step in the transmission of GM-CSF proliferative stimuli, since it creates a high affinity binding site for the Grb2/S0S complex, whose function is to activate Ras and, for the Grb2/p140 complex, whose function remains unknown.

Original languageEnglish
Pages (from-to)907-917
Number of pages11
JournalOncogene
Volume10
Issue number5
Publication statusPublished - Mar 2 1995

Keywords

  • GM-CSF
  • Grb2
  • Shc
  • Signal

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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