Platelet-derived growth factor negatively regulates the insulin-like growth factor signaling pathway through the coordinated action of phosphatidylinositol 3-kinase and protein kinase C beta I

Claudine Lassarre, Christine Legay, Manale Karam, Jean Marc Ricort

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

We recently described that epidermal and fibroblast growth factors (EGF and FGF) regulate the IGF-I signaling pathway at the level of IRS-1 through the cooperative action of two independent signaling pathways; one dependent on phosphatidylinositol 3-kinase (PI 3-kinase) and the other on protein kinase D1 (PKD1) (Karam et al. [22]). To determine whether this mechanism could be generalized to another tyrosine kinase receptor-dependent growth factor, the effect of platelet-derived growth factor (PDGF) on the IGF-I signaling pathway was studied. PDGF inhibited IGF-I-stimulated IRS-1 tyrosine phosphorylation and subsequent IGF-I-induced PI 3-kinase activity, and stimulated IRS-1 serine 307 phosphorylation. These effects were mediated through a PI 3-kinase-dependent but extracellular signal-regulated kinase (ERK)-independent signaling pathway. However, PDGF-induced IRS-1 serine 307 phosphorylation was not sufficient per se to inhibit the IGF-I signaling but required another independent pathway. Noteworthy, although acutely stimulated by PDGF, and contrary to what we previously described (Karam et al. [22]), PKD1 did not associate with IRS-1and did not inhibit the IGF-I signaling in response to PDGF. However, we identified PKCβI as a new regulatory partner of PI 3-kinase for PDGF-induced inhibition of the IGF-I signaling pathway. Therefore, our results reinforce the idea that a coordinated action of two independent pathways seems absolutely necessary to negatively regulate IRS-1. Moreover, they also demonstrated that, depending of the cross-talk considered, subtle and specific regulatory mechanisms occur at the level of IRS-1 and that a unique regulatory model is not conceivable.

Original languageEnglish
Pages (from-to)1367-1377
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number6
DOIs
Publication statusPublished - 1 Jun 2013

    Fingerprint

Keywords

  • Insulin-like growth factor
  • Platelet-derived growth factor
  • Protein kinase C beta I
  • Signaling pathway cross-talk
  • Tyrosine kinase receptor dependent signaling pathway

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this