title: 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.
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.
authors.affiliation: UMRS938, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Lassarre
authors.forename: Christine
authors.initials: C
authors.lastname: Legay
authors.forename: Manale
authors.initials: M
authors.lastname: Karam
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ricort
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; C075278:platelet-derived growth factor A; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D058539:Phosphatidylinositol 3-Kinase; C089212:protein kinase D; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases