Phosphatidylinositol 3-kinase and protein kinase D1 specifically cooperate to negatively regulate the insulin-like growth factor signaling pathway.
Insulin receptor substrate-1 (IRS-1) is a key protein in the insulin-like growth factor (IGF) signaling whose tyrosine phosphorylation by the type 1 IGF receptor is necessary for the recruitment and activation of the downstream effectors. Through the analysis of cross-talks occurring between different tyrosine kinase receptor-dependent signaling pathways, we investigated how two growth factors [epidermal growth factor (EGF) and fibroblast growth factor (FGF)] could modulate the IGF-I-induced IRS-1 tyrosine phosphorylation and its downstream signaling. EGF and FGF inhibited IGF-I-stimulated tyrosine phosphorylation of IRS-1 and the subsequent IGF-I-induced phosphatidylinositol 3-kinase (PI 3-kinase) activity. These EGF- and FGF-inhibitory effects were dependent on both PI 3-kinase and protein kinase D1 (PKD1) signaling pathways but independent on the extracellular signal-regulated kinase (ERK) pathway. PKD1, which was activated independently of the PI 3-kinase pathway, associated with IRS-1 in response to EGF or FGF. Unlike PI 3-kinase, PKD1 did not mediate the EGF- or FGF-induced-IRS-1 serine 307 phosphorylation which was described to inhibit IRS-1. Interestingly, specific inhibition of either PI 3-kinase or PKD1 totally impaired EGF- or FGF-induced inhibition of IGF-I-stimulated IRS-1 tyrosine phosphorylation. This indicated that serine 307 phosphorylation of IRS-1 is not sufficient per se to inhibit the IGF signaling pathway and demonstrated for the first time that the negative regulation of IRS-1 requires the coordinated action of PI 3-kinase and PKD1. This further suggests that PKD1 may be an attractive target for innovative strategies that target the IGF signaling pathway.
LBPA, ENS de Cachan, CNRS, Cachan, France.
Manale
M
Karam
Claudine
C
Lassarre
Christine
C
Legay
Jean-Marc
JM
Ricort
D000730:Androstadienes / Q000378:metabolism; D002227:Carbazoles / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D008301:Maleimides / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013002:Somatomedins / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D002227:Carbazoles; D004791:Enzyme Inhibitors; C526292:IRS1 protein, human; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; D008301:Maleimides; D013002:Somatomedins; C081021:Go 6976; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D058539:Phosphatidylinositol 3-Kinase; C089212:protein kinase D; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C070515:bisindolylmaleimide I; D000077191:Wortmannin