Article

Phosphatidylinositol 3-kinase and protein kinase D1 specifically cooperate to negatively regulate the insulin-like growth factor signaling pathway

LBPA, ENS de Cachan, CNRS, Cachan, France.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2012; 1823(2):558-69. DOI: 10.1016/j.bbamcr.2011.12.007
Source: PubMed

ABSTRACT

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.

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    • "We showed that PDGF negatively modulated the IGF-I signaling pathway by inhibiting the IGF-I-induced IRS-1 tyrosine phosphorylation through PI 3-kinase-and PKCβI-dependent and PKD1-independent signaling pathways. PI 3-kinase was previously demonstrated as a negative regulator of several tyrosine kinase receptor-dependent pathways such as IGF-I [22] or insulin [29] thus appearing as a major regulatory actor in signal transduction. In the in vitro cross-talk context, this enzyme acts in a dual way, either as a positive mediator of its upstream tyrosine kinase receptordependent stimulatory pathways [20] or as a negative regulator of its target tyrosine kinase receptor-dependent signaling pathways [6]. "
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