Activation of insulin-like growth factor type-1 receptor is required for H2O2-induced PKB phosphorylation in vascular smooth muscle cellsThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

2006 ◽  
Vol 84 (7) ◽  
pp. 777-786 ◽  
Author(s):  
Zeina M. Azar ◽  
Mohamad Z. Mehdi ◽  
Ashok K. Srivastava
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Second Messengers ◽  
Growth Factor Receptor ◽  
Specific Inhibitor ◽  
Insulin Like Growth Factor ◽  
Pkb Phosphorylation

Evidence accumulated in recent years has revealed a potential role for reactive oxygen species (ROS) in the pathophysiology of cardiovascular diseases. However, the precise mechanisms by which ROS contribute to the development of these diseases are not fully established. Previous work from our laboratory has indicated that exogenous hydrogen peroxide (H2O2) activates several signaling protein kinases, such as extracellular signal-regulated kinase 1 and 2 (ERK1/2) and protein kinase B (PKB) in A10 vascular smooth muscle cells (VSMC). However, the upstream elements responsible for this activation remain unclear. Although a role for epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) in H2O2-induced ERK1/2 signaling has been suggested, the contribution of this PTK or other receptor or nonreceptor PTKs to PKB activation is not well defined in VSMC. In this study, we used pharmacological inhibitors to investigate the role of receptor and Src-family-PTKs in H2O2-induced PKB phosphorylation. AG1478, a specific inhibitor of EGFR, failed to attenuate the H2O2-induced increase in PKB Ser473 phosphorylation, whereas AG1024, an inhibitor of insulin-like growth factor type1 receptor (IGF-1R)-PTK, almost completely blocked this response. H2O2treatment also enhanced tyrosine phosphorylation of the IGF-1Rβ subunit, which was significantly inhibited by AG1024 pretreatment of cells. Furthermore, pharmacological inhibition of Src by PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazole(3,4-d) pyrimidine) decreased PKB phosphorylation. Moreover, H2O2-induced PKB phosphorylation was associated with increased tyrosine phosphorylation of c-Src and Pyk2 in an AG1024- and PP2-inhibitable manner. In conclusion, these data provide evidence of the contribution of IGF-1R-PTK in initiating H2O2-evoked PKB phosphorylation in A10 VSMC, with an intermediary role for c-Src and Pyk2 in this process.

Role of insulin-like growth factor 1 receptor and c-Src in endothelin-1- and angiotensin II-induced PKB phosphorylation, and hypertrophic and proliferative responses in vascular smooth muscle cellsThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

2009 ◽  
Vol 87 (12) ◽  
pp. 1009-1018 ◽  
Author(s):  
Ali Bouallegue ◽  
George Vardatsikos ◽  
Ashok K. Srivastava
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Specific Inhibitor ◽  
Ang Ii ◽  
Vasoactive Peptides ◽  
Pkb Phosphorylation

Endothelin-1 (ET-1) and angiotensin II (Ang II) are vasoactive peptides believed to contribute to the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy, and restenosis. The concept of transactivation of growth factor receptors, such as epidermal growth factor receptor (EGFR), in triggering vasoactive peptide-induced signaling events has gained much recognition during the past several years. We have demonstrated that insulin-like growth factor type 1 receptor (IGF-1R) plays a role in transducing the effect of H2O2, leading to protein kinase B (PKB) phosphorylation. Since vasoactive peptides elicit their responses through generation of reactive oxygen species, including H2O2, we investigated whether IGF-1R transactivation plays a similar role in ET-1- and Ang II-induced PKB phosphorylation and hypertrophic responses in vascular smooth muscle cells (VSMC). AG1024, a specific inhibitor of IGF-1R protein tyrosine kinase (PTK), attenuated both ET-1- and Ang II-induced PKB phosphorylation in a dose-dependent manner. ET-1 and Ang II treatment also induced the phosphorylation of tyrosine residues in the autophosphorylation sites of IGF-1R, which were blocked by AG1024. In addition, both ET-1 and Ang II evoked tyrosine phosphorylation of c-Src, a nonreceptor PTK, whereas pharmacological inhibition of c-Src PTK activity by PP2, a specific inhibitor of Src-family tyrosine kinase, significantly reduced PKB phosphorylation as well as tyrosine phosphorylation of IGF-1R induced by the 2 vasoactive peptides. Furthermore, protein and DNA synthesis enhanced by ET-1 and Ang II were attenuated by AG1024 and PP2. In conclusion, these data suggest that IGF-1R PTK and c-Src PTK play a critical role in mediating PKB phosphorylation as well as hypertrophic and proliferative responses induced by ET-1 and Ang II in A10 VSMC.

Involvement of insulin-like growth factor 1 receptor transactivation in endothelin-1-induced signaling in vascular smooth muscle cells

2010 ◽  
Vol 88 (5) ◽  
pp. 501-509 ◽  
Author(s):  
Ali Bouallegue ◽  
George Vardatsikos ◽  
Ashok K. Srivastava
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Growth Factor Receptor ◽  
Muscle Cells ◽  
Insulin Like Growth Factor ◽  
Endothelin 1 ◽  
Receptor Transactivation

Endothelin-1 (ET-1) is a potent vasoactive peptide that exerts hypertrophic, migratory, and mitogenic effects in vascular smooth muscle cells. ET-1-induced activation of several signaling events has been shown to mediate the cellular effects of ET-1. In the past several years, transactivation of growth factor receptor has gained much recognition in transducing the signaling responses of ET-1. Among various growth factor receptors studied, the involvement of epidermal growth factor receptor transactivation in triggering ET-1-induced responses has been studied in some detail. However, recent studies have implicated insulin-like growth factor 1 receptor transactivation in this process. There are also some suggestions for a role of the Src family of nonreceptor protein tyrosine kinases, such as c-Src, in transducing the signaling responses of vasoactive peptides. In this review, we will examine the contribution of both insulin-like growth factor 1 receptor and c-Src in mediating ET-1-induced signaling responses in vascular smooth muscle cells.

Insulin-like growth factor type-1 receptor transactivation in vasoactive peptide and oxidant-induced signaling pathways in vascular smooth muscle cellsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

2007 ◽  
Vol 85 (1) ◽  
pp. 105-111 ◽  
Author(s):  
Zeina M. Azar ◽  
Mohamad Z. Mehdi ◽  
Ashok K. Srivastava
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Signaling Pathways ◽  
Growth Factor Receptor ◽  
Insulin Like Growth Factor ◽  
Ang Ii ◽  
Factor Type

Transactivation of epidermal growth factor receptor (EGFR) is a well-documented mechanism by which vasoactive peptides and H2O2 elicit their cellular responses. However, a role for the insulin-like growth factor type-1 receptor (IGF-1R) transactivation in mediating the effects of angiotensin II (Ang II) and H2O2 in vascular smooth muscle cells from different artery types have also been recently recognized. By using a series of pharmacological inhibitors of various growth factor receptor tyrosine kinases and a direct analysis of the phosphorylation status of the β-subunit of IGF-1R, a requirement of this growth factor receptor in Ang II and H2O2 response has been demonstrated. This review discusses some of the studies that highlight the importance of IGF-1R transactivation in mediating Ang II- and H2O2-induced mitogen-activated protein kinase and protein kinase B signaling pathways.

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