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  • Title: The critical role of c-Src and the Shc/Grb2/ERK2 signaling pathway in angiotensin II-dependent VSMC proliferation.
    Author: Sayeski PP, Ali MS.
    Journal: Exp Cell Res; 2003 Jul 15; 287(2):339-49. PubMed ID: 12837289.
    Abstract:
    Angiotensin II promotes vascular smooth muscle cell proliferation through the actions of the G protein-coupled AT(1) receptor. Recent evidence suggest that the tyrosine kinase c-Src may mediate this proliferative response. c-Src can signal through multiple intracellular signaling pathways including (1) the Shc/Grb2/ERK2 pathway, (2) the signal transducers and activators of transcription (STATs), (3) the focal adhesion kinase (FAK) signaling pathway, and (4) the phosphatidylinositol 3-kinase (PI3K) signaling pathway. In this study, we sought to determine the extent to which c-Src mediates vascular smooth muscle cell proliferation through the Shc/Grb2/ERK2 signaling pathway. Here we demonstrate that treatment of vascular smooth muscle cells with angiotensin II results in activation of the Shc/Grb2/ERK2 signaling pathway as measured by (1) increased Shc tyrosine phosphorylation, (2) increased c-Src/Shc cellular co-localization, (3) increased Shc/Grb2 co-association, and (4) ERK2 activation. Furthermore, these events are critically dependent on c-Src as pharmacological inhibition of c-Src activity blocked all these cellular occurrences. Most importantly, angiotensin II-dependent cellular proliferation was measured in the presence and absence of c-Src and MEK pharmacological inhibitors. We found that pharmacological inhibition of either c-Src or ERK2 completely eliminated angiotensin II-dependent cellular proliferation. Thus, the data suggest that c-Src and the Shc/Grb2/ERK2 signaling pathway play a critical role in angiotensin II-mediated VSMC proliferation.
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