The critical role of c-Src and the Shc/Grb2/ERK2 signaling pathway in angiotensin II-dependent VSMC proliferation.
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.
Sayeski
Peter P
PP
Department of Physiology and Functional Genomics, University of Florida College of Medicine, P.O. Box 100274, Gainesville, FL 32610, USA.
Ali
M Showkat
MS
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D002455:Cell Division; D002478:Cells, Cultured; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D016391:Genes, src; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D011506:Proteins; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000804:Angiotensin II; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1