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PMID:12837289

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Citation

Sayeski, PP and Ali, MS (2003) The critical role of c-Src and the Shc/Grb2/ERK2 signaling pathway in angiotensin II-dependent VSMC proliferation. Exp. Cell Res. 287:339-49

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.

Links

PubMed

Keywords

Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Angiotensin II/pharmacology; Animals; Aorta; Cell Division; Cells, Cultured; Enzyme Activation; GRB2 Adaptor Protein; Genes, src; Glutathione Transferase/metabolism; Male; Mitogen-Activated Protein Kinase 1/metabolism; Muscle, Smooth, Vascular/cytology; Muscle, Smooth, Vascular/drug effects; Muscle, Smooth, Vascular/metabolism; Phosphorylation; Protein-Tyrosine Kinases/metabolism; Proteins/metabolism; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Angiotensin/metabolism; Recombinant Fusion Proteins/metabolism; Shc Signaling Adaptor Proteins; Signal Transduction; src Homology Domains

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:SHC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:620795

F

Seeded From UniProt

complete

RAT:SHC1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:SHC1

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:SHC1

involved_in

GO:0048661: positive regulation of smooth muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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