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Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras.

dc.contributor.author Allen, LF
dc.contributor.author Hawes, BE
dc.contributor.author Koch, Walter J
dc.contributor.author Lefkowitz, Robert J
dc.coverage.spatial United States
dc.date.accessioned 2013-09-10T16:03:22Z
dc.date.issued 1994-12-20
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/7809106
dc.identifier.issn 0027-8424
dc.identifier.uri https://hdl.handle.net/10161/7843
dc.description.abstract Stimulation of Gi-coupled receptors leads to the activation of mitogen-activated protein kinases (MAP kinases). In several cell types, this appears to be dependent on the activation of p21ras (Ras). Which G-protein subunit(s) (G alpha or the G beta gamma complex) primarily is responsible for triggering this signaling pathway, however, is unclear. We have demonstrated previously that the carboxyl terminus of the beta-adrenergic receptor kinase, containing its G beta gamma-binding domain, is a cellular G beta gamma antagonist capable of specifically distinguishing G alpha- and G beta gamma-mediated processes. Using this G beta gamma inhibitor, we studied Ras and MAP kinase activation through endogenous Gi-coupled receptors in Rat-1 fibroblasts and through receptors expressed by transiently transfected COS-7 cells. We report here that both Ras and MAP kinase activation in response to lysophosphatidic acid is markedly attenuated in Rat-1 cells stably transfected with a plasmid encoding this G beta gamma antagonist. Likewise in COS-7 cells transfected with plasmids encoding Gi-coupled receptors (alpha 2-adrenergic and M2 muscarinic), the activation of Ras and MAP kinase was significantly reduced in the presence of the coexpressed G beta gamma antagonist. Ras-MAP kinase activation mediated through a Gq-coupled receptor (alpha 1-adrenergic) or the tyrosine kinase epidermal growth factor receptor was unaltered by this G beta gamma antagonist. These results identify G beta gamma as the primary mediator of Ras activation and subsequent signaling via MAP kinase in response to stimulation of Gi-coupled receptors.
dc.language eng
dc.relation.ispartof Proc Natl Acad Sci U S A
dc.subject Animals
dc.subject Cell Line
dc.subject Cercopithecus aethiops
dc.subject Cyclic AMP-Dependent Protein Kinases
dc.subject Enzyme Activation
dc.subject GTP-Binding Proteins
dc.subject Guanosine Triphosphate
dc.subject In Vitro Techniques
dc.subject Mitogen-Activated Protein Kinase 1
dc.subject Peptide Fragments
dc.subject Protein-Serine-Threonine Kinases
dc.subject Protein-Tyrosine Kinases
dc.subject Proto-Oncogene Proteins p21(ras)
dc.subject Rats
dc.subject Receptors, Adrenergic, beta
dc.subject Receptors, Cell Surface
dc.subject Receptors, G-Protein-Coupled
dc.subject Receptors, Lysophosphatidic Acid
dc.subject Signal Transduction
dc.subject beta-Adrenergic Receptor Kinases
dc.title Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/7809106
pubs.begin-page 12706
pubs.end-page 12710
pubs.issue 26
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
pubs.organisational-group Chemistry
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Cardiology
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Trinity College of Arts & Sciences
pubs.publication-status Published
pubs.volume 91


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