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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.

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Date
1994-12-20
Authors
Koch, WJ
Hawes, BE
Allen, LF
Lefkowitz, RJ
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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.
Type
Journal article
Subject
Animals
Cell Line
Cercopithecus aethiops
Cyclic AMP-Dependent Protein Kinases
Enzyme Activation
GTP-Binding Proteins
Guanosine Triphosphate
In Vitro Techniques
Mitogen-Activated Protein Kinase 1
Peptide Fragments
Protein-Serine-Threonine Kinases
Protein-Tyrosine Kinases
Proto-Oncogene Proteins p21(ras)
Rats
Receptors, Adrenergic, beta
Receptors, Cell Surface
Receptors, G-Protein-Coupled
Receptors, Lysophosphatidic Acid
Signal Transduction
beta-Adrenergic Receptor Kinases
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https://hdl.handle.net/10161/7843
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Scholars@Duke

Lefkowitz

Robert J. Lefkowitz

The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win. Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the
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