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

Koch, WJ

Hawes, BE

Allen, LF

Lefkowitz, RJ

United States

2013-09-10T16:03:22Z

1994-12-20

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.

http://www.ncbi.nlm.nih.gov/pubmed/7809106

0027-8424

https://hdl.handle.net/10161/7843

eng

Proceedings of the National Academy of Sciences

Proc Natl Acad Sci U S A

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

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

Journal article

http://www.ncbi.nlm.nih.gov/pubmed/7809106

12706

12710

26

Basic Science Departments

Biochemistry

Chemistry

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Cardiology

Pathology

School of Medicine

Trinity College of Arts & Sciences

Published

91