G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors.
G-protein-coupled receptors that mediate cellular responses to a variety of humoral, endothelial-, or platelet-derived substances are able to stimulate MAP kinase activity. In transfected model systems, G-protein-coupled receptors that couple to pertussis toxin-insensitive G proteins of the Gq/11 family mediate this activation predominantly via a PKC-dependent mechanism. In contrast, activation of MAP kinase by receptors that couple to pertussis toxin-sensitive Gi proteins is PKC-independent and requires downstream activation of the low-molecular-weight G protein, Ras. This pathway can be inhibited by coexpression of peptides that sequester Gbetagamma subunits, and is mimicked by overexpression of Gbetagamma subunits. This Ras-dependent MAP kinase activation requires tyrosine phosphorylation of "docking proteins," including the shc adapter protein, and depends upon recruitment of Grb2/Sos1 complexes to the plasma membrane, thus resembling the pathway of MAP kinase activation employed by the receptor tyrosine kinases. Other molecules, including PI-3-kinases and phosphotyrosine phosphatases, probably also contribute to Gbetagamma-subunit-mediated assembly of a mitogenic signaling complex. Identification of the G-protein-coupled, receptor-regulated tyrosine kinase(s), and the means by which the mitogenic signaling complex is assembled at the plasma membrane, remain subjects of further study.
Duke Scholars
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- ras Proteins
- Tyrosine
- Signal Transduction
- Receptors, Cell Surface
- Phosphorylation
- Phosphoproteins
- Humans
- GTP-Binding Proteins
- Enzyme Activation
- Calcium-Calmodulin-Dependent Protein Kinases
Citation
Published In
ISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- ras Proteins
- Tyrosine
- Signal Transduction
- Receptors, Cell Surface
- Phosphorylation
- Phosphoproteins
- Humans
- GTP-Binding Proteins
- Enzyme Activation
- Calcium-Calmodulin-Dependent Protein Kinases