G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Galpha(q) and Galpha(i) signals.

Ludwig Institute for Cancer Research, Uppsala, Sweden.
G protein-coupled receptors (GPCRs) have been shown to stimulate extracellular regulated kinases (ERKs) through a number of linear pathways that are initiated by G(q/11) or G(i) proteins. We studied signaling to the ERK cascade by receptors that simultaneously activate both G protein subfamilies. In HEK293T cells, bradykinin B(2) receptor (B(2)R)-induced stimulation of ERK2 and transcriptional activity of Elk1 are dependent on Galpha(q)-mediated protein kinase C (PKC) and on Galpha(i)-induced Ras activation, while they are independent of Gbetagamma subunits, phosphatidylinositol 3-kinase, and tyrosine kinases. Similar results were obtained with m(1) and m(3) muscarinic receptors in HEK293T cells and with the B(2)R in human and mouse fibroblasts, indicating a general mechanism in signaling toward the ERK cascade. Furthermore, the bradykinin-induced activation of ERK is strongly reduced in Galpha(q/11)-deficient fibroblasts. In addition, we found that constitutively active mutants of Galpha(q/11) or Galpha(i) proteins alone poorly stimulate ERK2, whereas a combination of both led to synergistic effects. We conclude that dually coupled GPCRs require a cooperation of Galpha(i)- and G(q/11)-mediated pathways for efficient stimulation of the ERK cascade. Cooperative signaling by multiple G proteins thus might represent a novel concept implicated in the regulation of cellular responses by GPCRs.
Mesh Terms:
Animals, Cell Line, Cell Line, Transformed, Cyclic AMP-Dependent Protein Kinases, DNA-Binding Proteins, Enzyme Activation, GTP-Binding Protein alpha Subunits, Gi-Go, GTP-Binding Protein alpha Subunits, Gq-G11, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, GTP-Binding Proteins, Heterotrimeric GTP-Binding Proteins, Humans, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Phosphatidylinositol 3-Kinases, Potassium Channels, Protein Kinase C, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-raf, Receptor, Bradykinin B2, Receptor, Muscarinic M1, Receptor, Muscarinic M3, Receptors, Bradykinin, Receptors, Cell Surface, Receptors, Muscarinic, Transcription Factors, Transcriptional Activation, Virulence Factors, Bordetella, beta-Adrenergic Receptor Kinases, ets-Domain Protein Elk-1, ras Proteins
Mol. Cell. Biol. Sep. 01, 2000; 20(18);6837-48 [PUBMED:10958680]
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