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Molecular and Cellular Biology, September 2000, p. 6837-6848, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

G Protein-Coupled Receptor-Mediated Mitogen-Activated Protein Kinase Activation through Cooperation of Galpha q and Galpha i Signals

Andree Blaukat,1 Ana Barac,1 Michael J. Cross,2 Stefan Offermanns,3 and Ivan Dikic1,*

Ludwig Institute for Cancer Research, S-75124 Uppsala,1 and Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-75185 Uppsala,2 Sweden, and Institut für Pharmakologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, D-14195 Berlin, Germany3

Received 3 March 2000/Returned for modification 19 April 2000/Accepted 14 June 2000

G protein-coupled receptors (GPCRs) have been shown to stimulate extracellular regulated kinases (ERKs) through a number of linear pathways that are initiated by Gq/11 or Gi proteins. We studied signaling to the ERK cascade by receptors that simultaneously activate both G protein subfamilies. In HEK293T cells, bradykinin B2 receptor (B2R)-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 Gbeta gamma subunits, phosphatidylinositol 3-kinase, and tyrosine kinases. Similar results were obtained with m1 and m3 muscarinic receptors in HEK293T cells and with the B2R 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 Gq/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.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Biomedical Center, Box 595, S-75124 Uppsala, Sweden. Phone: 46-18-160403. Fax: 46-18-160420. E-mail: Ivan.Dikic{at}licr.uu.se.

Molecular and Cellular Biology, September 2000, p. 6837-6848, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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