G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Gαq, and Gαi signals

被引:82
作者
Blaukat, A
Barac, A
Cross, MJ
Offermanns, S
Dikic, I
机构
[1] Biomed Ctr, Ludwig Inst Canc Res, S-75124 Uppsala, Sweden
[2] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, S-75185 Uppsala, Sweden
[3] Free Univ Berlin, Klinikum Benjamin Franklin, Inst Pharmakol, D-14195 Berlin, Germany
关键词
D O I
10.1128/MCB.20.18.6837-6848.2000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (B2R)-induced stimulation of ERK2 and transcriptional activity of Elk1 are dependent on G alpha(q)-mediated protein kinase C (PKC) and on Ga-i-induced Ras activation, while they are independent of G beta gamma 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 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 G alpha(q/11)-deficient fibroblasts. In addition, we found that constitutively active mutants of G alpha(q/11) or G alpha(i) proteins alone poorly stimulate ERK, whereas a combination of both led to synergistic effects. We conclude that dually coupled GPCRs require a cooperation of G alpha(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.
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页码:6837 / 6848
页数:12
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