beta-Arrestin 2 expression determines the transcriptional response to lysophosphatidic acid stimulation in murine embryo fibroblasts.
G protein-coupled receptors often employ novel signaling mechanisms, such as transactivation of epidermal growth factor ( EGF) receptors or G protein-independent signals transmitted by beta-arrestins, to control the activity of extracellular signal-regulated kinases 1 and 2 ( ERK1/2). In this study we investigated the role of beta-arrestins in lysophosphatidic acid (LPA) receptor-stimulated ERK1/2 activation using fibroblast lines derived from wild type, beta-arrestin 1, beta-arrestin 2, and beta-arrestin 1/2 knock-out mice. LPA stimulation produced robust ERK1/2 phosphorylation in all four backgrounds. In cells lacking beta-arrestin 2, >80% of LPA-stimulated ERK1/2 phosphorylation was mediated by transactivated EGF receptors. In contrast, ERK1/2 activation in cells expressing beta-arrestin 2 was predominantly EGF receptor-independent. Introducing FLAG epitope-tagged beta-arrestin 2 into the beta-arrestin 1/2 null background restored EGF receptor-independent ERK1/2 activation, indicating that beta-arrestin 2 expression confers ERK1/2 activation via a distinct mechanism. To determine the contributions of beta-arrestin 2, transactivated EGF receptors, and ERK1/2 to LPA-stimulated transcriptional responses, we employed gene expression arrays containing cDNA markers for G protein-coupled receptor-mediated signaling. In the beta-arrestin 1/2 null background, 1 h of exposure to LPA significantly increased transcription of seven marker genes. Six of these responses were EGF receptor-dependent, and two required ERK1/2 activation. In beta-arrestin 2 expressing cells, three of the seven LPA-stimulated transcriptional responses observed in the beta-arrestin 1/2 null background were lost. The four residual responses were independent of EGF receptor transactivation, but all were ERK1/2-dependent. These data indicate that beta-arrestin 2 functions both to attenuate EGF receptor transactivation-dependent signaling and to promote a distinct subset of ERK1/2- mediated responses to LPA receptor activation.[1]References
- beta-Arrestin 2 expression determines the transcriptional response to lysophosphatidic acid stimulation in murine embryo fibroblasts. Gesty-Palmer, D., Shewy, H.E., Kohout, T.A., Luttrell, L.M. J. Biol. Chem. (2005) [Pubmed]
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