beta-Arrestin 2 expression determines the transcriptional response to lysophosphatidic acid stimulation in murine embryo fibroblasts.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gesty-Palmer, D; El Shewy, H; Kohout, TA; Luttrell, LM

Published Date

  • September 16, 2005

Published In

Volume / Issue

  • 280 / 37

Start / End Page

  • 32157 - 32167

PubMed ID

  • 16027114

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M507460200


  • eng

Conference Location

  • United States