β-Arrestin 2 Expression Determines the Transcriptional Response to Lysophosphatidic Acid Stimulation in Murine Embryo Fibroblasts

Diane Gesty-Palmer, Hesham El Shewy, Trudy A. Kohout, Louis M. Luttrell
2005 Journal of Biological Chemistry  
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 ␤-arrestins, to control the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2). In this study we investigated the role of ␤-arrestins in lysophosphatidic acid (LPA) receptor-stimulated ERK1/2 activation using fibroblast lines derived from wild type, ␤-arrestin 1, ␤-arrestin 2, and ␤-arrestin 1/2
more » ... nd ␤-arrestin 1/2 knock-out mice. LPA stimulation produced robust ERK1/2 phosphorylation in all four backgrounds. In cells lacking ␤-arrestin 2, >80% of LPA-stimulated ERK1/2 phosphorylation was mediated by transactivated EGF receptors. In contrast, ERK1/2 activation in cells expressing ␤-arrestin 2 was predominantly EGF receptor-independent. Introducing FLAG epitope-tagged ␤-arrestin 2 into the ␤-arrestin 1/2 null background restored EGF receptor-independent ERK1/2 activation, indicating that ␤-arrestin 2 expression confers ERK1/2 activation via a distinct mechanism. To determine the contributions of ␤-arrestin 2, transactivated EGF receptors, and ERK1/2 to LPAstimulated transcriptional responses, we employed gene expression arrays containing cDNA markers for G protein-coupled receptormediated signaling. In the ␤-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 ␤-arrestin 2 expressing cells, three of the seven LPA-stimulated transcriptional responses observed in the ␤-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 ␤-arrestin 2 functions both to attenuate EGF receptor transactivationdependent signaling and to promote a distinct subset of ERK1/2mediated responses to LPA receptor activation.
doi:10.1074/jbc.m507460200 pmid:16027114 fatcat:khde5dcuunectbqfvobokhxauq