Integrating Different Signals

Science Signaling  29 Apr 2008:
Vol. 1, Issue 17, pp. ec157
DOI: 10.1126/stke.117ec157

Migrating cells need to integrate promigratory diffusible signals that act through heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) with integrin-mediated cues from the extracellular matrix. Penela et al. found that overexpression of GPCR kinase 2 (GRK2, a serine/threonine kinase implicated in GPCR regulation) in epithelial-derived cell lines promoted migration toward fibronectin. A catalytically inactive mutant had effects similar to those of wild-type GRK2, whereas knockdown of endogenous GRK2 decreased migration toward fibronectin (but not collagen), which was also attenuated in fibroblasts derived from GRK2+/– mouse embryos. Indeed, wound healing in skin was decreased in the GRK2+/– mice. Pharmacological analysis indicated that GRK2-dependent stimulation of migration toward fibronectin depended on a pertussis toxin-sensitive GPCR and on the lipid messenger sphingosine 1-phosphate (S1P). Fibronectin promoted internalization of the S1P1 receptor (indicative of its occupancy by S1P) and increased S1P concentration (both in cytosol and in conditioned medium). Moreover, cells overexpressing GRK2 migrated more rapidly in response to exogenous S1P than did control cells, whereas S1P-induced migration was decreased in cells with decreased GRK2 abundance. Increased or decreased GRK2 expression was paralleled by activation of extracellular signal-regulated kinase (ERK1/2) in response to either S1P or adhesion to fibronectin; further, treatment with pertussis toxin or a sphingosine kinase inhibitor decreased the latter response. The effects of GRK2 on S1P-dependent ERK1/2 signaling and migration were independent of β-arrestin-1 and -2; rather, they involved the dynamic phosphorylation of GRK2 and its association with the scaffolding protein GIT1. The authors thus conclude that GRK2 integrates adhesion- and S1P-based signals to promote epithelial cell migration.

P. Penela, C. Ribas, I. Aymerich, N. Eijkelkamp, O. Barreiro, C. J. Heijnen, A. Kavelaars, F. Sánchez-Madrid, F. Mayor Jr., G protein-coupled receptor kinase 2 positively regulates epithelial cell migration. EMBO J. 27, 1206-1218 (2008). [PubMed]