| First Author | Chun KS | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 51 | Pages | 39672-81 |
| PubMed ID | 20959465 | Mgi Jnum | J:167580 |
| Mgi Id | MGI:4868563 | Doi | 10.1074/jbc.M110.117689 |
| Citation | Chun KS, et al. (2010) The prostaglandin E2 receptor, EP2, stimulates keratinocyte proliferation in mouse skin by G protein-dependent and {beta}-arrestin1-dependent signaling pathways. J Biol Chem 285(51):39672-81 |
| abstractText | The prostaglandin E(2) (PGE(2)) G protein-coupled receptor (GPCR), EP2, plays important roles in mouse skin tumor development (Chun, K. S., Lao, H. C., Trempus, C. S., Okada, M., and Langenbach, R. (2009) Carcinogenesis 30, 1620-1627). Because keratinocyte proliferation is essential for skin tumor development, EP2-mediated signaling pathways that contribute to keratinocyte proliferation were investigated. A single topical application of the EP2 agonist, butaprost, dose-dependently increased keratinocyte replication via activation of epidermal growth factor receptor (EGFR) and PKA signaling. Because GPCR-mediated activation of EGFR can involve the formation of a GPCR-beta-arrestin-Src signaling complex, the possibility of a beta-arrestin1-Src complex contributing to EP2-mediated signaling in keratinocytes was investigated. Butaprost induced beta-arrestin1-Src complex formation and increased both Src and EGFR activation. A role for beta-arrestin1 in EP2-mediated Src and EGFR activation was demonstrated by the observation that beta-arrestin1 deficiency significantly reduced Src and EGFR activation. In agreement with a beta-arrestin1-Src complex contributing to EGFR activation, Src and EGFR inhibition (PP2 and AG1478, respectively) indicated that Src was upstream of EGFR. Butaprost also induced the activation of Akt, ERK1/2, and STAT3, and both beta-arrestin1 deficiency and EGFR inhibition (AG1478 or gefitinib) decreased their activation. In addition to beta-arrestin1-dependent EGFR activation, butaprost increased PKA activation, as measured by phospho-GSK3beta (p-GSK3beta) and p-cAMP-response element-binding protein formation. PKA inhibition (H89 or R(P)-adenosine-3',5'-cyclic monophosphorothioate (R(P)-cAMPS)) decreased butaprost-induced cAMP-response element-binding protein and ERK activation but did not affect EGFR activation, whereas beta-arrestin1 deficiency decreased EGFR activation but did not affect butaprost-induced PKA activation, thus indicating that they were independent EP2-mediated pathways. Therefore, the results indicate that EP2 contributed to mouse keratinocyte proliferation by G protein-independent, beta-arrestin1-dependent activation of EGFR and G protein-dependent activation of PKA. |
