The prostaglandin E2 (PGE2) G protein coupled receptor (GPCR), EP2, plays important roles in mouse skin tumor development (Chun et al., Carcinogenesis, 30:1620, 2009). 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 EGFR and PKA signaling. Because GPCR-mediated activation of EGFR can involve the formation of a GPCR/B-arrestin/Src signaling complex, the possibility of a B-arrestin1/Src complex contributing to EP2-mediated signaling in keratinocytes was investigated. Butaprost induced B-arrestin1/Src complex formation and increased both Src and EGFR activation. A role for B-arrestin1 in EP2-mediated Src and EGFR activation was demonstrated by the observation that β-arrestin1-deficiency significantly reduced Src and EGFR activation. In agreement with a B-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 B-arrestin1-deficiency and EGFR inhibition (AG1478 or gefitinib) decreased their activation. In addition to B-arrestin1-dependent EGFR activation, butaprost also increased PKA activation, as measured by p-GSK3βand p-CREB formation. PKA inhibition (H89 or RP-cAMPS) decreased butaprost-induced CREB and ERK activation, but did not affect EGFR activation, whereas B-arrestin1-deficiency decreased EGFR activation but did not affect butaprost-induced PKA activation;thus indicating their independent EP2-mediated activation. Therefore, the results indicate that EP2 contributed to mouse keratinocyte proliferation by G protein-independent, B-arrestin1-dependent activation of EGFR, and G protein-dependent activation of PKA.
| Chun, Kyung-Soo; Langenbach, Robert (2011) The prostaglandin E2 receptor, EP2, regulates survivin expression via an EGFR/STAT3 pathway in UVB-exposed mouse skin. Mol Carcinog 50:439-48 |
| Chun, Kyung-Soo; Lao, Huei-Chen; Langenbach, Robert (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 285:39672-81 |
| Chun, Kyung-Soo; Lao, Huei-Chen; Trempus, Carol S et al. (2009) The prostaglandin receptor EP2 activates multiple signaling pathways and beta-arrestin1 complex formation during mouse skin papilloma development. Carcinogenesis 30:1620-7 |
