caa a22 4500 606177477 CHVBK 20210128100752.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00018-014-1802-1 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1802-1 Transactivation of EGFR by prostaglandin E2 receptors: a nuclear story? [Elektronische Daten] [Ana Fernández-Martínez, Francisco Lucio-Cazaña] The pharmacological modulation of hypoxia-inducible factor-1α (HIF-1α) and HIF-1α-regulated vascular endothelial growth factor-A (VEGF-A) in the kidney has therapeutic interest. Although it is assumed that prostaglandin E2 (PGE2) exerts its biological effects from the extracellular medium through activation of EP receptors located at the cell membrane, we have shown in human renal proximal tubular HK-2 cells (and other cell lines) that intracellular PGE2 regulates the expression of HIF-1α expression and the production of VEGF-A. Here, we have found—through experiments involving EP receptors agonists, EP receptor gene silencing and inhibition of the prostaglandin uptake transporter—that these biological effects of PGE2 are mediated by intracellular EP2 receptors. In sharp contrast with cell membrane EP2, whose activation results in increased production of cAMP, intracellular EP2 signaling was independent of cAMP. Instead, it involved c-src-dependent transactivation of epidermal growth factor receptor, which led to p38/ERK1/2-dependent activation of mitogen- and stress-activated kinase-1 (MSK-1) and to MSK-1-dependent-histone H3 phosphorylation and transcriptional up-regulation of retinoic acid receptor-β. Even more important, this signaling pathway was fully reproduced in nuclei isolated from HK-2 cell, which highlights the relevance of nuclear EP receptors in the up-regulation of HIF-1α. These results open the possibility that signal cascades that proceed entirely in the cell nucleus might be responsible for several PGE2 effects that are assumed to be due to cell membrane EP receptors. Springer Basel, 2014 Hypoxia-inducible factor-1α nationallicence Intracellular prostaglandin E2 nationallicence Prostaglandin transporter nationallicence Epidermal growth factor receptor nationallicence Human proximal tubular epithelial nationallicence BG : Bromocresol green nationallicence EGFR : Epidermal growth factor receptor nationallicence HIF-1α : Hypoxia-inducible factor-1α nationallicence MSK-1 : Mitogen-and stress-activated kinase-1 nationallicence PGE2 : Prostaglandin E2 nationallicence PGT : Prostaglandin transporter nationallicence VEGF-A : Vascular endothelial growth factor-A nationallicence RARβ : Retinoic acid receptor-β nationallicence RARE : Retinoic acid receptor response element nationallicence Fernández-Martínez Ana Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut Lucio-Cazaña Francisco Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut Cellular and Molecular Life Sciences Springer Basel 72/11(2015-06-01), 2187-2198 1420-682X 72:11<2187 2015 72 18 https://doi.org/10.1007/s00018-014-1802-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1802-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fernández-Martínez Ana Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut NATIONALLICENCE 700 1- Lucio-Cazaña Francisco Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/11(2015-06-01), 2187-2198 1420-682X 72:11<2187 2015 72 18