title: Transactivation of EGFR by prostaglandin E2 receptors: a nuclear story?
abstract: 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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) are mediated by intracellular EP(2) receptors. In sharp contrast with cell membrane EP(2), whose activation results in increased production of cAMP, intracellular EP(2) 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 PGE(2) effects that are assumed to be due to cell membrane EP receptors.
authors.affiliation: Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain, anab.fernandez@uah.es.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Fernández-Martínez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Lucio-Cazaña
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D010766:Phosphorylation; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018168:Receptors, Retinoic Acid; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C082925:retinoic acid receptor beta; D000242:Cyclic AMP; C512478:EGFR protein, human; D066246:ErbB Receptors; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases