Estrogen receptor ESR1 mediates activation of ERK1/2, CREB, and ELK1 in the corpus of the epididymis Fernanda N Cavalcanti, Thais F G Lucas, Maria Fatima M Lazari and Catarina S Porto Section of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de Sa ˜o Paulo, Rua Tre ˆ s de maio 100, INFAR, Vila Clementino, Sa ˜ o Paulo, Sa ˜ o Paulo 04044-020, Brazil Correspondence should be addressed to C S Porto Email csporto@unifesp.br or csegretiporto@gmail.com Abstract Expression of the estrogen receptor ESR1 is higher in the corpus than it is in the initial segment/caput and cauda of the epididymis. ESR1 immunostaining in the corpus has been localized not only in the nuclei but also in the cytoplasm and apical membrane, which indicates that ESR1 plays a role in membrane-initiated signaling. The present study investigated whether ESR1 mediates the activation of rapid signaling pathways by estradiol (E 2 ) in the epididymis. We investigated the effect of E 2 and the ESR1-selective agonist (4,4 0 ,4 00 -(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) on the activation of extracellular signal-regulated protein kinases (ERK1/2), CREB protein, and ETS oncogene-related protein (ELK1). Treatment with PPT did not affect ERK1/2 phosphorylation in the cauda, but it rapidly increased ERK1/2 phosphorylation in the initial segment/caput and corpus of the epididymis. PPT also activated CREB and ELK1 in the corpus of the epididymis. The PPT-induced phosphorylation of ERK1/2, CREB, and ELK1 was blocked by the ESR1-selective antagonist MPP and by pretreatment with a non-receptor tyrosine kinase SRC inhibitor, an EGFR kinase inhibitor, an MEK1/2 inhibitor, and a phosphatidylinositol-3-kinase inhibitor. In conclusion, these results indicate that the corpus, which is a region with high expression of the estrogen receptor ESR1, is a major target in the epididymis for the activation of rapid signaling by E 2 . The sequence of events that follow E 2 interaction with ESR1 includes the SRC-mediated transactivation of EGFR and the phosphorylation of ERK1/2, CREB, and ELK1. This rapid estrogen signaling may modulate gene expression in the corpus of the epididymis, and it may play a role in the dynamic microenvironment of the epididymal lumen. Key Words " ESR1 " ERK1/2 " CREB " ELK1 " epididymis Journal of Molecular Endocrinology (2015) 54, 339–349 Introduction The epididymis plays an important role in sperm transport, maturation, protection, and storage. In rodents, this organ can be functionally divided into four regions: the initial segment, the caput, the corpus, and the cauda (Turner 1995, Turner et al. 2003). Each of these segments possesses a distinct pattern of gene expression related to the physiological functions of the epididymis (Johnston et al. 2005, Henderson et al. 2006, Guyonnet et al. 2009; reviewed by Belleanne ´e et al. 2012). Journal of Molecular Endocrinology Research F N CAVALCANTI and others ESR1 activates ERK1/2, CREB, and ELK1 54 :3 339–349 http://jme.endocrinology-journals.org Ñ 2015 Society for Endocrinology DOI: 10.1530/JME-15-0086 Printed in Great Britain Published by Bioscientifica Ltd. Downloaded from Bioscientifica.com at 08/30/2023 11:59:56PM via free access