The MAPK/ERK-Signaling Pathway Regulates the Expression and Distribution of Tight Junction Proteins in the Mouse Proximal Epididymis1

Abstract

The initial segment (IS) in rodents is functionally and structurally distinct from other epididymal segments and plays an important role in sperm maturation. The MAPK/ERK1/2 pathway is maintained active in the IS by testicular luminal factors and plays crucial roles in the maintenance and differentiation of the IS epithelium. Tight junctions (TJs) are constituents of the blood-epididymis barrier, which mediates the paracellular transport of ions, solutes, and water and controls epithelial cell differentiation, thereby contributing to the establishment of a unique luminal environment. We examine here the role of the MAPK/ERK1/2 pathway in the regulation of TJ proteins in the IS. Inhibition of mitogen activated protein kinase kinase (MAPKK or MEK1/2) with PD325901, followed by reduction of ERK1/2 phosphorylation (pERK), decreased zonula occludens (ZO)-2 expression and increased ZO-3 expression in TJs but had no effect on ZO-1 expression. In control mice, in addition to being located in TJs, claudin (Cldn)-1, Cldn-3, and Cldn-4 were detected in the basolateral membrane of epithelial cells, with enriched expression of Cldn-1 and Cldn-4 in basal cells. PD325901 reduced the expression of Cldn-1 and Cldn-4 at all locations without affecting Cldn-3. Occludin was undetectable in the IS of control mice, but PD325901 triggered its expression in TJs. No effect was observed for any of the proteins examined in the other epididymal regions. Our results indicate the participation of the MAPK/ERK1/2 pathway in the regulation of cell-cell events that control the formation and maintenance of the blood-epididymis barrier.

Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes

“…There are disagreements in the literature regarding the general role of ERK and JNK in claudin regulation. ERK was shown to be required both for downregulation of Cldn-1 during epithelial-mesenchymal transition (Medici et al, 2006) and its steady-state maintenance in epididymis (Kim and Breton, 2016). Hyperosmolarity increased Cldn-4 expression through ERK and JNK in MDCK tubular cells (Ikari et al, 2013), but ERK was a mediator of Cldn-4 downregulation in ovarian adenocarcinoma and intestinal epithelial cells (Pinton et al, 2010;Ogawa et al, 2012).…”

Characterization of in vitro effects of microcystin‐LR on intestinal epithelial cells

“…Rao et al have found that the expression of occludin and ZO‐1 was regulated by PI3K/Akt pathway(Sheth et al, ). A recent study has indicated the participation of the MAPK/ERK1/2 pathway in the regulation of cell‐cell events that control the formation and maintenance of the blood‐epididymis barrier in mouse (Kim and Breton, ). Our results showed that MC‐LR can quickly lead to phosphorylation of key proteins in PI3K/Akt and MAPK signaling pathway.…”

Metformin prevents colonic barrier dysfunction by inhibiting mast cell activation in maternal separation‐induced IBS‐like rats

“…Posttranslational modification of tight junction proteins is responsible for tight junction function . ERK activation regulates the expression and distribution of tight junction proteins . Cong et al demonstrated that clau‐4 is phosphorylated by ERK activation to trigger clau‐4 internalization .…”

“…Additionally, knockdown or knockout of PAR‐2 inhibits the phosphorylation of ERKs . Moreover, ERKs (serine/threonine protein kinases) regulate the expression and distribution of tight junction proteins . Cong et al reported that ERK activation phosphorylates clau‐4 to recruit β‐arrestin 2 and then interacts with clathrin to promote clau‐4 internalization .…”