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The Regulation of Intestinal Mucosal Barrier by Myosin Light Chain Kinase/Rho Kinases

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The Regulation of Intestinal Mucosal Barrier by Myosin Light Chain Kinase/Rho Kinases International Journal of Molecular Sciences Review The Regulation of Intestinal Mucosal Barrier by Myosin Light Chain Kinase/Rho Kinases Younggeon Jin 1 and Anthony T. Blikslager 2,* 1 Department of Animal and Avian Sciences, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA; [email protected] 2 Department of Clinical Sciences, Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA * Correspondence: [email protected] Received: 29 April 2020; Accepted: 16 May 2020; Published: 18 May 2020 Abstract: The intestinal epithelial apical junctional complex, which includes tight and adherens junctions, contributes to the intestinal barrier function via their role in regulating paracellular permeability. Myosin light chain II (MLC-2), has been shown to be a critical regulatory protein in altering paracellular permeability during gastrointestinal disorders. Previous studies have demonstrated that phosphorylation of MLC-2 is a biochemical marker for perijunctional actomyosin ring contraction, which increases paracellular permeability by regulating the apical junctional complex. The phosphorylation of MLC-2 is dominantly regulated by myosin light chain kinase- (MLCK-) and Rho-associated coiled-coil containing protein kinase- (ROCK-) mediated pathways. In this review, we aim to summarize the current state of knowledge regarding the role of MLCK- and ROCK-mediated pathways in the regulation of the intestinal barrier during normal homeostasis and digestive diseases. Additionally, we will also suggest potential therapeutic targeting of MLCK- and ROCK-associated pathways in gastrointestinal disorders that compromise the intestinal barrier. Keywords: myosin light chain kinase; rho-associated coiled-coil containing protein kinase; apical junction complex; tight junction; adherens junction 1. Introduction The single layer of intestinal columnar epithelium forms the body’s largest interface between the external environments in the form of luminal contents [1]. Intestinal epithelial cells allow for the absorption of nutrients and water while providing a physical barrier to harmful components within the gut lumen, including microorganisms and their toxins, from gaining access into subepithelial tissues and the circulatory system [2]. Intestinal epithelial cells are linked by the apical junctional complex (AJC), including tight junctions (TJs) and adherens junctions (AJs) [3]. The AJC, in large part, regulates epithelial barrier function [4]. Intestinal barrier function, and the associated regulatory events centered at AJC regulation, are altered in a number of gastrointestinal disorders, including inflammatory bowel diseases (IBD) [5] and celiac disease [6]. However, there is a lack of well-defined therapeutic or diagnostic targets for AJC in patients with gastrointestinal disorders. To date, various studies have demonstrated that phosphorylation of myosin light chain II (pMLC-2) is a keyregulatoryeventinthephysiologicalandpathologicalmodulationofAJC[7–14]. Briefly,theperijunctional actomyosin rings are critical to maintaining AJC stability, and contraction of the perijunctional actomyosin ring induces the internalization of AJC proteins. This contraction is largely regulated by pMLC-2 (Figure1). Myosin light chain kinase (MLCK) and Rho-associated coiled-coil containing protein kinase (ROCK) have been shown to utilize phosphorylation of MLC-2 as a mechanism to regulate the AJC in various forms of intestinal mucosal injury (Figure2) [ 7–10,15–17]. However, the mechanistic role of MLCK and ROCK in the Int. J. Mol. Sci. 2020, 21, 3550; doi:10.3390/ijms21103550 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 17 AJs, has not been studied in depth. Therefore, this review focuses on MLCK- and ROCK-mediated intracellular pathways that may play important roles in the regulation of AJC, which in turn is responsibleInt. J. Mol. Sci. 2020for , 21regulating, 3550 intestinal barrier function in specific gastrointestinal disorders.2 of 17 Additionally, we review the role of pharmaceutical inhibitors for MLCK or ROCK, suggesting potential therapeutic targeting of MLCK- or ROCK-associated regulation of AJC in gastrointestinal regulation ofInt. AJC, J. Mol. including Sci. 2020, 21, x TJs FOR and PEERAJs, REVIEW has not been studied in depth. Therefore, this review2 of focuses 17 on disordersMLCK- and that ROCK-mediated compromise intestinal intracellular epithelial pathways integrity. that may play important roles in the regulation of AJC, which in turnAJs, is responsiblehas not been studied for regulating in depth. intestinalTherefore, this barrier review function focuses inon specificMLCK- and gastrointestinal ROCK-mediated disorders. intracellular pathways that may play important roles in the regulation of AJC, which in turn is Additionally,responsible we review for the regulating role of pharmaceutical intestinal barrier inhibitors function forin specific MLCK orgastrointestinal ROCK, suggesting disorders. potential therapeutic targetingAdditionally, of MLCK-we review or the ROCK-associated role of pharmaceutical regulation inhibitors of AJCfor MLCK in gastrointestinal or ROCK, suggesting disorders that compromisepotential intestinal therapeutic epithelial targeting integrity. of MLCK- or ROCK-associated regulation of AJC in gastrointestinal disorders that compromise intestinal epithelial integrity. Figure 1. The role of phosphorylation of myosin light chain-2 (MLC-2) in the apical junctional complex inFigure the intestinal 1. TheFigure role epithelial 1. of The phosphorylation role ofparacellular phosphorylation of myosinpathway. of myosin light lightThe chain-2 chain apical-2 (MLC (MLC-2) junctional-2) in inthethe apicalcomplex apical junctional junctionalconsists complex of complex tight in the intestinal epithelial paracellular pathway. The apical junctional complex consists of tight junctionsin the intestinal (TJs) and epithelial adherens paracellular junctions pathway.(AJs). TJs Theconsist apical of tra junctionalnsmembrane complex proteins consists (e.g., of tightclaudins junctions and (TJs) and adherensjunctions junctions (TJs) and adherens (AJs). TJs junctions consist (AJs). of TJs transmembrane consist of transmembrane proteins proteins (e.g., claudins(e.g., claudins and and occludin), occludin), andoccludin), scaffold and PDZ scaffold domain PDZ domain-expressing-expressing zonula zonula occludin occludin (ZO) proteins, proteins, which which serve serveto form to form and scaffold PDZ domain-expressing zonula occludin (ZO) proteins, which serve to form complex complex linkingcomplex transmembrane linking transmembrane protein proteins to thes to cytoskeletalthe cytoskeletal actomyosin actomyosin ring. ring. AJs AJs are locatedare located below below linking transmembrane proteins to the cytoskeletal actomyosin ring. AJs are located below the TJ the TJ and arethe TJcompri and aresed compri of twosed offamilies two families of adhesive of adhesive units: units: The EE-cadherin/catenin-cadherin/catenin family family and and and are comprisednectin/afadin of two complexes. families These of adhesive proteins are units: dynamically The E-cadherin regulated to /maintaincatenin epithelial family andintegrity. nectin In /afadin nectin/afadin complexes. These proteins are dynamically regulated to maintain epithelial integrity. In complexes.intestinal These proteins disorders, are increased dynamically phosphorylation regulated of MLC to-2 maintain induces contraction epithelial of integrity.the perijunctional In intestinal intestinal disorders,actomyosin increased ring and disruptphosphorylation the apical junctional of MLC complex.-2 induces This resultscontraction in elevated of the paracellular perijunctional disorders, increased phosphorylation of MLC-2 induces contraction of the perijunctional actomyosin actomyosin ringpermeability and disrupt during the the pathogenesis apical junctional of various digestivecomplex. diseases. This results in elevated paracellular ring and disrupt the apical junctional complex. This results in elevated paracellular permeability during permeability during the pathogenesis of various digestive diseases. the pathogenesis of various digestive diseases. Figure 2. Regulation of phosphorylation of myosin light chain-2 (MLC-2) by myosin light chain kinase (MLCK)/Rho-associated coiled coil containing protein kinase (ROCK) to regulate AJC barrier in intestinal epithelial cells. Paracellular permeability is principally determined by the phosphorylation level of the regulatory light chain of myosin, MLC-2, which is regulated by the enzymes MLCK and Figure 2. RegulationROCK. Increased of phosphorylation intracellular Ca2+ levels of myosinstimulate lightMLCKchain-2 activity, which (MLC-2) directly by phosphorylates myosin light chain Figure 2. Regulation of phosphorylation of myosin light chain-2 (MLC-2) by myosin light chain kinase kinase (MLCK) /Rho-associated coiled coil containing protein kinase (ROCK) to regulate AJC barrier in (MLCK)/Rho-associated coiled coil containing protein kinase (ROCK) to regulate AJC barrier in intestinal epithelial cells. Paracellular permeability is principally determined by the phosphorylation intestinal epithelial cells. Paracellular permeability is principally determined by the phosphorylation level of the regulatory light chain of myosin, MLC-2, which is regulated by the enzymes MLCK and level of the regulatory light chain of myosin, MLC-2, which is
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