Abstract
Myosin light chain kinase (MLCK) induces contraction of the perijunctional apical actomyosin ring in response to phosphorylation of the myosin light chain. Abnormal expression of MLCK has been observed in respiratory diseases, pancreatitis, cardiovascular diseases, cancer, and inflammatory bowel disease. The signaling pathways involved in MLCK activation and triggering of endothelial barrier dysfunction are discussed in this review. The pharmacological effects of regulating MLCK expression by inhibitors such as ML-9, ML-7, microbial products, naturally occurring products, and microRNAs are also discussed. The influence of MLCK in inflammatory diseases starts with endothelial barrier dysfunction. The effectiveness of anti-MLCK treatment may depend on alleviation of that primary pathological mechanism. This review summarizes evidence for the potential benefits of anti-MLCK agents in the treatment of inflammatory disease and the importance of avoiding treatment-related side effects, as MLCK is widely expressed in many different tissues.
In mammals, myosin light chain kinase (MLCK) is encoded by the mylk1 and mylk2 genes (Herring et al., 2006). mylk2 encodes an MLCK isoform that is exclusively expressed in skeletal muscle cells (Herring et al., 2006; Wang L. et al., 2016). Because of the lack of data on mylk2 gene coding products, we mainly discuss mylk1 gene products, which include long chain MLCK (220 kDa), short chain MLCK (130 kDa), and the non-catalytic carboxy-terminal (17 kDa) protein, telokin (Chen et al., 2013; Chen C. et al., 2014; An et al., 2015). mylk1 gene coding products are expressed in diverse cell types and tissues including muscle, platelets, and secretory and brain cells (Jin et al., 2002). Numerous cell activities, such as contraction, adhesion, cell migration, and epithelial barrier formation occur in a myosin regulatory light chain (MLC) phosphorylation dependent or independent manner (Chen et al., 2013; Chen C. et al., 2014; Kim and Helfman, 2016). Abnormal expression of MLCK has been observed in many inflammatory diseases including pancreatitis (Shi et al., 2014), respiratory diseases (Zhou et al., 2015), cardiovascular diseases (Cheng et al., 2015), cancer (Zhou et al., 2014), and inflammatory bowel disease (IBD) (Yi et al., 2014). The involvement of MLCK and the MLCK signaling pathway that underlie representative inflammatory diseases is discussed. Some diseases in which MLCK is involved are listed in Table 1.
Table 1
| Diseases | MLCK changes | MLCK isoform | Representative References |
|---|---|---|---|
| Atherosclerosis | Increased expression | nmMLCK | Zhu et al., 2013 |
| Hypertension | Increased activity | smMLCK | Cho et al., 2011 |
| Heart injury/Heart failure | Increased activity | Cardiac MLCK | Lin et al., 2012; Chang et al., 2013 |
| Glaucoma | Increased activity | smMLCK | Prayitnaningsih et al., 2016 |
| Asthma | Increased expression/Gene variant | nmMLCK | Zhou et al., 2015 |
| Lung inflammation/Lung injury | Increased expression /Gene variant | nmMLCK | Mirzapoiazova et al., 2009; Wu et al., 2011 |
| Brain injury /Kidney injury | Increased expression | nmMLCK | Xu et al., 2015; Droylefaix et al., 2013 |
| Intestinal inflammation /IBD/Barrier dysfunction | Increased expression | nmMLCK | Du et al., 2016; Jin and Blikslager, 2016; Xiong et al., 2016 |
| Intestinal motility disorder | Increased/Decreased expression | smMLCK | Chen et al., 2015 |
| Pancreatitis | Increased | nmMLCK | Shi et al., 2014 |
| Prostate Cancer | – | nmMLCK | Spans et al., 2014 |
| Breast cancer | – | nmMLCK | Kim and Helfman, 2016 |
| Pancreatic cancer | – | nmMLCK | Kaneko et al., 2002 |
| Non-small cell lung cancer | Increased | nmMLCK | Minamiya et al., 2005 |
| Cervical cancer | – | nmMLCK | Shen et al., 2002 |
| Gastric cancer | – | nmMLCK | Chen et al., 2016 |
Role of myosin light chain kinase (MLCK) in selected diseases.
nmMLCK, non-muscle MLCK; smMLCK, smooth muscle MLCK.
MLCK in Respiratory Diseases, Atherosclerosis, and Pancreatitis
In inflammatory lung disorders, damage to lung endothelial cell barrier integrity alters vascular permeability, and alveolar flooding often results (Mao et al., 2015). Abnormal expression of MLCK occurs in lung injury, and the MLCK inhibitor ML-7 or deletion of the MLCK gene can attenuate lung injury (Wang T. et al., 2016). MLCK has similar activity in asthmatic and in lung inflammation, and variation of the MYLK gene is strongly associated with acute lung injury and asthma susceptibility (Wang et al., 2014, 2015; Wang T. et al., 2016).
MLCK-induced endothelial barrier dysfunction is also involved in pancreatitis and atherosclerosis (Cheng et al., 2015; Wang et al., 2014; Wang T. et al., 2016). Severe acute pancreatitis is associated with high morbidity and mortality. Its pathogenesis is not completely understood (Zerem, 2014), but MLCK expression is significantly increased in rat models of acute pancreatitis (Shi et al., 2014), and elevation of tumor necrosis factor (TNF)-α in severe acute pancreatitis has been shown to mediate MLCK-dependent regulation of the cytoskeleton, leading to destruction of the endothelial barrier function (Shi et al., 2014; Yu et al., 2016). The initiation and development of atherosclerosis often leads to progressive vascular injury, which is accompanied by endothelial dysfunction (Phinikaridou et al., 2015). The involvement of MLCK in the natural history of atherosclerosis has been confirmed by alleviation of vascular injury and atherosclerosis by ML-7, an MLCK inhibitor (Cheng et al., 2015).
MLCK in Cancer Development
Abnormal expression of MLCK has been observed in pancreatic, lung, and prostate cancer cell lines (Tohtong et al., 2003; Nagaraj et al., 2010; Chen et al., 2011). Rapid, dynamic changes of the cytoskeleton are needed for invasion and metastasis of cancer cells. MLCK-dependent phosphorylation of cytoskeletal myosin II increases the metastatic potential of tumor cells, and MLCK-dependent cytoskeleton rearrangement modulates vascular endothelial barrier functions associated with angiogenesis, which is a critical step in cancer development (Dudek and Garcia, 2001). On the other hand, the metastatic potential of breast cancer cells is increased by the loss of MLCK (Kim and Helfman, 2016). Changes in cell migration and adhesion are also characteristic early steps in inflammation but there are few reports of MLCK regulation of inflammatory cell migration.
MCLK in IBD
Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is characterized by chronic gastrointestinal inflammation, and is associated with significant patient impairment and high treatment costs (Rai et al., 2015). Although the pathogenesis of IBD remains obscure, there is evidence that intestinal barrier dysfunction is the primary driver (Hindryckx and Laukens, 2012; Pastorelli et al., 2015). Tight junction dysfunction leads to damage of the intestinal barrier, which permits passage of diverse pathogens (Jin and Blikslager, 2016). Tight junctions consist of transmembrane proteins such as occludins and claudins and peripheral membrane proteins, i.e., zonula occludens proteins (Van Itallie and Anderson, 2014). Tight junctions are located in the apicolateral region of endothelial cells and are bound to a perijunctional actomyosin ring. MLCK-induced phosphorylation of perijunctional actomyosin mediates tight junction loss, which can trigger the initiation and development of IBD. The expression and activity of MLCK is increased in human IBD and is associated with histological evidence of disease activity (Blair et al., 2006). Abnormal elevation of MLCK has also been observed in experimental colitis induced by gavage administration of dextran sulfate sodium or intracolonic administration of trinitrobenzenesulfonic acid (Su et al., 2013; Xiong et al., 2016).
MLCK Activation in IBD
TNF-α is a proinflammatory cytokine that causes intestinal tight junction barrier dysfunction, which is central to IBD pathogenesis (Saleh et al., 2016). In IBD, TNF receptor 2 (R2)-mediated signaling contributes to increased epithelial MLCK expression (Su et al., 2013; Suzuki et al., 2014). In a recent report by Al-Sadi et al. (2013), tight junction permeability of Caco-2 cell monolayers, in an in vitro model of intestinal epithelium, was increased by TNF-α activation of the ERK1/2 signaling pathway. Activation of the ERK1/2 pathway induced phosphorylation of ETS domain-containing transcription factor Elk-1. Activated Elk-1 then moved into the nucleus and bound to the MLCK promoter, finally resulting in epithelial MLCK expression. LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells) is a TNF core family member that is involved in the pathogenesis of human IBD (Krause et al., 2014), and in cultured epithelia, MLCK inhibition alleviated LIGHT-induced barrier loss, which suggested that LIGHT-induced epithelial barrier loss may depend on MLCK activation (Schwarz et al., 2007).
Increases in tight junction permeability through IL-1β–mediated increases in MLCK expression has been demonstrated in inflammatory diseases (Beard et al., 2014). In mesenchymal stem cell migration, IL-1β was shown to cause an increase in epithelial MLCK expression through activation of the PKCd/NF-κB pathway; it also stimulated MLCK activity via the PKCa/MEK/ERK signaling pathway (Lin et al., 2014).
IFN-γ has also been associated with activation of MLCK by promoting adhesion and internalization of commensal bacteria by epithelial MLCK-activated brush border fanning (Wu et al., 2014). However, as with LIGHT-mediated regulation of MLCK, further study of INF-γ-mediated regulation of MLCK is needed to determine if it is direct. Signaling pathways associated with regulation of MLCK are shown in Supplementary Figure S1.
MLCK-Associated Signaling Pathways That Can Trigger IBD
In IBD, MLCK-induced epithelial barrier dysfunction is triggered by two signaling pathways. Firstly, in the gut, the epithelium forms a barrier against pathogens in the lumen. Abnormal expression of MLCK in inflammatory gastrointestinal diseases leads to phosphorylation of myosin II regulatory light chain (MLC), contraction of the actomyosin ring and increased intestinal permeability (Yi et al., 2015). Thus, MLCK-dependent MLC phosphorylation is an essential mechanism underlying MLCK-induced epithelial barrier dysfunction. A second mechanism involves MLCK-stimulated upregulation of claudin-2 and occludin endocytosis (Su et al., 2013; Jin and Blikslager, 2016). Increased expression of claudin-2 has been associated with intestinal epithelial barrier dysfunction (Hu et al., 2015; Krishnan et al., 2015), as well as decreased absorption, leak flux diarrhea, and inflammatory responses (Hu et al., 2015). Down-regulation of occludin in IBD decreases gastrointestinal permeability, which may disrupt the integrity of the barrier against a variety of pathogens (Yin et al., 2015).
Potential Pathological Role of Smooth Muscle MLCK in IBD
Smooth muscle (sm) MLCK is transcribed from the same gene as epithelial MLCK. It is involved in the regulation of sm contraction, and variation of smMLCK content leads to motility disorders (Chen et al., 2015). The motility disorders secondarily cause abnormal growth of intestinal flora, which in turn aggravates the pathogenesis of intestinal inflammation (Chen D. et al., 2014; Welch et al., 2014). Whether there is a direct effect of smMLCK on inflammatory diseases needs further study.
MLCK Inhibitors with Potential Pharmaceutical Use
Myosin light chain kinase has catalytic, inhibitory, and calmodulin-binding domains (Chang et al., 2016). The activity of the catalytic domain can be disclosed by partial tryptic digestion, and can be blocked by MLCK inhibitors (Luck and Choh, 2011; Chang et al., 2016). MLCK inhibitors act by competitive binding at or near the ATP-binding site on the MLCK molecule (Saitoh et al., 1987; Luck and Choh, 2011). MLCK has been extensively studied in sm, but is widely distributed in animal cells and tissues. Consequently, determining the activities of MLCK in other tissues is critical; MLCK inhibitors are good tools for this. MLCK inhibitors also have pharmacological potential as vasodilators and anti-inflammatory agents. Some MLCK inhibitors, their origins and evidence of pharmacological effect are listed in Table 2.
Table 2
| Name | Source | Inhibited MLCK isoform | Disease or condition |
|---|---|---|---|
| ML-9 | Synthetic | nmMLCK, smMLCK | High blood pressure (Honjo et al., 2002). |
| ML-7 | Synthetic | nmMLCK, smMLCK | Heart ischemia/reperfusion injury (Lin et al., 2012; Zhang et al., 2015), IBD (Cheng et al., 2015), and atherosclerosis (Cheng et al., 2015). |
| K-252a | Microbial culture | nmMLCK, smMLCK | – |
| KT592 | Microbial culture | nmMLCK, smMLCK | – |
| Wortmannin | Microbial culture | NmMLCK, smMLCK | – |
| Quercetin | Natural source | SmMLCK | Gut hyper motility (Zhang et al., 2006) |
| Genistin | Natural source | smMLCK | Intestinal hyper motility (Xiong et al., 2013) |
| Wogonin | Natural source | nmMLCK | Diseases associated with the development of both inflammatory and tumor (Huang et al., 2015) |
| Capsaicin | Natural source | smMLCK, nmMLCK | Intestinal motility disorder (Chen et al., 2015) |
| Salvianolic acid B | Natural source | NmMLCK | IBD (Xiong et al., 2016) |
| Lithium | Natural source | smMLCK | Intestinal hyper motility (Tang et al., 2010) |
Myosin light chain kinase inhibitors with potential pharmaceutical use.
The diseases or conditions in which MLCK inhibition and/or MLCK inhibitors have shown a therapeutic effect are discussed in “Diseases and condition.” nmMLCK, non-muscle MLCK; smMLCK, smooth muscle MLCK.
ML-9 and ML-7
ML-9 [1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine] is a classical MLCK inhibitor (IC50 = 3.8 μM), which was found to inhibit both Ca2+-calmodulin–dependent and -independent smMLCK (Saitoh et al., 1987; Shi et al., 2007). Both ML-9 and its synthetic derivatives are good selective inhibitors of smMLCK (Ito et al., 2004). ML-9 has been shown to reduce intraocular pressure in rabbit eyes (Honjo et al., 2002).
Another MLCK inhibitor, ML-7 [1-(5-iodonaphthalene-1-sulphonyl) 1H-hexahydro 1, 4-diazepine hydrochloride], is a membrane-permeable agent (Shi et al., 2007). Both ML-9 and ML-7 are naphthalene sulfonamide derivatives (Shi et al., 2007). ML-7 inhibition is more than 30-fold more potent than that of ML-9 (IC50 = 300 nM) (Shi et al., 2007). However, compared with ML-9, specific MLCK inhibition of smMLCK and other MLCK isoforms may be less potent (Saitoh et al., 1987). Beneficial effects of ML-7 has been shown in many conditions including heart ischemia/reperfusion injury (Lin et al., 2012; Zhang et al., 2015), IBD (Cheng et al., 2015), and atherosclerosis (Cheng et al., 2015).
Microbial Product Inhibitors of MLCK
K-252a, a microbial alkaloid purified from microbial cultures, is a non-selective inhibitor of MLCK (Nakanishi et al., 1992) as well as other protein kinases including protein kinase C and some cyclic nucleotide-dependent protein kinases (Nakanishi et al., 1992). KT592 is a derivative of K-252a with increased selectivity. Wortmannin, isolated and purified from the fungal strain Talaromyces wortmannin KY12420, is another microbial product inhibitor of MLCK (Nakanishi et al., 1992), It has been shown to decrease secretory responses in rat adrenal medullary cells through inhibition of MLCK (Warashina, 2000) and to have antifungal, hemorrhagic, and anti-inflammatory activity that may not be related to inhibition of MLCK (Nakanishi et al., 1992). The potential pharmacological effects of these inhibitors warrant further study.
Naturally Occurring Potential Inhibitors of MLCK
As shown in Table 2, some naturally occurring bioactive constituents may be inhibitors of MLCK. In an in vitro system including purified myosin and MLCK, quercetin inhibited myosin phosphorylation. The inhibition can be blocked by the MLCK inhibitor ML-7, indicating that quercetin may be a direct MLCK inhibitor (Zhang et al., 2006). In an animal model of gut motility disorder, capsaicin administration significantly decreased MLCK expression, which also implicates MLCK as a target for inhibition by capsaicin (Chen et al., 2015). The inhibition in response to salvianolic acid B may be indirect; other signaling is involved. Salvianolic acid B decreases MLCK expression by upregulation of microRNA1 (Xiong et al., 2016). Upregulation of microRNA-374a, microRNA-155, miR-520c-3p, and miR-1290 has also been found to reduce MLCK expression in various tissues (Adyshev et al., 2013; Weber et al., 2014). Naturally occurring bioactive compounds that act indirectly through microRNAs are an alternative inhibition pathway. However, disease-specific pharmacological experiments are needed to confirm the effects of potential naturally occurring inhibitors of MLCK.
Summary
This review summarizes the evidence for a role of MLCK in inflammatory diseases, especially IBD. Abnormal expression of MLCK is involved in diverse pathological events, mainly by causing cytoskeletal changes that disrupt epithelial barrier function. The effect of anti-MLCK agents in specific inflammatory diseases depends on the extent to which endothelial function is involved. Prevention of treatment-related side effects is a key consideration because MLCK is abundantly expressed in many tissues. Consideration of two aspects of selectivity helps to anticipate and prevent side effects of MLCK inhibitors. First is the selective inhibition of MLCK and other protein kinases such as protein kinase C and cyclic nucleotide-dependent protein kinase; the other is selective inhibition of the different MLCK isoforms such as smMLCK and nmMLCK. Potential anti-MLCK pharmaceutical agents offer a novel insight into the treatment of inflammatory diseases that differs from traditional anti-inflammatory therapy.
Statements
Author contributions
Conceived and designed the review: DC. References check: DC, YX, CW, LW, ZZ, and LS. Drafted the paper and revised it critically for important intellectual content: DC, YX, CW, LW, ZZ, and LS. The manuscript has been approved by all the authors.
Acknowledgments
This study was supported by National Natural Science Foundation of China (grant number 81600440, 81273919) and Dalian Municipal Medical Research Foundation.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary material
The Supplementary Material for this article can be found online at: http://journal.frontiersin.org/article/10.3389/fphar.2017.00292/full#supplementary-material
FIGURE S1Mechanisms underlying MLCK-induced regulation of the endothelial barrier function are shown. Solid arrows indicate direct interaction and dotted arrows indicate indirect interactions.
References
1
AdyshevD. M.MoldobaevaN.MapesB.ElangovanV.GarciaJ. G. (2013). MicroRNA regulation of nonmuscle myosin light chain kinase expression in human lung endothelium.Am. J. Respir. Cell Mol. Biol.4958–66. 10.1165/rcmb.2012-0397OC
2
Al-SadiR.GuoS.YeD.MaT. Y. (2013). TNF-α modulation of intestinal epithelial tight junction barrier is regulated by ERK1/2 activation of Elk-1.Am. J. Pathol.1831871–1884. 10.1016/j.ajpath.2013.09.001
3
AnC.BhetwalB. P.SandersK. M.SomlyoA. V.PerrinoB. A. (2015). Role of telokin in regulating murine gastric fundus smooth muscle tension.PLoS ONE10:e0134876. 10.1371/journal.pone.0134876
4
BeardR. J.HainesR. J.WuK. Y.ReynoldsJ. J.DavisS. M.ElliottJ. E.et al (2014). Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells.J. Cell Sci.1271840–1853. 10.1242/jcs.144550
5
BlairS. A.KaneS. V.ClayburghD. R.TurnerJ. R. (2006). Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease.Lab. Invest.86191–201. 10.1038/labinvest.3700373
6
ChangA. N.HuangJ.BattiproluP. K.HillJ. A.KammK. E.StullJ. T. (2013). The effects of neuregulin on cardiac myosin light chain kinase gene-ablated hearts.PLoS ONE8:e66720. 10.1371/journal.pone.0066720
7
ChangA. N.MahajanP.KnappS.BartonH.SweeneyH. L.KammK. E.et al (2016). Cardiac myosin light chain is phosphorylated by Ca2+/calmodulin-dependent and -independent kinase activities.Proc. Natl. Acad. Sci. U.S.A.113E3824–E3833. 10.1073/pnas.1600633113
8
ChenC.TaoT.WenC.HeW. Q.QiaoY. N.GaoY. Q.et al (2014). Myosin light chain kinase (MLCK) regulates cell migration in a myosin regulatory light chain phosphorylation-independent mechanism.J. Biol. Chem.28928478–28488. 10.1074/jbc.M114.567446
9
ChenD.XiongY.LinY.TangZ.WangJ.WangL.et al (2015). Capsaicin alleviates abnormal intestinal motility through regulation of enteric motor neurons and MLCK activity: relevance to intestinal motility disorders.Mol. Nutr. Food Res.591482–1490. 10.1002/mnfr.201500039
10
ChenD.YuanL.XiongY. (2014). Epithelial MLCK and smooth muscle MLCK may play different roles in the development of inflammatory bowel disease.Dig. Dis. Sci.591068–1069. 10.1007/s10620-014-3101-y
11
ChenM.ZhangW.LuX.HoggattA. M.GunstS. J.KassabG. S.et al (2013). Regulation of 130-kDa smooth muscle myosin light chain kinase expression by an intronic CArG element.J. Biol. Chem.28834647–34657. 10.1074/jbc.M113.510362
12
ChenQ. Y.XuL. Q.JiaoD. M.YaoQ. H.WangY. Y.HuH. Z.et al (2011). Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs.Int. J. Mol. Med.28769–776. 10.3892/ijmm.2011.775
13
ChenZ.LiuS.XiaY.WuK. (2016). MiR-31 regulates Rho-associated kinase-myosin light chain (ROCK-MLC) pathway and inhibits gastric cancer invasion: roles of RhoA.Med. Sci. Monit.224679–4691. 10.12659/MSM.898399
14
ChengX.WangX.WanY.ZhouQ.ZhuH.WangY. (2015). Myosin light chain kinase inhibitor ML7 improves vascular endothelial dysfunction via tight junction regulation in a rabbit model of atherosclerosis.Mol. Med. Rep.124109–4116. 10.3892/mmr.2015.3973
15
ChoY. E.AhnD. S.MorganK. G.LeeY. H. (2011). Enhanced contractility and myosin phosphorylation induced by Ca2+-independent MLCK activity in hypertensive rats.Cardiovasc. Res.91162–170. 10.1093/cvr/cvr043
16
DroylefaixM. T.BuenoL.CaronP.BelotE.RocheO. (2013). Ocular inflammation and corneal permeability alteration by benzalkonium chloride in rats: a protective effect of a myosin light chain kinase inhibitor.Invest. Ophthalmol. Vis. Sci.542705–2710. 10.1167/iovs.12-10193
17
DuL.KimJ. J.ShenJ.DaiN. (2016). Crosstalk between inflammation and ROCK/MLCK signaling pathways in gastrointestinal disorders with intestinal hyperpermeability.Gastroenterol. Res. Pract.2016:7374197. 10.1155/2016/7374197
18
DudekS. M.GarciaJ. G. N. (2001). Cytoskeletal regulation of pulmonary vascular permeability.J. Appl. Physiol.911487–1500.
19
HerringB. P.ElmounayriO.GallagherP. J.YinF.ZhouJ. (2006). Regulation of myosin light chain kinase and telokin expression in smooth muscle tissues.Am. J. Physiol. Cell Physiol.291C817–C827. 10.1152/ajpcell.00198.2006
20
HindryckxP.LaukensD. (2012). “Intestinal barrier dysfunction: the primary driver of IBD?,” inInflammatory Bowel Disease Advances in Pathogenesis & Management, (Rijeka: In-Tech), 23–40.
21
HonjoM.InataniM.KidoN.SawamuraT.YueB. Y. J. T.HondaY.et al (2002). A myosin light chain kinase inhibitor, ML-9, lowers the intraocular pressure in rabbit eyes.Exp. Eye Res.75135–142. 10.1006/exer.2002.2009
22
HuC. A. A.HouY.YiD.QiuY.WuG.KongX.et al (2015). Autophagy and tight junction proteins in the intestine and intestinal diseases.Anim. Nutr.1123–127. 10.1016/j.aninu.2015.08.014
23
HuangY.LuoX.LiX.SongX.WeiL.LiZ.et al (2015). Wogonin inhibits LPS-induced vascular permeability via suppressing MLCK/MLC pathway.Vasc. Pharmacol.7243–52. 10.1016/j.vph.2015.04.012
24
ItoS.KumeH.HonjoH.KodamaI.KatohH.HayashiH.et al (2004). ML-9, a myosin light chain kinase inhibitor, reduces intracellular Ca2+ concentration in guinea pig trachealis.Eur. J. Pharmacol.486325–333. 10.1016/j.ejphar.2004.01.013
25
JinY.BlikslagerA. T. (2016). Myosin light chain kinase mediates intestinal barrier dysfunction via occludin endocytosis during anoxia/reoxygenation injury.Am. J. Physiol. Cell Physiol.311C996–C1004. 10.1152/ajpcell.00113.2016
26
JinY.HouL.DixonS. A. (2002). 220- and 130-kDa MLCKs have distinct tissue distributions and intracellular localization patterns.Am. J. Physiol. Cell Physiol.282C451–C460.
27
KanekoK.SatohK.MasamuneA.SatohA.ShimosegawaT. (2002). Myosin light chain kinase inhibitors can block invasion and adhesion of human pancreatic cancer cell lines.Pancreas2434–41. 10.1097/00006676-200201000-00005
28
KimD. Y.HelfmanD. M. (2016). Loss of MLCK leads to disruption of cell–cell adhesion and invasive behavior of breast epithelial cells via increased expression of EGFR and ERK/JNK signaling.Oncogene4350–57. 10.1038/onc.2015.508
29
KrauseP.ZahnerS. P.KimG.ShaikhR. B.SteinbergM. W.KronenbergM. (2014). The tumor necrosis factor family member TNFSF14 (LIGHT) is required for resolution of intestinal inflammation in mice.Gastroenterology1461752–1762. 10.1053/j.gastro.2014.02.010
30
KrishnanM.SayocA.MccoleD. (2015). PTPN2 gene deficiency leads to increased epithelial permeability and promotes STAT-1-dependent Claudin-2 expression.FASEB J.29(Suppl. 1), 998.
31
LinC. Y.ZuC. H.YangC. C.TsaiP. J.ShyuJ. F.ChenC. P.et al (2014). IL-1β-induced mesenchymal stem cell migration involves MLCK activation via PKC signaling.Cell Transplant.242011–2028. 10.3727/096368914X685258
32
LinH. B.CadeteV. J. J.SawickaJ.WozniakM.SawickiG. (2012). Effect of the myosin light chain kinase inhibitor ML-7 on the proteome of hearts subjected to ischemia–reperfusion injury.J. Proteomics755386–5395. 10.1016/j.jprot.2012.06.016
33
LuckS.ChohV. (2011). Effects of a myosin light chain kinase inhibitor on the optics and accommodation of the avian crystalline lens.Mol Vis.172759–2764.
34
MaoS. Z.YeX.LiuG.SongD.LiuS. F. (2015). Resident endothelial cells and endothelial progenitor cells restore endothelial barrier function after inflammatory lung injury.Arterioscler. Thromb. Vasc. Biol.351635–1644. 10.1161/ATVBAHA.115.305519
35
MinamiyaY.NakagawaT.SaitoH.MatsuzakiI.TaguchiK.ItoM.et al (2005). Increased expression of myosin light chain kinase mRNA is related to metastasis in non-small cell lung cancer.Tumor Biol.26153–157. 10.1159/000086487
36
MirzapoiazovaT.MoitraJ.SammaniS.MambetsarievB.ChiangE. T.EvenovskiC.et al (2009). Critical role for non-muscle MLCK in ventilator-induced lung injury (VILI).J. Investig. Med.179529–530. 10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a3822
37
NagarajN. S.SmithJ. J.RevettaF.WashingtonM. K.MerchantN. B. (2010). Targeted inhibition of Src kinase signaling attenuates pancreatic tumorigenesis.Mol. Cancer Ther.92322–2332. 10.1158/1535-7163.MCT-09-1212
38
NakanishiS.KakitaS.TakahashiI.KawaharaK.TsukudaE.SanoT.et al (1992). Wortmannin, a microbial product inhibitor of myosin light chain kinase.J. Biol. Chem.2672157–2163.
39
PastorelliL.DozioE.PisaniL. F.BoscoloanzolettiM.VianelloE.MunizioN.et al (2015). Procoagulatory state in inflammatory bowel diseases is promoted by impaired intestinal barrier function.Gastroenterol. Res. Pract.2015:189341. 10.1155/2015/189341
40
PhinikaridouA.AndiaM. E.PlazaB. L.SahaP.SmithA.BotnarR. (2015). Increased vascular permeability is a surrogate marker of atherosclerotic plaque instability.J. Cardiovasc. Magn. Reson.17(Suppl. 1):Q111. 10.1186/1532-429x-17-s1-q111
41
PrayitnaningsihS.SujutiH.EffendiM.AbdullahA.AnanditaN. W.YohanaF.et al (2016). Neuropathy optic glaucomatosa induced by systemic hypertension through activation endothelin-1 signaling pathway in central retinal artery in rats.Int. J. Ophthalmol.91568–1577.
42
RaiT.WuX.ShenB. (2015). Frequency and risk factors of low immunoglobulin levels in patients with inflammatory bowel disease.Gastroenterol. Rep.3115–121. 10.1093/gastro/gou082
43
SaitohM.IshikawaT.MatsushimaS.NakaM.HidakaH. (1987). Selective inhibition of catalytic activity of smooth muscle myosin light chain kinase.J. Biol. Chem.2627796–7801.
44
SalehA. M. E.Al-RobayanA. A.MubarakA. O. M.MisbahulA.Al-AsmariA. K. (2016). Association of tumor necrosis factor-α and -β gene polymorphisms in inflammatory bowel disease.J. Inflamm. Res.9133–140. 10.2147/JIR.S101225
45
SchwarzB. T.WangF.ShenL.ClayburghD. R.SuL.WangY.et al (2007). LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms.Gastroenterology1322383–2394. 10.1053/j.gastro.2007.02.052
46
ShenM. R.FurlaP.ChouC. Y.ElloryJ. C. (2002). Myosin light chain kinase modulates hypotonicity-induced Ca2+ entry and Cl- channel activity in human cervical cancer cells.Eur. J. Physiol.444276–285. 10.1007/s00424-002-0811-3
47
ShiH. R.TangG. D.QinM. B.HeJ. P. (2014). Expression of MLCK in severe acute pancreatitis in rats.World Chin. J. Digestol.223904–3910. 10.1016/j.kjms.2016.07.008
48
ShiJ.TakahashiS.JinX. H.LiY. Q.ItoY.MoriY.et al (2007). Myosin light chain kinase-independent inhibition by ML-9 of murine TRPC6 channels expressed in HEK293 cells.Br. J. Pharmacol.152122–131. 10.1038/sj.bjp.0707368
49
SpansL.HelsenC.ClinckemalieL.BroeckT. V. D.PrekovicS.JoniauS.et al (2014). Comparative genomic and transcriptomic analyses of LNCaP and C4-2B prostate cancer cell lines.PLoS ONE9:e90002. 10.1371/journal.pone.0090002
50
SuL.NalleS.ShenL.TurnerE.SinghG.BreskinL.et al (2013). TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis.Gastroenterology145407–415. 10.1053/j.gastro.2013.04.011
51
SuzukiM.NagaishiT.YamazakiM.OnizawaM.WatabeT.SakamakiY.et al (2014). Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.PLoS ONE9:e88369. 10.1371/journal.pone.0088369
52
TangZ. Y.LiuZ. N.FuL.ChenD. P.AiQ. D.LinY. (2010). Effect of lithium on smooth muscle contraction and phosphorylation of myosin light chain by MLCK.Physiol. Res.59919–926.
53
TohtongR.PhattarasakulK.JiraviriyakulA.SutthiphongchaiT. (2003). Dependence of metastatic cancer cell invasion on MLCK-catalyzed phosphorylation of myosin regulatory light chain.Prostate Cancer Prostatic Dis.6212–216. 10.1038/sj.pcan.4500663
54
Van ItallieC. M.AndersonJ. M. (2014). Architecture of tight junctions and principles of molecular composition.Semin. Cell Dev. Biol.36157–165. 10.1016/j.semcdb.2014.08.011
55
WangL.ZuoL.HuJ.ShaoH.LeiC.QiW.et al (2016). Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family.Europace18602–609. 10.1093/europace/euv043
56
WangT.MathewB.WuX.ShimizuY.RizzoA. N.DudekS. M.et al (2016). Nonmuscle myosin light chain kinase activity modulates radiation-induced lung injury.Pulm. Circ.6234–239. 10.1086/686491
57
WangT.Moreno-VinascoL.MaS. F.ZhouT.ShimizuY.SammaniS.et al (2014). Nonmuscle myosin light chain kinase regulates murine asthmatic inflammation.Am. J. Respir. Cell Mol. Biol.501129–1135. 10.1165/rcmb.2013-0434OC
58
WangT.ZhouT.SaadatL.GarciaJ. G. (2015). A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure.Eur. J. Hum. Genet.23874–876. 10.1038/ejhg.2014.201
59
WarashinaA. (2000). Mechanism of wortmannin-induced inhibition of secretory responses in rat adrenal medullary cells.Life Sci.672587–2593. 10.1016/S0024-3205(00)00842-0
60
WeberM.KimS.PattersonN.RooneyK.SearlesC. D. (2014). MiRNA-155 targets myosin light chain kinase and modulates actin cytoskeleton organization in endothelial cells.Am. J. Physiol. Heart Circ. Physiol.3061192–1203. 10.1152/ajpheart.00521.2013
61
WelchM. G.MargolisK. G.LiZ.GershonM. D. (2014). Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice.Am. J. Physiol. Gastrointest. Liver Physiol.307848–862. 10.1152/ajpgi.00176.2014
62
WuL. L.PengW. H.KuoW. T.HuangC. Y.NiY. H.LuK. S.et al (2014). Commensal bacterial endocytosis in epithelial cells is dependent on myosin light chain kinase-activated brush border fanning by interferon-γ.Am. J. Pathol.1842260–2274. 10.1016/j.ajpath.2014.05.003
63
WuY. H.ZhangX.WangD. H. (2011). Role of asymmetric dimethylarginine in acute lung injury induced by cerebral ischemia/reperfusion injury in rats.J. South. Med. Univ.311289–1294.
64
XiongY.WangJ.ChuH.ChenD.GuoH. (2016). Salvianolic acid B restored impaired barrier function via downregulation of MLCK by microRNA-1 in rat colitis model.Front. Pharmacol.7:320. 10.3389/fphar.2016.00134
65
XiongY. J.ChenD. P.LvB. C.LiuF. F.WangL.LinY. (2013). The characteristics of genistin-induced inhibitory effects on intestinal motility.Arch. Pharm. Res.36345–352. 10.1007/s12272-013-0053-2
66
XuC.WuX.HackB. K.BaoL.CunninghamP. N. (2015). TNF causes changes in glomerular endothelial permeability and morphology through a Rho and myosin light chain kinase-dependent mechanism.Physiol. Rep.3:e12636. 10.14814/phy2.12636
67
YiZ.FanH.LiuX.TangQ.ZuoD.YangJ. (2015). Adrenomedullin improves intestinal epithelial barrier function by downregulating myosin light chain phosphorylation in ulcerative colitis rats.Mol. Med. Rep.123615–3620. 10.3892/mmr.2015.3887
68
YiZ. F.FanH.YangJ. (2014). Role of myosin light chain kinase in inflammatory bowel disease.World Chin. J. Digestol.225467–5472. 10.11569/wcjd.v22.i35.5467
69
YinJ.WuM.DuanJ.LiuG.CuiZ.ZhengJ.et al (2015). Pyrrolidine dithiocarbamate inhibits NF-KappaB activation and upregulates the expression of Gpx1, Gpx4, occludin, and ZO-1 in DSS-induced colitis.Appl. Biochem. Biotechnol.1771716–1728. 10.1007/s12010-015-1848-z
70
YuQ. H.GuoJ. F.ChenY.GuoX. R.DuY. Q.LiZ. S. (2016). Captopril pretreatment protects the lung against severe acute pancreatitis induced injury via inhibiting angiotensin II production and suppressing Rho/ROCK pathway.Kaohsiung J. Med. Sci.32439–445. 10.1016/j.kjms.2016.07.008
71
ZeremE. (2014). Treatment of severe acute pancreatitis and its complications.World J. Gastroenterol.2013879–13892. 10.3748/wjg.v20.i38.13879
72
ZhangH. L.TangZ. Y.YangJ. X.ZhangY.LiY.LinY. (2006). Bi-directional regulation of emodin and quercetin on smooth muscle myosin of gizzard.FEBS Lett.580469–473. 10.1016/j.febslet.2005.12.041
73
ZhangY. S.LiuB.LuoX. J.LiT. B.ZhangJ. J.PengJ. J.et al (2015). Nuclear cardiac myosin light chain 2 modulates NADPH oxidase 2 expression in myocardium: a novel function beyond muscle contraction.Archiv Für Kreislaufforschung110:494. 10.1007/s00395-015-0494-5
74
ZhouT.WangT.GarciaJ. G. (2014). Genes influenced by the non-muscle isoform of Myosin light chain kinase impact human cancer prognosis.PLoS ONE9:e94325. 10.1371/journal.pone.0094325
75
ZhouT.WangT.GarciaJ. G. (2015). A nonmuscle myosin light chain kinase-dependent gene signature in peripheral blood mononuclear cells is linked to human asthma severity and exacerbation status.Pulmonary Circulation5335–338. 10.1086/680357
76
ZhuH. Q.WangX. B.HanJ. X.HuZ. P.WangY.ZhouQ.et al (2013). Myosin light chain kinase inhibitor attenuates atherosclerosis and permeability via reduced endothelial tight junction in rabbits.Int. J. Cardiol.1685042–5043. 10.1016/j.ijcard.2013.07.219
Summary
Keywords
myosin light chain kinase, inflammatory bowel diseases, cancer, tight junctions, endothelium
Citation
Xiong Y, Wang C, Shi L, Wang L, Zhou Z, Chen D, Wang J and Guo H (2017) Myosin Light Chain Kinase: A Potential Target for Treatment of Inflammatory Diseases. Front. Pharmacol. 8:292. doi: 10.3389/fphar.2017.00292
Received
02 January 2017
Accepted
08 May 2017
Published
23 May 2017
Volume
8 - 2017
Edited by
Salvatore Salomone, University of Catania, Italy
Reviewed by
Bashir M. Rezk, Southern University at New Orleans, United States; Andrea Huwiler, University of Bern, Switzerland
Updates
Copyright
© 2017 Xiong, Wang, Shi, Wang, Zhou, Chen, Wang and Guo.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dapeng Chen, cdp.9527@163.com Jingyu Wang, wangjingyus@163.com Huishu Guo, guohuishu1@126.com
†These authors have contributed equally to this work.
This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
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