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Gene Review

MYLK3  -  myosin light chain kinase 3

Homo sapiens

Synonyms: Cardiac-MLCK, Cardiac-MyBP-C-associated Ca/CaM kinase, MLCK, MLCK2, Myosin light chain kinase 3, ...
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Disease relevance of MLCK

  • Results: Colitis induced in vivo by adoptive transfer of CD4(+)CD45RB(hi) T cells was associated with increased epithelial MLCK expression and myosin II regulatory light chain (MLC) phosphorylation as well as morphologic tight junction disruption [1].
  • Recent studies show that mice with selective knockout of the endothelial MLCK are less susceptible to endotoxin-induced acute lung injury and that a new small-molecule inhibitor of MLCK also protects against lung injury [2].
  • In addition, conformational changes associated with CaM binding to target peptides from myosin light chain kinase (MLCK), phosphodiesterase (PDE), and simian immunodeficiency virus (SIV) were accurately determined compared with small-angle X-ray scattering results [3].
  • LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK [4].
  • PURPOSE: A peptide inhibitor of myosin light chain kinase (MLCK), termed membrane permeant inhibitor of myosin light chain kinase (PIK), has previously been demonstrated to correct paracellular barrier defects associated with in vitro cell models of infectious and inflammatory intestinal disease [5].

Psychiatry related information on MLCK

  • These results suggest that the enhanced Ca response observed in bipolar disorder might be relevant to decreased function of MLCK and that the mechanism of action of lithium may include a compensatory effect on MLCK modulation [6].

High impact information on MLCK

  • Ca2+ sensitivity of smooth muscle and nonmuscle myosin II reflects the ratio of activities of myosin light-chain kinase (MLCK) to myosin light-chain phosphatase (MLCP) and is a major, regulated determinant of numerous cellular processes [7].
  • These data indicate that MLCK is a target for PAKs and that PAKs may regulate cytoskeletal dynamics by decreasing MLCK activity and MLC phosphorylation [8].
  • MLCK activity and MLC phosphorylation were decreased, and cell spreading was inhibited in baby hamster kidney-21 and HeLa cells expressing constitutively active PAK1 [8].
  • I discuss proposed functions for MLCK, ROCK, citron kinase and myosin phosphatase during cytokinesis and consider the possibility of a link between these molecules and the signals transmitted by the mitotic spindle [9].
  • In intestinal epithelia, TNF causes tight junction disruption and epithelial barrier loss by up-regulating myosin light chain kinase (MLCK) activity and expression [1].

Biological context of MLCK

  • In vitro studies showed that TNF caused similar increases in MLCK expression and MLC phosphorylation, as well as barrier dysfunction, in Caco-2 monolayers only after interferon (IFN)-gamma pretreatment [1].
  • MLCK inhibition also delayed barrier function recovery [10].
  • It is widely accepted that actin filaments and the conventional double-headed myosin interact to generate force for many types of nonmuscle cell motility, and that this interaction occurs when the myosin regulatory light chain (MLC) is phosphorylated by MLC kinase (MLCK) together with calmodulin and Ca(2+) [11].
  • Activation of myosin II by myosin light chain kinase (MLCK) produces the force for many cellular processes including muscle contraction, mitosis, migration, and other cellular shape changes [12].
  • However, at doses below those needed for nuclear factor-kappaB inhibition, sulfasalazine was able to prevent TNF-alpha-induced barrier dysfunction, MLCK up-regulation, and MLC phosphorylation [13].

Anatomical context of MLCK

  • More rapid and extensive stress fiber contraction was induced by MLCK than was by Rho-kinase [11].
  • When the activity of Rho-kinase but not MLCK was inhibited, cells not only lost their stress fibers and focal adhesions but also appeared to lose cytoplasmic tension [11].
  • The Ca(2+)/calmodulin-dependent endothelial cell myosin light chain kinase (MLCK) triggers actomyosin contraction essential for vascular barrier regulation and leukocyte diapedesis [14].
  • These results demonstrate unique physiologically relevant patterns of expression and subcellular localization for long MLCK isoforms and show that MLCK1 is the isoform responsible for tight junction regulation in absorptive enterocytes [15].
  • We examined the spatiotemporal segregation of MLCK isoform function and expression along the crypt-villus axis and found that long MLCK, which is expressed as two alternatively spliced isoforms, accounts for 97 +/- 4% of MLC kinase activity in interphase intestinal epithelial cells [15].

Associations of MLCK with chemical compounds

  • These results demonstrate for the first time that p60(Src)-mediated tyrosine phosphorylation represents an important mechanism for splice variant-specific regulation of nonmuscle MLCK and vascular cell function [14].
  • Last, elevated cAMP prevents histamine-induced loss of the barrier integrity, not only by blocking inactivation of MLC phosphatase but also by inactivating MLCK [16].
  • The results of this study indicate that ethanol at low noncytotoxic doses causes a functional and structural opening of the Caco-2 intestinal epithelial TJ barrier by activating MLCK [17].
  • The cycloheximide inhibition of MLCK protein expression prevented the TNF-alpha increase in MLCK activity and Caco-2 TJ permeability [18].
  • The effects of KENESKA and other peptides on MLCK and MLC activation and on failures in both wild-type and NCAM 180 null junctions supported this pathway, and serine phosphorylation of KENESKA was critical [19].

Physical interactions of MLCK

  • We conclude that initial adherence of MDCK cells to a collagen I substratum is mediated by peripheral actin filaments and adhesion complexes regulated by MLCK but not by stress fibers and adhesion complexes controlled by RhoA [20].
  • The CaMKI complex demonstrates a collapse analogous to that observed for MLCK, PDE, and SIV, while the SIV-N shows only a partial collapse [3].

Enzymatic interactions of MLCK

  • Biochemical assays show that Aurora B binds and phosphorylates the IgG domain of the long MLCK [21].

Regulatory relationships of MLCK

  • Among the cell signaling agents, myosin light chain kinase (MLCK) inhibitors significantly inhibited the H2O2-induced activation of TREK-2 currents [22].
  • MLCK-inhibited cells did not assemble zyxin-containing adhesions at the periphery, but maintained focal adhesions in the center [23].

Other interactions of MLCK

  • Application of both Rho kinase inhibitor and MLCK inhibitor inhibited GTPgammaS-induced currents [24].
  • LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment [25].
  • HeLa ZIPK is the first non-muscle MLCK that phosphorylates MRLC at two sites [26].
  • ACTN3 and MLCK genotype associations with exertional muscle damage [27].
  • Functional effects of the p.R853C mutation were investigated in a physiological cellular environment by expressing MYO7A IQ5-containing peptides in smooth muscle cells of microarteries, in which overexpression of wildtype IQ5 (with intact calmodulin binding) would be expected to compete with myosin light chain kinase (MLCK) for CaM binding [28].

Analytical, diagnostic and therapeutic context of MLCK


  1. IFN-gamma-Induced TNFR2 Expression Is Required for TNF-Dependent Intestinal Epithelial Barrier Dysfunction. Wang, F., Schwarz, B.T., Graham, W.V., Wang, Y., Su, L., Clayburgh, D.R., Abraham, C., Turner, J.R. Gastroenterology (2006) [Pubmed]
  2. Isoform-specific knockout of endothelial myosin light chain kinase: closing the gap on inflammatory lung disease. Tinsley, J.H., Yuan, S.Y., Wilson, E. Trends Pharmacol. Sci. (2004) [Pubmed]
  3. Protein conformational changes studied by diffusion NMR spectroscopy: application to helix-loop-helix calcium binding proteins. Weljie, A.M., Yamniuk, A.P., Yoshino, H., Izumi, Y., Vogel, H.J. Protein Sci. (2003) [Pubmed]
  4. LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK. Eutamene, H., Theodorou, V., Schmidlin, F., Tondereau, V., Garcia-Villar, R., Salvador-Cartier, C., Chovet, M., Bertrand, C., Bueno, L. Eur. Respir. J. (2005) [Pubmed]
  5. A strategy to identify stable membrane-permeant peptide inhibitors of myosin light chain kinase. Owens, S.E., Graham, W.V., Siccardi, D., Turner, J.R., Mrsny, R.J. Pharm. Res. (2005) [Pubmed]
  6. Effects of lithium and valproate on agonist-induced platelet intracellular calcium mobilization: relevance to myosin light chain kinase. Suzuki, K., Kusumi, I., Akimoto, T., Sasaki, Y., Koyama, T. Prog. Neuropsychopharmacol. Biol. Psychiatry (2004) [Pubmed]
  7. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Somlyo, A.P., Somlyo, A.V. Physiol. Rev. (2003) [Pubmed]
  8. Inhibition of myosin light chain kinase by p21-activated kinase. Sanders, L.C., Matsumura, F., Bokoch, G.M., de Lanerolle, P. Science (1999) [Pubmed]
  9. Regulation of myosin II during cytokinesis in higher eukaryotes. Matsumura, F. Trends Cell Biol. (2005) [Pubmed]
  10. Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure. Russo, J.M., Florian, P., Shen, L., Graham, W.V., Tretiakova, M.S., Gitter, A.H., Mrsny, R.J., Turner, J.R. Gastroenterology (2005) [Pubmed]
  11. Rho-kinase--mediated contraction of isolated stress fibers. Katoh, K., Kano, Y., Amano, M., Onishi, H., Kaibuchi, K., Fujiwara, K. J. Cell Biol. (2001) [Pubmed]
  12. Myosin ii light chain phosphorylation regulates membrane localization and apoptotic signaling of tumor necrosis factor receptor-1. Jin, Y., Atkinson, S.J., Marrs, J.A., Gallagher, P.J. J. Biol. Chem. (2001) [Pubmed]
  13. Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Wang, F., Graham, W.V., Wang, Y., Witkowski, E.D., Schwarz, B.T., Turner, J.R. Am. J. Pathol. (2005) [Pubmed]
  14. Differential regulation of alternatively spliced endothelial cell myosin light chain kinase isoforms by p60(Src). Birukov, K.G., Csortos, C., Marzilli, L., Dudek, S., Ma, S.F., Bresnick, A.R., Verin, A.D., Cotter, R.J., Garcia, J.G. J. Biol. Chem. (2001) [Pubmed]
  15. A differentiation-dependent splice variant of myosin light chain kinase, MLCK1, regulates epithelial tight junction permeability. Clayburgh, D.R., Rosen, S., Witkowski, E.D., Wang, F., Blair, S., Dudek, S., Garcia, J.G., Alverdy, J.C., Turner, J.R. J. Biol. Chem. (2004) [Pubmed]
  16. Histamine-induced phosphorylation of the regulatory light chain of myosin II disrupts the barrier integrity of corneal endothelial cells. Srinivas, S.P., Satpathy, M., Guo, Y., Anandan, V. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  17. Ethanol modulation of intestinal epithelial tight junction barrier. Ma, T.Y., Nguyen, D., Bui, V., Nguyen, H., Hoa, N. Am. J. Physiol. (1999) [Pubmed]
  18. Mechanism of TNF-{alpha} modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Ma, T.Y., Boivin, M.A., Ye, D., Pedram, A., Said, H.M. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  19. NCAM 180 acting via a conserved C-terminal domain and MLCK is essential for effective transmission with repetitive stimulation. Polo-Parada, L., Plattner, F., Bose, C., Landmesser, L.T. Neuron (2005) [Pubmed]
  20. Regulation of MDCK cell-substratum adhesion by RhoA and myosin light chain kinase after ATP depletion. Prahalad, P., Calvo, I., Waechter, H., Matthews, J.B., Zuk, A., Matlin, K.S. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  21. The long myosin light chain kinase is differentially phosphorylated during interphase and mitosis. Dulyaninova, N.G., Bresnick, A.R. Exp. Cell Res. (2004) [Pubmed]
  22. Hydrogen peroxide selectively increases TREK-2 currents via myosin light chain kinases. Kim, Y., Lee, S.H., Ho, W.K. Front. Biosci. (2007) [Pubmed]
  23. Distinct roles of MLCK and ROCK in the regulation of membrane protrusions and focal adhesion dynamics during cell migration of fibroblasts. Totsukawa, G., Wu, Y., Sasaki, Y., Hartshorne, D.J., Yamakita, Y., Yamashiro, S., Matsumura, F. J. Cell Biol. (2004) [Pubmed]
  24. Involvement of calmodulin and myosin light chain kinase in activation of mTRPC5 expressed in HEK cells. Kim, M.T., Kim, B.J., Lee, J.H., Kwon, S.C., Yeon, D.S., Yang, D.K., So, I., Kim, K.W. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  25. LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment. Smith, A., Bracke, M., Leitinger, B., Porter, J.C., Hogg, N. J. Cell. Sci. (2003) [Pubmed]
  26. ZIP kinase identified as a novel myosin regulatory light chain kinase in HeLa cells. Murata-Hori, M., Suizu, F., Iwasaki, T., Kikuchi, A., Hosoya, H. FEBS Lett. (1999) [Pubmed]
  27. ACTN3 and MLCK genotype associations with exertional muscle damage. Clarkson, P.M., Hoffman, E.P., Zambraski, E., Gordish-Dressman, H., Kearns, A., Hubal, M., Harmon, B., Devaney, J.M. J. Appl. Physiol. (2005) [Pubmed]
  28. Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11). Bolz, H., Bolz, S.S., Schade, G., Kothe, C., Mohrmann, G., Hess, M., Gal, A. Hum. Mutat. (2004) [Pubmed]
  29. Tumor necrosis factor-induced long myosin light chain kinase transcription is regulated by differentiation-dependent signaling events. Characterization of the human long myosin light chain kinase promoter. Graham, W.V., Wang, F., Clayburgh, D.R., Cheng, J.X., Yoon, B., Wang, Y., Lin, A., Turner, J.R. J. Biol. Chem. (2006) [Pubmed]
  30. Phorbol esters increase MLC phosphorylation and actin remodeling in bovine lung endothelium without increased contraction. Bogatcheva, N.V., Verin, A.D., Wang, P., Birukova, A.A., Birukov, K.G., Mirzopoyazova, T., Adyshev, D.M., Chiang, E.T., Crow, M.T., Garcia, J.G. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  31. A single human myosin light chain kinase gene (MLCK; MYLK). Lazar, V., Garcia, J.G. Genomics (1999) [Pubmed]
  32. Mutation analysis of the non-muscle myosin light chain kinase (MLCK) deletion constructs on CV1 fibroblast contractile activity and proliferation. Wadgaonkar, R., Nurmukhambetova, S., Zaiman, A.L., Garcia, J.G. J. Cell. Biochem. (2003) [Pubmed]
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