5jth

Structural highlights

Disease

[MYLK_HUMAN] Defects in MYLK are the cause of familial aortic aneurysm thoracic type 7 (AAT7) [MIM:613780]. AAT7 is a disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance.^[1]

Function

[MYLK_HUMAN] Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA-dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis.^{[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]}

References

1. ↑ Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E, Li L, Shete S, He WQ, Zhu MS, Offermanns S, Gilchrist D, Elefteriades J, Stull JT, Milewicz DM. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010 Nov 12;87(5):701-7. doi: 10.1016/j.ajhg.2010.10.006. Epub, 2010 Nov 4. PMID:21055718 doi:10.1016/j.ajhg.2010.10.006
2. ↑ Birukov KG, Csortos C, Marzilli L, Dudek S, Ma SF, Bresnick AR, Verin AD, Cotter RJ, Garcia JG. Differential regulation of alternatively spliced endothelial cell myosin light chain kinase isoforms by p60(Src). J Biol Chem. 2001 Mar 16;276(11):8567-73. Epub 2000 Dec 11. PMID:11113114 doi:10.1074/jbc.M005270200
3. ↑ Dulyaninova NG, Patskovsky YV, Bresnick AR. The N-terminus of the long MLCK induces a disruption in normal spindle morphology and metaphase arrest. J Cell Sci. 2004 Mar 15;117(Pt 8):1481-93. PMID:15020676 doi:10.1242/jcs.00993
4. ↑ Shen MR, Furla P, Chou CY, Ellory JC. Myosin light chain kinase modulates hypotonicity-induced Ca2+ entry and Cl- channel activity in human cervical cancer cells. Pflugers Arch. 2002 May;444(1-2):276-85. Epub 2002 Mar 6. PMID:11976941 doi:10.1007/s00424-002-0811-3
5. ↑ Russo JM, Florian P, Shen L, Graham WV, Tretiakova MS, Gitter AH, Mrsny RJ, Turner JR. Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure. Gastroenterology. 2005 Apr;128(4):987-1001. PMID:15825080
6. ↑ Connell LE, Helfman DM. Myosin light chain kinase plays a role in the regulation of epithelial cell survival. J Cell Sci. 2006 Jun 1;119(Pt 11):2269-81. PMID:16723733 doi:10.1242/jcs.02926
7. ↑ Shimizu S, Yoshida T, Wakamori M, Ishii M, Okada T, Takahashi M, Seto M, Sakurada K, Kiuchi Y, Mori Y. Ca2+-calmodulin-dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK293 cells. J Physiol. 2006 Jan 15;570(Pt 2):219-35. Epub 2005 Nov 10. PMID:16284075 doi:10.1113/jphysiol.2005.097998
8. ↑ Zhou X, Liu Y, You J, Zhang H, Zhang X, Ye L. Myosin light-chain kinase contributes to the proliferation and migration of breast cancer cells through cross-talk with activated ERK1/2. Cancer Lett. 2008 Nov 8;270(2):312-27. doi: 10.1016/j.canlet.2008.05.028. Epub, 2008 Aug 16. PMID:18710790 doi:10.1016/j.canlet.2008.05.028
9. ↑ Xu J, Gao XP, Ramchandran R, Zhao YY, Vogel SM, Malik AB. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating beta2 integrins. Nat Immunol. 2008 Aug;9(8):880-6. doi: 10.1038/ni.1628. Epub 2008 Jun 29. PMID:18587400 doi:10.1038/ni.1628
10. ↑ Shin DH, Chun YS, Lee KH, Shin HW, Park JW. Arrest defective-1 controls tumor cell behavior by acetylating myosin light chain kinase. PLoS One. 2009 Oct 14;4(10):e7451. doi: 10.1371/journal.pone.0007451. PMID:19826488 doi:10.1371/journal.pone.0007451
11. ↑ Cui WJ, Liu Y, Zhou XL, Wang FZ, Zhang XD, Ye LH. Myosin light chain kinase is responsible for high proliferative ability of breast cancer cells via anti-apoptosis involving p38 pathway. Acta Pharmacol Sin. 2010 Jun;31(6):725-32. doi: 10.1038/aps.2010.56. Epub 2010, May 10. PMID:20453870 doi:10.1038/aps.2010.56
12. ↑ Miao H, Crabb AW, Hernandez MR, Lukas TJ. Modulation of factors affecting optic nerve head astrocyte migration. Invest Ophthalmol Vis Sci. 2010 Aug;51(8):4096-103. doi: 10.1167/iovs.10-5177., Epub 2010 Apr 7. PMID:20375339 doi:10.1167/iovs.10-5177
13. ↑ Godin CM, Ferguson SS. The angiotensin II type 1 receptor induces membrane blebbing by coupling to Rho A, Rho kinase, and myosin light chain kinase. Mol Pharmacol. 2010 Jun;77(6):903-11. doi: 10.1124/mol.110.063859. Epub 2010 Feb , 24. PMID:20181817 doi:10.1124/mol.110.063859
14. ↑ Mirzapoiazova T, Moitra J, Moreno-Vinasco L, Sammani S, Turner JR, Chiang ET, Evenoski C, Wang T, Singleton PA, Huang Y, Lussier YA, Watterson DM, Dudek SM, Garcia JG. Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury. Am J Respir Cell Mol Biol. 2011 Jan;44(1):40-52. doi: 10.1165/rcmb.2009-0197OC., Epub 2010 Feb 5. PMID:20139351 doi:10.1165/rcmb.2009-0197OC