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MGP002017

UniProt Annotations

Entry Information
Gene Namemyosin light chain kinase
Protein EntryMYLK_HUMAN
UniProt IDQ15746
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing, Alternative initiation; Named isoforms=11; Comment=Additional isoforms seem to exist.; Name=1; Synonyms=Non-muscle isozyme; IsoId=Q15746-1; Sequence=Displayed; Name=2; IsoId=Q15746-2; Sequence=VSP_004791; Name=3A; IsoId=Q15746-3; Sequence=VSP_004794; Note=Ref.3 (AAD15922) sequence differs from that shown due to frameshifts in positions 1433 and 1439. {ECO:0000305}; Name=3B; IsoId=Q15746-4; Sequence=VSP_004791, VSP_004794; Note=Ref.3 (AAD15923) sequence differs from that shown due to frameshifts in positions 1433 and 1439. {ECO:0000305}; Name=4; IsoId=Q15746-5; Sequence=VSP_004793; Note=Ref.3 (AAD15924) sequence differs from that shown due to frameshifts in positions 1433 and 1439. {ECO:0000305}; Name=Del-1790; IsoId=Q15746-6; Sequence=VSP_004795; Name=5; Synonyms=Smooth-muscle isozyme; IsoId=Q15746-7; Sequence=VSP_018845; Note=Produced by alternative initiation at Met-923 of isoform 1.; Name=6; Synonyms=Telokin; IsoId=Q15746-8; Sequence=VSP_018846; Note=Produced by alternative initiation at Met-1761 of isoform 1. Has no catalytic activity.; Name=7; IsoId=Q15746-9; Sequence=VSP_053791; Name=8; IsoId=Q15746-10; Sequence=VSP_018846, VSP_004795; Note=Produced by alternative initiation at Met-1761 of isoform 1.; Name=9; IsoId=Q15746-11; Sequence=VSP_018845, VSP_004795; Note=Produced by alternative initiation at Met-923 of isoform 1.;
Biophysicochemical PropertiesKinetic parameters: KM=6.5 uM for MLC (isoform 1 at 22 degrees Celsius) {ECO:0000269|PubMed:11113114}; KM=7.2 uM for MLC (isoform 2 at 22 degrees Celsius) {ECO:0000269|PubMed:11113114}; Vmax=11.9 umol/min/mg enzyme (isoform 1 at 22 degrees Celsius) {ECO:0000269|PubMed:11113114}; Vmax=10.9 umol/min/mg enzyme (isoform 1 at 22 degrees Celsius) {ECO:0000269|PubMed:11113114};
Catalytic ActivityATP + [myosin light-chain] = ADP + [myosin light-chain] phosphate.
CofactorName=Ca(2+); Xref=ChEBI:CHEBI:29108;
CofactorName=Mg(2+); Xref=ChEBI:CHEBI:18420;
DiseaseAortic aneurysm, familial thoracic 7 (AAT7) [MIM:613780]: 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. {ECO:0000269|PubMed:21055718}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Enzyme RegulationIsoform 1 is activated by phosphorylation on Tyr-464 and Tyr-471. Isoforms which lack these tyrosine residues are not regulated in this way. All catalytically active isoforms require binding to calcium and calmodulin for activation. Repressed by organometallic pyridylnaphthalimide complexes, wortmannin, ML-7 (a synthetic naphthalenesulphonyl derivative that inhibits the binding of ATP to MLCK) and ML-9. {ECO:0000269|PubMed:11113114, ECO:0000269|PubMed:11976941, ECO:0000269|PubMed:14741352, ECO:0000269|PubMed:16284075, ECO:0000269|PubMed:16723733, ECO:0000269|PubMed:21918590}.
FunctionCalcium/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. {ECO:0000269|PubMed:11113114, ECO:0000269|PubMed:11976941, ECO:0000269|PubMed:15020676, ECO:0000269|PubMed:15825080, ECO:0000269|PubMed:16284075, ECO:0000269|PubMed:16723733, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18710790, ECO:0000269|PubMed:19826488, ECO:0000269|PubMed:20139351, ECO:0000269|PubMed:20181817, ECO:0000269|PubMed:20375339, ECO:0000269|PubMed:20453870}.
InductionAccumulates in individuals with asthma (at protein levels). Induced by tumor necrosis factor (TNF). Repressed by androgens (e.g. R1881). {ECO:0000269|PubMed:16835238, ECO:0000269|PubMed:19011151, ECO:0000269|PubMed:19429448}.
InteractionP16333:NCK1; NbExp=2; IntAct=EBI-968482, EBI-389883;
MiscellaneousIn asthmatic patients, overexpression promotes actin filament propulsion, thus contributing to airway hyperresponsiveness. Some MYLK variants may contribute to acute lung injury (ALI) susceptibility. Potential therapeutic target in the treatment of burn edema.
PtmAcetylated at Lys-608 by NAA10/ARD1 via a calcium-dependent signaling; this acetylation represses kinase activity and reduces tumor cell migration. {ECO:0000269|PubMed:19826488}.
PtmCan probably be down-regulated by phosphorylation. Tyrosine phosphorylation by ABL1 increases kinase activity, reverses MLCK- mediated inhibition of Arp2/3-mediated actin polymerization, and enhances CTTN-binding. Phosphorylation by SRC at Tyr-464 and Tyr- 471 promotes CTTN binding. {ECO:0000269|PubMed:11113114, ECO:0000269|PubMed:12408982, ECO:0000269|PubMed:18088087, ECO:0000269|PubMed:18318008, ECO:0000269|PubMed:20861316}.
PtmThe C-terminus is deglutamylated by AGTPBP1/CCP1, AGBL1/CCP4 and AGBL4/CCP6, leading to the formation of Myosin light chain kinase, smooth muscle, deglutamylated form. The consequences of C- terminal deglutamylation are unknown (By similarity). {ECO:0000250}.
Sequence CautionSequence=AAD15922.1; Type=Frameshift; Positions=1433; Evidence={ECO:0000305}; Sequence=AAD15923.1; Type=Frameshift; Positions=1433; Evidence={ECO:0000305}; Sequence=AAD15924.1; Type=Frameshift; Positions=1433; Evidence={ECO:0000305};
SimilarityBelongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. {ECO:0000305}.
SimilarityContains 1 fibronectin type-III domain. {ECO:0000255|PROSITE-ProRule:PRU00316}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 9 Ig-like C2-type (immunoglobulin-like) domains. {ECO:0000305}.
Subcellular LocationCytoplasm. Cell projection, lamellipodium. Cleavage furrow. Cytoplasm, cytoskeleton. Note=Localized to stress fibers during interphase and to the cleavage furrow during mitosis.
SubunitAll isoforms including Telokin bind calmodulin. Interacts with SVIL (By similarity). Interacts with CTTN; this interaction is reduced during thrombin-induced endothelial cell (EC) contraction but is promoted by the barrier-protective agonist sphingosine 1-phosphate (S1P) within lamellipodia. A complex made of ABL1, CTTN and MYLK regulates cortical actin-based cytoskeletal rearrangement critical to sphingosine 1-phosphate (S1P)-mediated endothelial cell (EC) barrier enhancement. Binds to NAA10/ARD1 and PTK2B/PYK2. {ECO:0000250, ECO:0000269|PubMed:12408982, ECO:0000269|PubMed:18462678, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:19826488, ECO:0000269|PubMed:20053363, ECO:0000269|PubMed:20861316}.
Tissue SpecificitySmooth muscle and non-muscle isozymes are expressed in a wide variety of adult and fetal tissues and in cultured endothelium with qualitative expression appearing to be neither tissue- nor development-specific. Non-muscle isoform 2 is the dominant splice variant expressed in various tissues. Telokin has been found in a wide variety of adult and fetal tissues. Accumulates in well differentiated enterocytes of the intestinal epithelium in response to tumor necrosis factor (TNF). {ECO:0000269|PubMed:10536370, ECO:0000269|PubMed:16835238, ECO:0000269|PubMed:20053363, ECO:0000269|PubMed:8575746}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MYLKID43364ch3q21.html";
Web ResourceName=Wikipedia; Note=Myosin light-chain kinase entry; URL="http://en.wikipedia.org/wiki/Myosin_light-chain_kinase";
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