A Single Human Myosin Light Chain Kinase Gene (MLCK; MYLK)Transcribes Multiple Nonmuscle Isoforms

Lazar, Virginie; Garcia, Joe G.N.

doi:10.1006/geno.1999.5774

Cited by 124 publications

(140 citation statements)

References 47 publications

(38 reference statements)

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“…2). [73][74][75][76][77][78][79] These studies showed diphosphorylation of MLC as an important determinant of endothelial contraction. MLC phosphorylation has also been shown to regulate the permeability of intact isolated postcapillary venules and pulmonary microvessels in response to histamine and thrombin.…”

Section: Signaling Mechanisms Regulating Ajsmentioning

confidence: 93%

Mechanisms Regulating Endothelial Permeability

et al. 2014

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The endothelial monolayer partitioning underlying tissue from blood components in the vessel wall maintains tissue fluid balance and host defense through dynamically opening intercellular junctions. Edemagenic agonists disrupt endothelial barrier function by signaling the opening of the intercellular junctions leading to the formation of protein-rich edema in the interstitial tissue, a hallmark of tissue inflammation that, if left untreated, causes fatal diseases, such as acute respiratory distress syndrome. In this review, we discuss how intercellular junctions are maintained under normal conditions and after stimulation of endothelium with edemagenic agonists. We have focused on reviewing the new concepts dealing with the alteration of adherens junctions after inflammatory stimulus.

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Section: Signaling Mechanisms Regulating Ajsmentioning

confidence: 93%

Mechanisms Regulating Endothelial Permeability

et al. 2014

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“…In contrast, a 220-kDa MLCK (long MLCK) containing a 922-amino acid amino-terminal extension is expressed in many nonmuscle cells, including embryonic tissues and endothelium (13,14). Long MLCK is expressed as at least five different splice variants that all contain the amino-terminal extension; these variants are distinguished by the presence or absence of short (Ͻ70 amino acids) regions as a result of alternative mRNA splicing (15). Long MLCK isoform 2, or MLCK2, is the predominant isoform expressed and differs from the full-length long MLCK isoform, MLCK1, by the absence of a 207-base pair sequence from nucleotides 1428 -1634 (15).…”

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confidence: 99%

“…Long MLCK is expressed as at least five different splice variants that all contain the amino-terminal extension; these variants are distinguished by the presence or absence of short (Ͻ70 amino acids) regions as a result of alternative mRNA splicing (15). Long MLCK isoform 2, or MLCK2, is the predominant isoform expressed and differs from the full-length long MLCK isoform, MLCK1, by the absence of a 207-base pair sequence from nucleotides 1428 -1634 (15). The corresponding 69-amino acid region contains Src kinase phosphorylation sites and a potential SH2-binding domain (15).…”

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confidence: 99%

A Differentiation-dependent Splice Variant of Myosin Light Chain Kinase, MLCK1, Regulates Epithelial Tight Junction Permeability

Clayburgh

Rosen

Witkowski

et al. 2004

Journal of Biological Chemistry

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Activation of Na؉ -nutrient cotransport leads to increased tight junction permeability in intestinal absorptive (villus) enterocytes. This regulation requires myosin II regulatory light chain (MLC) phosphorylation mediated by MLC kinase (MLCK). 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. Expression of the MLCK1 isoform is limited to well differentiated enterocytes, both in vitro and in vivo, and this expression correlates closely with development of Na ؉ -nutrient cotransport-dependent tight junction regulation. Consistent with this role, MLCK1 is localized to the perijunctional actomyosin ring. Furthermore, specific knockdown of MLCK1 using siRNA reduced tight junction permeability in monolayers with active Na ؉ -glucose cotransport, confirming a functional role for MLCK1. 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.

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“…6 The gene also encodes a ~19-kDa protein known as kinase-related protein (KRP) or telokin that is transcribed from the C-terminal exons [30][31][32][33], and it serves to stabilize actin filaments. 7 In addition to smooth muscle myosin light chain kinase (smMLCK) and KRP, 5 splice variants were identified that use the start codon of the 210-kDa isoform, but they have internal exon deletions compared with the longest variant (nmMLCK1).…”

Section: Translational Significancementioning

confidence: 99%

A transgenic mouse with vascular endothelial over-expression of the non-muscle myosin light chain kinase-2 isoform is susceptible to inflammatory lung injury: role of sexual dimorphism and age

Moitra

Evenoski

Sammani

et al. 2008

Translational Research

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We have generated genetically engineered mice that are uniquely susceptible to lipopolysaccharide (LPS)-induced and mechanical ventilation-induced lung injury in a sex-specific and age-specific manner. These mice express a nonmuscle isoform of the myosin light chain kinase gene (nmMLCK2) targeted to the endothelium. Homozygous mice have significantly reduced fecundity and litter survival until weaning, and they are initially growth delayed but eventually exceed the size of wildtype littermates. Mice at all ages show increased protein transport across the lung barrier; however, the phenotype is most discernible in 8-12-week-old male mice. When subjected to a clinically relevant LPS-induced lung injury model, 8-12-week-old young females and 30-36-week-old males seem to be the most significantly injured group. In contrast, 30-36-week-old males remain the most significantly injured group when mechanically ventilated at high tidal volumes, which is a clinically relevant model of mechanical stress lung injury. These data reveal that nmMLCK2 overexpression in the endothelium exacerbates lung injury in vivo in a sexually dimorphic and age-dependent manner.Actin microfilaments generate force by virtue of their ability to contract away from their site of attachment to the plasma membrane, and they do so via traction of the myosin light chain head groups attached to actin filaments by cross-bridges. The cross-bridge pulling action of myosin involves a conformational change in the molecule initiated by energetic phosphorylation of Ser19 on the myosin light chains. 1 The key enzyme involved in this phosphorylation event is myosin light chain kinase (MLCK), which exists in different tissues, and it may be characterized broadly as skeletal/cardiac, smooth muscle, and nonmuscle myosin light chain kinase (nmMLCK) isoforms. Although biochemical evidence for the existence of a Ca 2+ /calmodulin-dependent nonmuscle isoform in cultured endothelial cell (EC) was suggested earlier, [ 2 ] and [ 3 ] the controversy as to whether this enzymatic activity is identical to the 110-kDa protein found abundantly in smooth muscle preparations was resolved when we provided conclusive proof of a larger MLCK protein isoform (210 kDa) by cloning the gene (MYLK) from a human EC-derived cDNA library. 4 The gene was subsequently mapped to chromosome 3q21. 5

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A Single Human Myosin Light Chain Kinase Gene (MLCK; MYLK)Transcribes Multiple Nonmuscle Isoforms

Cited by 124 publications

References 47 publications

Mechanisms Regulating Endothelial Permeability

Mechanisms Regulating Endothelial Permeability

A Differentiation-dependent Splice Variant of Myosin Light Chain Kinase, MLCK1, Regulates Epithelial Tight Junction Permeability

A transgenic mouse with vascular endothelial over-expression of the non-muscle myosin light chain kinase-2 isoform is susceptible to inflammatory lung injury: role of sexual dimorphism and age

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