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A nonmuscle myosin light chain kinase-dependent gene signature in peripheral blood mononuclear cells is linked to human asthma severity and exacerbation status.

ABSTRACT: Asthma is increasingly recognized as a heterogeneous disease influenced by complex genetic and environmental contributions. Myosin light chain kinase (MLCK; gene symbol, MYLK), especially the nonmuscle isoform nmMLCK, is a cytoskeleton protein known to be related to human asthma susceptibility and severity, findings confirmed in preclinical models of asthmatic inflammation. In this study, we define the central capacity for a nmMLCK-influenced gene signature in human peripheral blood mononuclear cells to predict human asthma severity and exacerbation status. We refined this signature from a list of nmMLCK-influenced genes identified in lung tissues of nmMLCK knockout mice exposed to inflammatory stimuli (ventilator-induced lung injury), with subsequent identification of nmMLCK-influenced genes in a list of human asthma severity-related genes expressed in blood. The enriched nmMLCK-influenced gene signature successfully predicted human asthma severity and exacerbation status in both discovery and validation human asthma cohorts. These findings validate the central role played by nmMLCK in asthma susceptibility, severity, and exacerbation and further provide novel gene signatures as effective asthma biomarkers for severity, exacerbation, and prognosis.

SUBMITTER: Zhou T

PROVIDER: S-EPMC4449245 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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A nonmuscle myosin light chain kinase-dependent gene signature in peripheral blood mononuclear cells is linked to human asthma severity and exacerbation status.

Zhou Tong T Wang Ting T Garcia Joe G N JG

Pulmonary circulation 20150601 2

Asthma is increasingly recognized as a heterogeneous disease influenced by complex genetic and environmental contributions. Myosin light chain kinase (MLCK; gene symbol, MYLK), especially the nonmuscle isoform nmMLCK, is a cytoskeleton protein known to be related to human asthma susceptibility and severity, findings confirmed in preclinical models of asthmatic inflammation. In this study, we define the central capacity for a nmMLCK-influenced gene signature in human peripheral blood mononuclear ...[more]

PMID: 26064459

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Project description:Myosin light chain kinase (MLCK) phosphorylates S19 of the myosin regulatory light chain (RLC), which is required to activate myosin's ATPase activity and contraction. Smooth muscles are known to display plasticity in response to factors such as inflammation, developmental stage, or stress, which lead to differential expression of nonmuscle and smooth muscle isoforms. Here, we compare steady-state kinetics parameters for phosphorylation of different MLCK substrates: (1) nonmuscle RLC, (2) smooth muscle RLC, and heavy meromyosin subfragments of (3) nonmuscle myosin IIB, and (4) smooth muscle myosin II. We show that MLCK has a ~2-fold higher kcat for both smooth muscle myosin II substrates compared with nonmuscle myosin IIB substrates, whereas Km values were very similar. Myosin light chain kinase has a 1.6-fold and 1.5-fold higher specificity (kcat /Km ) for smooth versus nonmuscle-free RLC and heavy meromyosin, respectively, suggesting that differences in specificity are dictated by RLC sequences. Of the 10 non-identical RLC residues, we ruled out 7 as possible underlying causes of different MLCK kinetics. The remaining 3 residues were found to be surface exposed in the N-terminal half of the RLC, consistent with their importance in substrate recognition. These data are consistent with prior deletion/chimera studies and significantly add to understanding of MLCK myosin interactions.Significance of the studyPhosphorylation of nonmuscle and smooth muscle myosin by myosin light chain kinase (MLCK) is required for activation of myosin's ATPase activity. In smooth muscles, nonmuscle myosin coexists with smooth muscle myosin, but the two myosins have very different chemo-mechanical properties relating to their ability to maintain force. Differences in specificity of MLCK for different myosin isoforms had not been previously investigated. We show that the MLCK prefers smooth muscle myosin by a significant factor. These data suggest that nonmuscle myosin is phosphorylated more slowly than smooth muscle myosin during a contraction cycle.

Dataset Information

A nonmuscle myosin light chain kinase-dependent gene signature in peripheral blood mononuclear cells is linked to human asthma severity and exacerbation status.

Publications

A nonmuscle myosin light chain kinase-dependent gene signature in peripheral blood mononuclear cells is linked to human asthma severity and exacerbation status.

Similar Datasets

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