A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart

Seguchi, Osamu; Takashima, Seiji; Yamazaki, Satoru; Asakura, Masanori; Asano, Yoshihiro; Shintani, Yasunori; Wakeno, Masakatsu; Minamino, Tetsuo; Kondo, Hiroya; Furukawa, Hidehiko; Nakamaru, Kenji; Naito, Asuka; Takahashi, Tomoko; Ohtsuka, Toshiaki; Kikuchi, Kôichi; Isomura, Tadashi; Kitamura, Soichiro; Tomoike, Hitonobu; Mochizuki, Naoki; Kitakaze, Masafumi

doi:10.1172/jci30804

Cited by 146 publications

(165 citation statements)

References 29 publications

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“…cRLC mutations associated with hypertrophic cardiomyopathy abolish cRLC phosphorylation in vitro (15), and mice expressing nonphosphorylatable cRLCs show severe cardiac dysfunction (10,16). In the vertebrate heart, cRLCs are phosphorylated almost exclusively by the cardiac isoform of myosin light chain kinase (cMLCK) (17,18), and cMLCK gene ablation leads to severe cardiac hypertrophy (19).…”

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confidence: 99%

Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments

Kampourakis

Sun

Irving

2016

Proc. Natl. Acad. Sci. U.S.A.

116

141

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Contraction of heart muscle is triggered by calcium binding to the actin-containing thin filaments but modulated by structural changes in the myosin-containing thick filaments. We used phosphorylation of the myosin regulatory light chain (cRLC) by the cardiac isoform of its specific kinase to elucidate mechanisms of thick filamentmediated contractile regulation in demembranated trabeculae from the rat right ventricle. cRLC phosphorylation enhanced active force and its calcium sensitivity and altered thick filament structure as reported by bifunctional rhodamine probes on the cRLC: the myosin head domains became more perpendicular to the filament axis. The effects of cRLC phosphorylation on thick filament structure and its calcium sensitivity were mimicked by increasing sarcomere length or by deleting the N terminus of the cRLC. Changes in thick filament structure were highly cooperative with respect to either calcium concentration or extent of cRLC phosphorylation. Probes on unphosphorylated myosin heads reported similar structural changes when neighboring heads were phosphorylated, directly demonstrating signaling between myosin heads. Moreover probes on troponin showed that calcium sensitization by cRLC phosphorylation is mediated by the thin filament, revealing a signaling pathway between thick and thin filaments that is still present when active force is blocked by Blebbistatin. These results show that coordinated and cooperative structural changes in the thick and thin filaments are fundamental to the physiological regulation of contractility in the heart. This integrated dual-filament concept of contractile regulation may aid understanding of functional effects of mutations in the protein components of both filaments associated with heart disease.cardiac muscle regulation | myosin regulatory light chain | phosphorylation

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confidence: 99%

Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments

Kampourakis

Sun

Irving

2016

Proc. Natl. Acad. Sci. U.S.A.

116

141

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“…The potential transcription factors regulating downregulated genes were labeled in blue, while transcription factors regulating downregulated genes were labeled in red reassembly (Medjkane et al, 2009). SCIN (scinderin) is a Ca(2+)-dependent actin-severing and -capping protein, might act as a molecular switch in the control of cortical F-actin dynamics during secretion (Seguchi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Bioinformation Analysis of the MRNA Profile of Fascin Knockdown in Esophageal Squamous Cell Carcinoma

Wu¹,

Luo²,

Li³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Fascin, an actin-bundling protein forming actin bundles including filopodia and stress fibers, is overexpressed in multiple human epithelial cancers including esophageal squamous cell carcinoma (ESCC). Previously we conducted a microarray experiment to analyze fascin knockdown by RNAi in ESCC. Method: In this study, the differentially expressed genes from mRNA expression profilomg of fascin knockdown were analyzed by multiple bioinformatics methods for a comprehensive understanding of the role of fascin. Results: Gene Ontology enrichment found terms associated with cytoskeleton organization, including cell adhesion, actin filament binding and actin cytoskeleton, which might be related to fascin function. Except GO categories, the differentially expressed genes were annotated by 45 functional categories from the Functional Annotation Chart of DAVID. Subpathway analysis showed thirty-nine pathways were disturbed by the differentially expressed genes, providing more detailed information than traditional pathway enrichment analysis. Two subpathways derivated from regulation of the actin cytoskeleton were shown. Promoter analysis results indicated distinguishing sequence patterns and transcription factors in response to the co-expression of downregulated or upregulated differentially expressed genes. MNB1A, c-ETS, GATA2 and Prrx2 potentially regulate the transcription of the downregulated gene set, while Arnt-Ahr, ZNF42, Ubx and TCF11-MafG might co-regulate the upregulated genes. Conclusions: This multiple bioinformatic analysis helps provide a comprehensive understanding of the roles of fascin after its knockdown in ESCC.

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“…• A novel cardiac-specific myosin light chain kinase (cardiac-MLCK) that was identified in failing human myocardium was shown to be required for zebrafish cardiac development, since MO knockdown induced cardiac dilatation and oedema [91].…”

Section: The Genetics Of Cardiovascular Disease 193mentioning

confidence: 99%

The genetics of cardiovascular disease: new insights from emerging approaches

Chico¹,

Milo²,

Crossman³

2009

The Journal of Pathology

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The prospect that sequencing the human genome would see rapid translation of a greater understanding of cardiovascular genetics into novel diagnostics and therapeutics has so far met with only limited success. However, diverse technological advances and exploitation of novel animal models of cardiovascular development and disease are providing ever more insight into cardiovascular diseases and development, and bring closer the prospect of 'postgenomic' diagnostics and therapies. Here we review some of these emerging approaches (genome wide association studies, deep sequencing, microRNA regulation, and zebrafish as a model of cardiovascular disease and development) and discuss their potential for finally fulfilling the promise of application to clinical cardiovascular medicine.

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A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart

Cited by 146 publications

References 29 publications

Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments

Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments

Comprehensive Bioinformation Analysis of the MRNA Profile of Fascin Knockdown in Esophageal Squamous Cell Carcinoma

The genetics of cardiovascular disease: new insights from emerging approaches

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