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Abl Tyrosine Kinase Phosphorylates Non-muscle Myosin Light Chain Kinase to Regulate Endothelial Barrier Function

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Title: Abl Tyrosine Kinase Phosphorylates Non-muscle Myosin Light Chain Kinase to Regulate Endothelial Barrier Function
Author(s): Dudek, Steven M.; Chiang, Eddie T.; Camp, Sara M.; Guo, Yurong; Zhao, Jing; Brown, Mary E.; Singleton, Patrick A.; Wang, Lichun; Desai, Anjali; Arce, Fernando T.; Lal, Ratnesh; Van Eyk, Jennifer E.; Imam, Syed Z.; Garcia, Joe G. N.
Subject(s): endothelial barrier myosin
Abstract: Nonmuscle myosin light chain kinase (nmMLCK), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-Abl–mediated nmMLCK phosphorylation sites by mass spectroscopy analysis (including Y231, Y464, Y556, Y846) and examined their influence on nmMLCK function and human lung endothelial cell (EC) barrier regulation. Tyrosine phosphorylation of nmMLCK increased kinase activity, reversed nmMLCK-mediated inhibition of Arp2/3-mediated actin polymerization, and enhanced binding to the critical actin-binding phosphotyrosine protein, cortactin. EC challenge with sphingosine 1-phosphate (S1P), a potent barrier-enhancing agonist, resulted in c-Abl and phosphorylated nmMLCK recruitment into caveolin-enriched microdomains, rapid increases in Abl kinase activity, and spatial targeting of c-Abl to barrier-promoting cortical actin structures. Conversely, reduced c-Abl expression in EC (siRNA) markedly attenuated S1P-mediated cortical actin formation, reduced the EC modulus of elasticity (assessed by atomic force microscopy), reduced nmMLCK and cortactin tyrosine phosphorylation, and attenuated S1P-mediated barrier enhancement. These studies indicate an essential role for Abl kinase in vascular barrier regulation via posttranslational modification of nmMLCK and strongly support c-Abl-cortactin-nmMLCK interaction as a novel determinant of cortical actin-based cytoskeletal rearrangement critical to S1P-mediated EC barrier enhancement.
Issue Date: 2010-11-15
Publisher: American Society for Cell Biology
Citation Info: Dudek, S. M., Chiang, E. T., Camp, S. M., Guo, Y., Zhao, J., Brown, M. E., Singleton, P. A., Wang, L., Desai, A., Arce, F. T., Lal, R., Van Eyk, J. E., Imam, S. Z., & Garcia, J. G. 2010. Abl Tyrosine Kinase Phosphorylates Non-muscle Myosin Light Chain Kinase to Regulate Endothelial Barrier Function. Molecular Biology of the Cell. DOI: 10.1091/mbc.E09-10-0876
Type: Article
Description: The original source for this publication is at the American Society for Cell Biology; DOI: 10.1091/mbc.E09-10-0876
URI: http://hdl.handle.net/10027/7597
ISSN: 1059-1524
Sponsor: This work was supported by grants from the National Heart, Lung, and Blood Institute, National Institutes of Health Grant P01 HL 58064, R01 HL 91889, and R01 HL 68071 (to J.G.N.G.) and R01 HL 88144 (to S.M.D.).
Date Available in INDIGO: 2011-05-11
 

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