DOI: 10.1083/jcb.146.1.149. Myosin Light Chain Kinase Functions Downstream of Ras/ERK to Promote Migration of Urokinase-Type Plasminogen Activator-Stimulated Cells in an Integrin-Selective Manner

Myosin Light Chain Kinase Functions Downstream of Ras/ERK to Promote Migration of Urokinase-Type Plasminogen Activator-Stimulated Cells in an Integrin-Selective Manner

10.1083/jcb.146.1.149

Crossref journal-article

Rockefeller University Press

The Journal of Cell Biology (291)

Abstract

Urokinase-type plasminogen activator (uPA) activates the mitogen activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) 1 and 2, in diverse cell types. In this study, we demonstrate that uPA stimulates migration of MCF-7 breast cancer cells, HT 1080 fibrosarcoma cells, and uPAR-overexpressing MCF-7 cells by a mechanism that depends on uPA receptor (uPAR)-ligation and ERK activation. Ras and MAP kinase kinase (MEK) were necessary and sufficient for uPA-induced ERK activation and stimulation of cellular migration, as demonstrated in experiments with dominant-negative and constitutively active mutants of these signaling proteins. Myosin light chain kinase (MLCK) was also required for uPA-stimulated cellular migration, as determined in experiments with three separate MLCK inhibitors. When MCF-7 cells were treated with uPA, MLCK was phosphorylated by a MEK-dependent pathway and apparently activated, since serine-phosphorylation of myosin II regulatory light chain (RLC) was also increased. Despite the transient nature of ERK phosphorylation, MLCK remained phosphorylated for at least 6 h. The uPA-induced increase in MCF-7 cell migration was observed selectively on vitronectin-coated surfaces and was mediated by a β1-integrin (probably αVβ1) and αVβ5. When MCF-7 cells were transfected to express αVβ3 and treated with uPA, ERK was still phosphorylated; however, the cells did not demonstrate increased migration. Neutralizing the function of αVβ3, with blocking antibody, restored the ability of uPA to promote cellular migration. Thus, we have demonstrated that uPA promotes cellular migration, in an integrin-selective manner, by initiating a uPAR-dependent signaling cascade in which Ras, MEK, ERK, and MLCK serve as essential downstream effectors.

Bibliography

Nguyen, D. H. D., Catling, A. D., Webb, D. J., Sankovic, M., Walker, L. A., Somlyo, A. V., Weber, M. J., & Gonias, S. L. (1999). Myosin Light Chain Kinase Functions Downstream of Ras/ERK to Promote Migration of Urokinase-Type Plasminogen Activator-Stimulated Cells in an Integrin-Selective Manner. The Journal of Cell Biology, 146(1), 149â164.

Authors 8

Diem H.D. Nguyen (first)
Andrew D. Catling (additional)
Donna J. Webb (additional)
Mauricio Sankovic (additional)
Lori A. Walker (additional)
Avril V. Somlyo (additional)
Michael J. Weber (additional)
Steven L. Gonias (additional)

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 12:45 p.m.)
Deposited	2 years, 1 month ago (July 28, 2023, 8:48 p.m.)
Indexed	1 month, 2 weeks ago (July 23, 2025, 9:01 a.m.)
Issued	26 years, 1 month ago (July 12, 1999)
Published	26 years, 1 month ago (July 12, 1999)
Published Online	26 years, 1 month ago (July 12, 1999)
Published Print	26 years, 1 month ago (July 12, 1999)

Funders 0

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BibTeX

@article{Nguyen_1999, title={Myosin Light Chain Kinase Functions Downstream of Ras/ERK to Promote Migration of Urokinase-Type Plasminogen Activator-Stimulated Cells in an Integrin-Selective Manner}, volume={146}, ISSN={1540-8140}, url={http://dx.doi.org/10.1083/jcb.146.1.149}, DOI={10.1083/jcb.146.1.149}, number={1}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Nguyen, Diem H.D. and Catling, Andrew D. and Webb, Donna J. and Sankovic, Mauricio and Walker, Lori A. and Somlyo, Avril V. and Weber, Michael J. and Gonias, Steven L.}, year={1999}, month=jul, pages={149–164} }

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  "abstract": "<jats:p>Urokinase-type plasminogen activator (uPA) activates the mitogen activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) 1 and 2, in diverse cell types. In this study, we demonstrate that uPA stimulates migration of MCF-7 breast cancer cells, HT 1080 fibrosarcoma cells, and uPAR-overexpressing MCF-7 cells by a mechanism that depends on uPA receptor (uPAR)-ligation and ERK activation. Ras and MAP kinase kinase (MEK) were necessary and sufficient for uPA-induced ERK activation and stimulation of cellular migration, as demonstrated in experiments with dominant-negative and constitutively active mutants of these signaling proteins. Myosin light chain kinase (MLCK) was also required for uPA-stimulated cellular migration, as determined in experiments with three separate MLCK inhibitors. When MCF-7 cells were treated with uPA, MLCK was phosphorylated by a MEK-dependent pathway and apparently activated, since serine-phosphorylation of myosin II regulatory light chain (RLC) was also increased. Despite the transient nature of ERK phosphorylation, MLCK remained phosphorylated for at least 6 h. The uPA-induced increase in MCF-7 cell migration was observed selectively on vitronectin-coated surfaces and was mediated by a \u03b21-integrin (probably \u03b1V\u03b21) and \u03b1V\u03b25. When MCF-7 cells were transfected to express \u03b1V\u03b23 and treated with uPA, ERK was still phosphorylated; however, the cells did not demonstrate increased migration. Neutralizing the function of \u03b1V\u03b23, with blocking antibody, restored the ability of uPA to promote cellular migration. Thus, we have demonstrated that uPA promotes cellular migration, in an integrin-selective manner, by initiating a uPAR-dependent signaling cascade in which Ras, MEK, ERK, and MLCK serve as essential downstream effectors.</jats:p>",
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