Myosin light chain kinase plays a role in the regulation of epithelial cell survival

• Published in: Journal of cell science Vol. 119; no. 11; pp. 2269 - 2281
• Main Authors: Connell, Laureen E, Helfman, David M
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 01.06.2006
• Subjects: Amides - pharmacology; Azepines - pharmacology; Cell Line; Cell Line, Transformed; Cell Survival - drug effects; Cells, Cultured; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - physiology; Humans; Integrin beta1 - drug effects; Integrin beta1 - physiology; Intracellular Signaling Peptides and Proteins - physiology; Myosin Type II - antagonists & inhibitors; Myosin Type II - metabolism; Myosin-Light-Chain Kinase - antagonists & inhibitors; Myosin-Light-Chain Kinase - biosynthesis; Myosin-Light-Chain Kinase - physiology; Naphthalenes - pharmacology; Protein-Serine-Threonine Kinases - physiology; Pyridines - pharmacology; rho-Associated Kinases; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.02926

Myosin II activation is essential for stress fiber and focal adhesion formation, and is implicated in integrin-mediated signaling events. In this study we investigated the role of acto-myosin contractility, and its main regulators, i.e. myosin light chain kinase (MLCK) and Rho-kinase (ROCK) in cell survival in normal and Ras-transformed MCF-10A epithelial cells. Treatment of cells with pharmacological inhibitors of MLCK (ML-7 and ML-9), or expression of dominant-negative MLCK, led to apoptosis in normal and transformed MCF-10A cells. By contrast, treatment of cells with a ROCK inhibitor (Y-27632) did not induce apoptosis in these cells. Apoptosis following inhibition of myosin II activation by MLCK is probably meditated through the death receptor pathway because expression of dominant-negative FADD blocked apoptosis. The apoptosis observed after MLCK inhibition is rescued by pre-treatment of cells with integrin-activating antibodies. In addition, this rescue of apoptosis is dependent on FAK activity, suggesting the participation of an integrin-dependent signaling pathway. These studies demonstrate a newly discovered role for MLCK in the generation of pro-survival signals in both untransformed and transformed epithelial cells and supports previous work suggesting distinct cellular roles for Rho-kinase- and MLCK-dependent regulation of myosin II.