Myosin light chain kinase plays a role in the regulation of epithelial cell survival.
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.
Connell
Laureen E
LE
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Helfman
David M
DM
D000577:Amides / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D024462:Myosin Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases
D000577:Amides; D001381:Azepines; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D009281:Naphthalenes; D011725:Pyridines; C056218:ML 9; C070571:ML 7; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D024462:Myosin Type II