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Originally published online as doi:10.2353/ajpath.2009.080171 on January 15, 2009

Published online before print January 15, 2009
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(American Journal of Pathology. 2009;174:436-448.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080171

Non-Muscle Myosin IIA Differentially Regulates Intestinal Epithelial Cell Restitution and Matrix Invasion

Brian A. Babbin*, Stefan Koch*, Moshe Bachar*, Mary-Anne Conti{dagger}, Charles A. Parkos*, Robert S. Adelstein{dagger}, Asma Nusrat* and Andrei I. Ivanov*{ddagger}

From the Epithelial Pathobiology Research Unit,* the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; the Laboratory of Molecular Cardiology,{dagger} the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland; and the Gastroenterology and Hepatology Division,{ddagger} Department of Medicine, The University of Rochester, Rochester New York

Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin II motor. However, the role of myosin II in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Pharmacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of β1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SK-CO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression.




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A. I. Ivanov, C. A. Parkos, and A. Nusrat
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Am. J. Pathol., August 1, 2010; 177(2): 512 - 524.
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