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Articles in PresS, published online ahead of print December 4, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00371.2002
Submitted on August 15, 2002
Accepted on November 27, 2002
1 Surgery and Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
2 Physiology, Virginia Commonwealth University, Richmond, Virginia, USA
3 Medicine, University of California School of Medicine, San Diego, California, USA
* To whom correspondence should be addressed. E-mail: jwang{at}smail.umaryland.edu.
Polyamines are required for the early phase of mucosal restitution that occurs as a consequence of epithelial cell migration. Our previous studies have shown that polyamines increase RhoA activity by elevating cytosolic free Ca2+ concentration ([Ca2+]cyt) through controlling voltage-gated K+ channel expression and membrane potential (Em) during intestinal epithelial restitution. The current study went further to determine whether increased RhoA following elevated [Ca2+]cyt activates Rho-kinase (ROK/ROCK) resulting in myosin light chain (MLC) phosphorylation. Studies were conducted in stable Cdx2-transfected intestinal epithelial cells (IEC-Cdx2L1), which were associated with a highly differentiated phenotype. Reduced [Ca2+]cyt, by either polyamine depletion or exposure to the Ca2+-free medium, decreased RhoA protein expression, which was paralleled by significant decreases in GTP-bound RhoA, ROCK-1 and ROK
proteins, Rho-kinase activity, and MLC phosphorylation. The reduction of [Ca2+]cyt also inhibited cell migration after wounding. Elevation of [Ca2+]cyt induced by the Ca2+ ionophore ionomycin increased GTP-bound RhoA, ROCK-1 and ROK proteins, Rho-kinase activity, and MLC phosphorylation. Inhibition of RhoA function by a dominant negative mutant RhoA decreased ROKa protein expression and the Rho-kinase activity, and resulted in cytoskeletal reorganization. Inhibition of ROK/ROCK activity by the specific inhibitor Y27632 not only decreased MLC phosphorylation but also suppressed cell migration. These results indicate that increase in GTP-bound RhoA by polyamines via [Ca2+]cyt can interact with and activate Rho-kinase during intestinal epithelial restitution. Activation of Rho-kinase results in increased MLC phosphorylation, leading to the stimulation of myosin stress fiber formation and cell migration.
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