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Departments of 1 Surgery and 2 Pathology, University of Maryland School of Medicine and 3 Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; 4 Department of Physiology, Virginia Commonwealth University, Richmond, Virginia 23298; and 5 Department of Medicine, School of Medicine, University of California, San Diego, California 92103
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 the Rho-kinase activity and resulted in
cytoskeletal reorganization. Inhibition of ROK/ROCK activity by the
specific inhibitor Y-27632 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.
mucosal injury; intracellular calcium; Cdx2 gene; dominant negative mutant RhoA; cytoskeleton
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