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Elena A. Goncharova, Alexander V. Vorotnikov, Elena O. Gracheva, C.-L. Albert Wang, Reynold A. Panettieri Jr., Victoria V. Stepanova, Vsevolod A. Tkachuk
Activation of p38 MAP-Kinase and Caldesmon Phosphorylation Are Essential for Urokinase-Induced Human Smooth Muscle Cell Migration
We have explored intracellular pathways involved in the urokinase type plasminogen activator (urokinase or uPA)stimulated migration of human airway smooth muscle cells (hAWSMC). Using a set of uPA mutants we found that protease activity, growth factorlike and kringle domains of uPA differentially contribute to activation of p42/p44erk1,2 and p38 MAPkinases. Consistent with our earlier data [Mukhina et al., J. Biol. Chem. 275 (2000), 16450 16458], the kringle domain of uPA was sufficient and required to stimulate cell motility. Here we report that uPA mutants containing the kringle domain specifically activate the p38 MAPkinase pathway and actomyosin by increasing phosphorylation of the critical Ser-19 on the myosin regulatory light chain and MAPkinase sites of the actinassociated regulatory protein caldesmon. While pharmacological inhibition of p38 MAPkinase activation did not affect myosin light chain phosphorylation, it blocked the increase in caldesmon phosphorylation and uPAstimulated migration of hAWSMC on a collagencoated surface. We conclude that activation of p38 MAPkinase and downstream phosphorylation of nonmuscle caldesmon is essential for urokinasestimulated smooth muscle cell migration.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 383, 01/2002
Pages: 115 - 126