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Am J Physiol Cell Physiol 294: C1465-C1475, 2008. First published April 2, 2008; doi:10.1152/ajpcell.90638.2007
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VASCULAR BIOLOGY

CaM kinase II{delta}2-dependent regulation of vascular smooth muscle cell polarization and migration

Melissa Z. Mercure, Roman Ginnan, and Harold A. Singer

Center for Cardiovascular Sciences, Albany Medical College, Albany, New York

Submitted 18 December 2007 ; accepted in final form 27 March 2008

Previous studies indicate involvement of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) in vascular smooth muscle (VSM) cell migration. In the present study, molecular loss-of-function studies were used specifically to assess the role of the predominant CaMKII{delta}2 isoform on VSM cell migration using a scratch wound healing assay. Targeted CaMKII{delta}2 knockdown using siRNA or inhibition of activity by overexpressing a kinase-negative mutant resulted in attenuation of VSM cell migration. Temporal and spatial assessments of kinase autophosphorylation indicated rapid and transient activation in response to wounding, in addition to a sustained activation in the leading edge of migrating and spreading cells. Furthermore, siRNA-mediated suppression of CaMKII{delta}2 resulted in the inhibition of wound-induced Rac activation and Golgi reorganization, and disruption of leading edge morphology, indicating an important function for CaMKII{delta}2 in regulating VSM cell polarization. Numerous previous reports link activation of CaMKII to ERK1/2 signaling in VSM. Wound-induced ERK1/2 activation was also found to be dependent on CaMKII; however, ERK activity did not account for effects of CaMKII in regulating Golgi polarization, indicating alternative mechanisms by which CaMKII affects the complex events involved in cell migration. Wounding a VSM cell monolayer results in CaMKII{delta}2 activation, which positively regulates VSM cell polarization and downstream signaling, including Rac and ERK1/2 activation, leading to cell migration.

Ca2+/calmodulin-dependent protein kinase II; CaMKII; Golgi; calcium signaling; Rac; ERK1/2


Address for reprint requests and other correspondence: H. A. Singer, Center for Cardiovascular Sciences, Albany Medical College (MC8), 47 New Scotland Ave., Albany, NY 12208 (e-mail: singerh{at}mail.amc.edu)






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