Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 294, Issue 6, Pages C1465-C1475Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.90638.2007
Keywords
Ca(2+)/calmodulin-dependent protein kinase II; CaMKII; Golgi; calcium signaling; Rac; ERK1/2
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Funding
- NHLBI NIH HHS [R01 HL049426, R01 HL092510] Funding Source: Medline
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Previous studies indicate involvement of the multifunctional Ca(2+)/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.
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