Abstract
In addition to their role in cell proliferation, cyclin‐dependent kinases (CDKs) mediate cell migration; however the underlying mechanisms are not clear. Therefore, the objective of this study is to test whether cyclin/CDKs activate Pak1, an effector of Rac1, whose involvement in the modulation of cell migration and proliferation is well established. Monocyte chemotactic protein 1 (MCP1) induced Pak1 phosphorylation/activation in human aortic smooth muscle cells (HASMCs) in a time‐dependent but delayed manner. MCP1 also stimulated F‐actin stress fiber formation as well as the migration and proliferation of these cells and inhibition of Pak1 reversed these effects. MCP1 also induced cyclin D1 expression and CDK6/4 activities, and these effects were dependent on NFATc1 activation. Depletion of NFATc1, cyclin D1, CDK6, or CDK4 levels attenuated MCP1‐induced Pak1 phosphorylation/activation resulting in decreased HASMC F‐actin stress fiber formation, migration and proliferation. CDK4, which appeared to be activated downstream of CDK6, formed a complex with Pak1 in response to MCP1. Depletion/inhibition of Rac1 levels/activation abrogated MCP1‐induced NFATc1‐cyclin D1‐CDK6‐CDK4‐Pak1 signaling, and thereby, decreased HASMC F‐actin stress fiber formation, migration, and proliferation. In addition, smooth muscle‐specific deletion of NFATc1 led to decreased cyclin D1 expression and CDK6, CDK4, and Pak1 activities resulting in reduced neointima formation in response to injury. Thus, these observations reveal that Pak1 is a downstream effector of CDK4 and Rac1‐dependent NFATc1‐mediated cyclin D1 expression and CDK6 activity mediate this effect in the modulation of MCP1‐induced HASMC migration and proliferation in vitro and vascular wall remodeling in vivo.Grant Funding Source: NHLBI
Published Version
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