Protein Kinase D Regulates Cofilin Activity through p21-activated Kinase 4

Dynamic reorganization of the actin cytoskeleton at the leading edge is required for directed cell migration. Cofilin, a small actin-binding protein with F-actin severing activities, is a key enzyme initiating such actin remodeling processes. Cofilin activity is tightly regulated by phosphorylation...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-09, Vol.286 (39), p.34254-34261
Main Authors: Spratley, Samantha J., Bastea, Ligia I., Döppler, Heike, Mizuno, Kensaku, Storz, Peter
Format: Article
Language:English
Subjects:
Actin
Actin Depolymerizing Factors - genetics
Actin Depolymerizing Factors - metabolism
Actins - genetics
Actins - metabolism
Cell Migration
Cell Motility
Cell Movement - physiology
Cofilin
HeLa Cells
Humans
Lim Kinases - genetics
Lim Kinases - metabolism
LIMK
p21-Activated Kinases - genetics
p21-Activated Kinases - metabolism
PAK4
Phosphoprotein Phosphatases - genetics
Phosphoprotein Phosphatases - metabolism
PKD
Protein Kinase C - genetics
Protein Kinase C - metabolism
Serine/Threonine Protein Kinase
Signal Transduction
Slingshot
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Summary:Dynamic reorganization of the actin cytoskeleton at the leading edge is required for directed cell migration. Cofilin, a small actin-binding protein with F-actin severing activities, is a key enzyme initiating such actin remodeling processes. Cofilin activity is tightly regulated by phosphorylation and dephosphorylation events that are mediated by LIM kinase (LIMK) and the phosphatase slingshot (SSH), respectively. Protein kinase D (PKD) is a serine/threonine kinase that inhibits actin-driven directed cell migration by phosphorylation and inactivation of SSH. Here, we show that PKD can also regulate LIMK through direct phosphorylation and activation of its upstream kinase p21-activated kinase 4 (PAK4). Therefore, active PKD increases the net amount of phosphorylated inactive cofilin in cells through both pathways. The regulation of cofilin activity at multiple levels may explain the inhibitory effects of PKD on barbed end formation as well as on directed cell migration. Background: PKD inhibits actin-driven directed cell migration. Results: PKD regulates cofilin activity through LIMK and PAK4. Conclusion: PKD increases the net amount of inactive cofilin in cells. Significance: The regulation of cofilin activity at multiple levels explains the inhibitory effects of PKD on directed cell migration.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.259424