title: Protein kinase D regulates cofilin activity through p21-activated kinase 4.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Spratley
authors.forename: Ligia I
authors.initials: LI
authors.lastname: Bastea
authors.forename: Heike
authors.initials: H
authors.lastname: Döppler
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; C116367:PAK4 protein, human; C089212:protein kinase D; C515892:LIMK1 protein, human; D054461:Lim Kinases; D054462:p21-Activated Kinases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human