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.
Highlights
Active Protein kinase D (PKD) Isoforms Inhibit Cofilin Activity and Directed Cell Migration—The generation of F-actin free barbed ends through ADF/cofilin correlates with the ability of cells to migrate [3]
Increased phospho-cofilin levels correlated with a complete block of F-actin free barbed end formation and actin incorporation in cells where active PKD was expressed (Fig. 1B), suggesting that PKD effectively inhibits cofilin activity
Recent studies have suggested an involvement of PKD enzymes in processes that regulate actin reorganization and actin cytoskeleton-driven directed cell migration [20, 24, 41]
Summary
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. One mechanism of how PKD1 modulates cell motility is that it inhibits the formation of F-actin free barbed ends which has been linked to phosphorylation of SSH1L, resulting in a decrease in the pool of active cofilin [28]. Such inhibition of SSH1L is mediated by the phosphorylation-dependent recruitment of 14-3-3 proteins [14, 29]. PKD-mediated inhibition of cofilin through both of its regulatory pathways may explain its dramatic effects on actin incorporation at the leading edge and on directed cell motility
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