title: Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot.
abstract: Dynamic actin remodelling processes at the leading edge of migrating tumour cells are concerted events controlled by a fine-tuned temporal and spatial interplay of kinases and phosphatases. Actin severing is regulated by actin depolymerizing factor (ADF)/cofilin, which regulates stimulus-induced lamellipodia protrusion and directed cell motility. Cofilin is activated by dephosphorylation through phosphatases of the slingshot (SSH) family. SSH activity is strongly increased by its binding to filamentous actin (F-actin); however, other upstream regulators remain unknown. Here we show that in response to RhoA activation, protein kinase D1 (PKD1) phosphorylates the SSH enzyme SSH1L at a serine residue located in its actin-binding motif. This generates a 14-3-3-binding motif and blocks the localization of SSH1L to F-actin-rich structures in the lamellipodium by sequestering it in the cytoplasm. Consequently, expression of constitutively active PKD1 in invasive tumour cells enhanced the phosphorylation of cofilin and effectively blocked the formation of free actin-filament barbed ends and directed cell migration.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Eiseler
authors.forename: Heike
authors.initials: H
authors.lastname: Döppler
authors.forename: Irene K
authors.initials: IK
authors.lastname: Yan
authors.forename: Kanae
authors.initials: K
authors.lastname: Kitatani
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
authors.forename: Peter
authors.initials: P
authors.lastname: Storz