Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot

Tim Eiseler, Heike Döppler, Irene K. Yan, Kanae Kitatani, Kensaku Mizuno, Peter Storz

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)545-556
Number of pages12
JournalNature Cell Biology
Volume11
Issue number5
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Cell Biology

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