Spatial and temporal regulation of cofilin activity by LIM kinase and Slingshot is critical for directional cell migration

• Published in: The Journal of cell biology 2005-10, Vol.171 (2), p.349-359
• Main Authors: Nishita, Michiru, Tomizawa, Chinatsu, Yamamoto, Masahiro, Horita, Yuji, Ohashi, Kazumasa, Mizuno, Kensaku
• Format: Article
• Language: English
• Subjects: Actin depolymerizing factors; Actin Depolymerizing Factors - drug effects; Actin Depolymerizing Factors - genetics; Actin Depolymerizing Factors - metabolism; Actins; Actins - drug effects; Actins - metabolism; Cell adhesion & migration; Cell motility; Cell Movement - drug effects; Cell Movement - physiology; Chemokine CXCL12; Chemokines, CXC - pharmacology; Chemotaxis; Chemotaxis - drug effects; Chemotaxis - physiology; Humans; Jurkat Cells; Lim Kinases; Membranes; Microfilaments; Phosphatases; Phosphates; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - physiology; Plasmids; Protein Kinases - genetics; Protein Kinases - physiology; Pseudopodia - drug effects; Pseudopodia - physiology; RNA, Small Interfering - drug effects; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Small interfering RNA; Stromal cells; T lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200504029

Cofilin mediates lamellipodium extension and polarized cell migration by accelerating actin filament dynamics at the leading edge of migrating cells. Cofilin is inactivated by LIM kinase (LIMK)-1-mediated phosphorylation and is reactivated by cofilin phosphatase Slingshot (SSH)-1L. In this study, we show that cofilin activity is temporally and spatially regulated by LIMK1 and SSH1L in chemokine-stimulated Jurkat T cells. The knockdown of LIMK1 suppressed chemokine-induced lamellipodium formation and cell migration, whereas SSH1L knockdown produced and retained multiple lamellipodial protrusions around the cell after cell stimulation and impaired directional cell migration. Our results indicate that LIMK1 is required for cell migration by stimulating lamellipodium formation in the initial stages of cell response and that SSH1L is crucially involved in directional cell migration by restricting the membrane protrusion to one direction and locally stimulating cofilin activity in the lamellipodium in the front of the migrating cell. We propose that LIMK1- and SSH1L-mediated spatiotemporal regulation of cofilin activity is critical for chemokine-induced polarized lamellipodium formation and directional cell movement.