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Published online 17 October 2005. doi:10.1083/jcb.200504029
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 2, 349-359
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Article

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



Michiru Nishita, Chinatsu Tomizawa, Masahiro Yamamoto, Yuji Horita, Kazumasa Ohashi, and Kensaku Mizuno

Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan

Correspondence to Kensaku Mizuno: kmizuno{at}biology.tohoku.ac.jp

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.

M. Nishita, C. Tomizawa, and M. Yamamoto contributed equally to this paper.

Abbreviations used in this paper: LIMK, LIM kinase; P-cofilin, Ser-3–phosphorylated cofilin; PI3K, phosphatidylinositol-3 kinase; SDF-1{alpha}, stromal cell–derived factor-1{alpha}; siRNA, small interfering RNA; sr, siRNA resistant; SSH, Slingshot; WT, wild type.


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