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

Nishita M, Tomizawa C, Yamamoto M, Horita Y, Ohashi K, Mizuno K - J. Cell Biol. (2005)

Bottom Line: 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.We propose that LIMK1- and SSH1L-mediated spatiotemporal regulation of cofilin activity is critical for chemokine-induced polarized lamellipodium formation and directional cell movement.

View Article: PubMed Central - PubMed

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

ABSTRACT
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.

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A model for the LIMK1- and SSH1L-mediated spatiotemporal regulation of cofilin activity during SDF-1α–induced polarized F-actin assembly and cell migration. The unstimulated Jurkat cell has a round, symmetrical shape. Exposure of the cell to SDF-1α induces the activation of LIMK1 through Rac and leads to a transient increase in P-cofilin levels, which is required for the formation of F-actin–rich lamellipodial protrusions in the initial stages of cell response. SSH1L translocates to the lamellipodia and is activated by associating with F-actin. Because SSH1L knockdown cells retain multiple protrusions during the cell stimulation, SSH1L is required for the conversion of multiple protrusions to the single lamellipodium. In later stages, SSH1L locally stimulates cofilin activation and actin filament turnover in the lamellipodium in the front of the cell, whereas LIMK1 is diffusely distributed in the cell and may help to stabilize actin filaments in the rear of the cell.
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fig9: A model for the LIMK1- and SSH1L-mediated spatiotemporal regulation of cofilin activity during SDF-1α–induced polarized F-actin assembly and cell migration. The unstimulated Jurkat cell has a round, symmetrical shape. Exposure of the cell to SDF-1α induces the activation of LIMK1 through Rac and leads to a transient increase in P-cofilin levels, which is required for the formation of F-actin–rich lamellipodial protrusions in the initial stages of cell response. SSH1L translocates to the lamellipodia and is activated by associating with F-actin. Because SSH1L knockdown cells retain multiple protrusions during the cell stimulation, SSH1L is required for the conversion of multiple protrusions to the single lamellipodium. In later stages, SSH1L locally stimulates cofilin activation and actin filament turnover in the lamellipodium in the front of the cell, whereas LIMK1 is diffusely distributed in the cell and may help to stabilize actin filaments in the rear of the cell.

Mentions: Based on our observations, we propose the following model of LIMK1 and SSH1L actions in SDF-1α–induced actin filament remodeling and chemotactic migration of Jurkat cells (Fig. 9). In the initial stage of cell stimulation, SDF-1α induces the activation of LIMK1 through Rac activation (Nishita et al., 2002), and this transiently increases P-cofilin levels for up to 5 min and induces F-actin assembly; multiple membrane protrusions are first generated around the cell periphery at ∼1 min and are transformed to the single lamellipodium by 5 min. Because LIMK1 siRNA significantly suppressed SDF-1α–induced cofilin phosphorylation and lamellipodial protrusion formation, LIMK1 seems to play a critical role in lamellipodium formation during the initial stage of cell stimulation by inactivating cofilin and shifting the balance of actin filament dynamics to actin filament polymerization and stabilization. Because the extension of the lamellipodium provides the driving force for cell migration, impaired lamellipodium formation is a likely reason for the failure of LIMK1 knockdown cells to migrate in response to SDF-1α.


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

Nishita M, Tomizawa C, Yamamoto M, Horita Y, Ohashi K, Mizuno K - J. Cell Biol. (2005)

A model for the LIMK1- and SSH1L-mediated spatiotemporal regulation of cofilin activity during SDF-1α–induced polarized F-actin assembly and cell migration. The unstimulated Jurkat cell has a round, symmetrical shape. Exposure of the cell to SDF-1α induces the activation of LIMK1 through Rac and leads to a transient increase in P-cofilin levels, which is required for the formation of F-actin–rich lamellipodial protrusions in the initial stages of cell response. SSH1L translocates to the lamellipodia and is activated by associating with F-actin. Because SSH1L knockdown cells retain multiple protrusions during the cell stimulation, SSH1L is required for the conversion of multiple protrusions to the single lamellipodium. In later stages, SSH1L locally stimulates cofilin activation and actin filament turnover in the lamellipodium in the front of the cell, whereas LIMK1 is diffusely distributed in the cell and may help to stabilize actin filaments in the rear of the cell.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171197&req=5

fig9: A model for the LIMK1- and SSH1L-mediated spatiotemporal regulation of cofilin activity during SDF-1α–induced polarized F-actin assembly and cell migration. The unstimulated Jurkat cell has a round, symmetrical shape. Exposure of the cell to SDF-1α induces the activation of LIMK1 through Rac and leads to a transient increase in P-cofilin levels, which is required for the formation of F-actin–rich lamellipodial protrusions in the initial stages of cell response. SSH1L translocates to the lamellipodia and is activated by associating with F-actin. Because SSH1L knockdown cells retain multiple protrusions during the cell stimulation, SSH1L is required for the conversion of multiple protrusions to the single lamellipodium. In later stages, SSH1L locally stimulates cofilin activation and actin filament turnover in the lamellipodium in the front of the cell, whereas LIMK1 is diffusely distributed in the cell and may help to stabilize actin filaments in the rear of the cell.
Mentions: Based on our observations, we propose the following model of LIMK1 and SSH1L actions in SDF-1α–induced actin filament remodeling and chemotactic migration of Jurkat cells (Fig. 9). In the initial stage of cell stimulation, SDF-1α induces the activation of LIMK1 through Rac activation (Nishita et al., 2002), and this transiently increases P-cofilin levels for up to 5 min and induces F-actin assembly; multiple membrane protrusions are first generated around the cell periphery at ∼1 min and are transformed to the single lamellipodium by 5 min. Because LIMK1 siRNA significantly suppressed SDF-1α–induced cofilin phosphorylation and lamellipodial protrusion formation, LIMK1 seems to play a critical role in lamellipodium formation during the initial stage of cell stimulation by inactivating cofilin and shifting the balance of actin filament dynamics to actin filament polymerization and stabilization. Because the extension of the lamellipodium provides the driving force for cell migration, impaired lamellipodium formation is a likely reason for the failure of LIMK1 knockdown cells to migrate in response to SDF-1α.

Bottom Line: 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.We propose that LIMK1- and SSH1L-mediated spatiotemporal regulation of cofilin activity is critical for chemokine-induced polarized lamellipodium formation and directional cell movement.

View Article: PubMed Central - PubMed

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

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus