title: Spatial and temporal regulation of cofilin activity by LIM kinase and Slingshot is critical for directional cell migration.
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.
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors.forename: Michiru
authors.initials: M
authors.lastname: Nishita
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Tomizawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Horita
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ohashi
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
mesh_terms: D051339:Actin Depolymerizing Factors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D054461:Lim Kinases; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011554:Pseudopodia / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D034741:RNA, Small Interfering; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human