title: A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia.
abstract: Cofilin mediates lamellipodium extension and polarized cell migration by stimulating actin filament dynamics at the leading edge of migrating cells. Cofilin is inactivated by phosphorylation at Ser-3 and reactivated by cofilin-phosphatase Slingshot-1L (SSH1L). Little is known of signaling mechanisms of cofilin activation and how this activation is spatially regulated. Here, we show that cofilin-phosphatase activity of SSH1L increases approximately 10-fold by association with actin filaments, which indicates that actin assembly at the leading edge per se triggers local activation of SSH1L and thereby stimulates cofilin-mediated actin turnover in lamellipodia. We also provide evidence that 14-3-3 proteins inhibit SSH1L activity, dependent on the phosphorylation of Ser-937 and Ser-978 of SSH1L. Stimulation of cells with neuregulin-1beta induced Ser-978 dephosphorylation, translocation of SSH1L onto F-actin-rich lamellipodia, and cofilin dephosphorylation. These findings suggest that SSH1L is locally activated by translocation to and association with F-actin in lamellipodia in response to neuregulin-1beta and 14-3-3 proteins negatively regulate SSH1L activity by sequestering it in the cytoplasm.
authors.affiliation: Dept. of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nagata-Ohashi
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Ohta
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Goto
authors.forename: Shuhei
authors.initials: S
authors.lastname: Chiba
authors.forename: Reiko
authors.initials: R
authors.lastname: Mori
authors.forename: Michiru
authors.initials: M
authors.lastname: Nishita
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ohashi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kousaka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Iwamatsu
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Niwa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uemura
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
mesh_terms: D048948:14-3-3 Proteins; D008841:Actin Cytoskeleton / Q000378:metabolism; D051339:Actin Depolymerizing Factors; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D011554:Pseudopodia / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; D051339:Actin Depolymerizing Factors; D008840:Microfilament Proteins; D020890:Neuregulin-1; D014446:Tyrosine 3-Monooxygenase; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human