A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia.
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.
Nagata-Ohashi
Kyoko
K
Dept. of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Ohta
Yusaku
Y
Goto
Kazumichi
K
Chiba
Shuhei
S
Mori
Reiko
R
Nishita
Michiru
M
Ohashi
Kazumasa
K
Kousaka
Kazuyoshi
K
Iwamatsu
Akihiro
A
Niwa
Ryusuke
R
Uemura
Tadashi
T
Mizuno
Kensaku
K
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
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