Calcium signal-induced cofilin dephosphorylation is mediated by Slingshot via calcineurin.
Cofilin, an essential regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 and reactivated by dephosphorylation. Although cofilin undergoes dephosphorylation in response to extracellular stimuli that elevate intracellular Ca2+ concentrations, signaling mechanisms mediating Ca2+-induced cofilin dephosphorylation have remained unknown. We investigated the role of Slingshot (SSH) 1L, a member of a SSH family of protein phosphatases, in mediating Ca2+-induced cofilin dephosphorylation. The Ca2+ ionophore A23187 and Ca2+-mobilizing agonists, ATP and histamine, induced SSH1L activation and cofilin dephosphorylation in cultured cells. A23187- or histamine-induced SSH1L activation and cofilin dephosphorylation were blocked by calcineurin inhibitors or a dominant-negative form of calcineurin, indicating that calcineurin mediates Ca2+-induced SSH1L activation and cofilin dephosphorylation. Importantly, knockdown of SSH1L expression by RNA interference abolished A23187- or calcineurin-induced cofilin dephosphorylation. Furthermore, calcineurin dephosphorylated SSH1L and increased the cofilin-phosphatase activity of SSH1L in cell-free assays. Based on these findings, we suggest that Ca2+-induced cofilin dephosphorylation is mediated by calcineurin-dependent activation of SSH1L.
Wang
Yan
Y
Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
Shibasaki
Futoshi
F
Mizuno
Kensaku
K
D051339:Actin Depolymerizing Factors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002474:Cell-Free System; D005799:Genes, Dominant; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008840:Microfilament Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors
D051339:Actin Depolymerizing Factors; D007476:Ionophores; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000001:Calcimycin; D006632:Histamine; D000255:Adenosine Triphosphate; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human; D002118:Calcium