Calcium signal-induced cofilin dephosphorylation is mediated by slingshot via calcineurin
Calcium signal-induced cofilin dephosphorylation is mediated by slingshot via calcineurin
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DOI：
10.1074/jbc.m411494200
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发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Mizuno, K
中科院分区：
文献类型：
--
作者：
Wang, Y;Shibasaki, F;Mizuno, K
Cofilin是肌动蛋白细丝动态的重要调节因子，通过Ser-3的磷酸化失活，并通过去磷酸化重新激活。虽然Cofilin在细胞外刺激引起细胞内钙离子浓度升高时发生去磷酸化，但其介导钙离子诱导的Cofilin去磷酸化的信号机制仍不清楚。我们研究了SSH蛋白磷酸酶家族成员Slingshot(SSH)1L在钙离子诱导的Cofilin去磷酸化中的作用。钙离子载体A23187和钙动员激动剂，三磷酸腺苷和组胺，在培养细胞中诱导SSH1L激活和cofilin去磷酸化。钙调神经磷酸酶抑制剂或显性负性钙调神经磷酸酶可阻断A23187或组胺诱导的SSH1L激活和钙调神经磷酸酶去磷酸化，表明钙调神经磷酸酶介导了钙离子诱导的SSH1L激活和钙调神经磷酸酶去磷酸化。重要的是，通过RNA干扰抑制SSH1L的表达可以消除A23187或钙调神经磷酸酶诱导的cofilin去磷酸化。此外，在无细胞实验中，钙调神经磷酸酶使SSH1L去磷酸化，并增加SSH1L的粘附素-磷酸酶活性。基于这些发现，我们认为钙离子诱导的cofilin去磷酸化是通过依赖钙调神经磷酸酶激活SSH1L来实现的。
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.