Sema4D/plexin-B1 activates GSK-3β through R-Ras GAP activity, inducing growth cone collapse
Sema4D/plexin-B1 activates GSK-3β through R-Ras GAP activity, inducing growth cone collapse
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DOI：
10.1038/sj.embor.7400737
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发表时间：
2006-07-01
期刊：
影响因子：
7.7
通讯作者：
Negishi, Manabu
中科院分区：
文献类型：
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作者：
Ito, Yuri;Oinuma, Izumi;Negishi, Manabu
丛蛋白是称为信号素的轴突导向分子的受体，而信号素4D(Sema4D)受体Plexin-B1通过作为R-RAS GTP酶激活蛋白(GAP)来诱导排斥反应。在这里，我们描述了Plexin-B1介导的R-RAS间隙活性的下游信号，导致生长锥崩溃。Sema4D抑制海马神经元R-RAS活性，同时伴有Akt的去磷酸化和糖原合成酶-3β的激活。Akt组分活性突变体的异位表达或GSK-3抑制剂处理抑制了Sema4D诱导的生长锥体塌陷。Akt和GSK-3β上游的磷脂酰肌醇-3-羟基激酶(PI(3)K)的结构性激活也阻止了生长锥的塌陷。R-RAS GAP活性是Plexin-B1诱导Akt去磷酸化和GSK-3β激活所必需的，也是GSK-3β下游激酶-崩塌反应介体蛋白-2磷酸化所必需的。Plexin-A1还通过其R-RAS GAP活性诱导Akt和GSK-3β的去磷酸化。我们的结论是，Plexin-B1通过R-RAS GAP活性使PI(3)K失活，并使Akt和GSK-3β去磷酸化，导致生长锥塌陷。
Plexins are receptors for the axonal guidance molecules known as semaphorins, and the semaphorin 4D (Sema4D) receptor plexin-B1 induces repulsive responses by functioning as an R-Ras GTPase-activating protein (GAP). Here we characterized the downstream signalling of plexin-B1-mediated R-Ras GAP activity, inducing growth cone collapse. Sema4D suppressed R-Ras activity in hippocampal neurons, in parallel with dephosphorylation of Akt and activation of glycogen synthase kinase (GSK)-3 beta. Ectopic expression of the constitutively active mutant of Akt or treatment with GSK-3 inhibitors suppressed the Sema4D-induced growth cone collapse. Constitutive activation of phosphatidyl-inositol-3-OH kinase (PI(3)K), an upstream kinase of Akt and GSK-3 beta, also blocked the growth cone collapse. The R-Ras GAP activity was necessary for plexin-B1-induced dephosphorylation of Akt and activation of GSK-3 beta and was also required for phosphorylation of a downstream kinase of GSK-3 beta, collapsin response mediator protein-2. Plexin-A1 also induced dephosphorylation of Akt and GSK-3 beta through its R-Ras GAP activity. We conclude that plexin-B1 inactivates PI(3) K and dephosphorylates Akt and GSK-3 beta through R-Ras GAP activity, inducing growth cone collapse.