Semaphorin 4D/Plexin-B1 Stimulates PTEN Activity through R-Ras GTPase-activating Protein Activity, Inducing Growth Cone Collapse in Hippocampal Neurons
Semaphorin 4D/Plexin-B1 Stimulates PTEN Activity through R-Ras GTPase-activating Protein Activity, Inducing Growth Cone Collapse in Hippocampal Neurons
复制标题
DOI：
10.1074/jbc.m110.147546
复制
发表时间：
2010-09-03
影响因子：
4.8
通讯作者：
Negishi, Manabu
中科院分区：
文献类型：
--
作者：
Oinuma, Izumi;Ito, Yuri;Negishi, Manabu
丛蛋白是轴突引导分子信号素的受体。我们最近报道了信号素4D （Sema4D）受体Plexin-B1通过R-Ras gtpase激活蛋白（GAP）活性抑制PI3K信号，诱导生长锥塌陷。磷脂酰肌醇3-磷酸水平受PI3K和PTEN（磷酸酶和紧张素同源物缺失的第10染色体）的关键调控。在这里，我们研究了PTEN在丛蛋白b1诱导的排斥反应中的作用。已知PTEN Ser-380位点的磷酸化可抑制其磷酸酶活性。Sema4D诱导PTEN Ser-380位点去磷酸化，刺激海马神经元PTEN磷酸酶活性。敲低内源性PTEN抑制sema4d诱导的生长锥塌陷。磷酸化模拟PTEN突变体抑制sema4d诱导的生长锥塌陷，而磷酸化抗性PTEN突变体本身诱导生长锥塌陷。丛蛋白b1通过R-Ras GAP活性诱导PTEN去磷酸化，而R-Ras GAP活性本身就足以使PTEN去磷酸化和活化。我们还提出，sema4d诱导的PTEN去磷酸化和生长锥塌陷是通过抑制酪蛋白激酶2 α活性介导的。因此，我们提出Sema4D/Plexin-B1通过R-Ras GAP活性促进PTEN的去磷酸化和激活，从而诱导生长锥塌陷。
Plexins are receptors for axonal guidance molecules semaphorins. We recently reported that the semaphorin 4D (Sema4D) receptor, Plexin-B1, suppresses PI3K signaling through the R-Ras GTPase-activating protein (GAP) activity, inducing growth cone collapse. Phosphatidylinositol 3-phosphate level is critically regulated by PI3K and PTEN (phosphatase and tensin homologue deleted chromosome ten). Here we examined the involvement of PTEN in the Plexin-B1-induced repulsive response. Phosphorylation of PTEN at Ser-380 is known to suppress its phosphatase activity. Sema4D induced the dephosphorylation of PTEN at Ser-380 and stimulated PTEN phosphatase activity in hippocampal neurons. Knockdown of endogenous PTEN suppressed the Sema4D-induced growth cone collapse. Phosphorylation mimic PTEN mutant suppressed the Sema4D-induced growth cone collapse, whereas phosphorylation-resistant PTEN mutant by itself induced growth cone collapse. Plexin-B1-induced PTEN dephosphorylation through R-Ras GAP activity and R-Ras GAP activity was by itself sufficient for PTEN dephosphorylation and activation. We also suggested that the Sema4D-induced PTEN dephosphorylation and growth cone collapse were mediated by the inhibition of casein kinase 2 alpha activity. Thus, we propose that Sema4D/Plexin-B1 promotes the dephosphorylation and activation of PTEN through the R-Ras GAP activity, inducing growth cone collapse.