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p21-Activated Kinase 5 (Pak5) Localizes to Mitochondria and Inhibits Apoptosis by Phosphorylating BAD

机译:p21激活的激酶5(Pak5)定位于线粒体并通过磷酸化BAD抑制细胞凋亡

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Pak5 is the most recently identified and least understood member of the p21-activated kinase (Pak) family. This kinase is known to promote neurite outgrowth in vitro, but its localization, substrates, and effects on cell survival have not been reported. We show here that Pak5 has unique properties that distinguish it from all other members of the Pak family. First, Pak5, unlike Pak1, cannot complement an STE20 mutation in Saccharomyces cerevisiae. Second, Pak5 binds to the GTPases Cdc42 and Rac, but these GTPases do not regulate Pak5 kinase activity, which is constitutive and stronger than any other Pak. Third, Pak5 prevents apoptosis induced by camptothecin and C2-ceramide by phosphorylating BAD on Ser-112 in a protein kinase A-independent manner and prevents the localization of BAD to mitochondria, thereby inhibiting the apoptotic cascade that leads to apoptosis. Finally, we show that Pak5 itself is constitutively localized to mitochondria, and that this localization is independent of kinase activity or Cdc42 binding. These features make Pak5 unique among the Pak family and suggest that it plays an important role in apoptosis through BAD phosphorylation.
机译:Pak5是p21激活激酶(Pak)家族中最近被鉴定和了解最少的成员。已知该激酶可在体外促进神经突生长,但尚未报道其定位,底物和对细胞存活的影响。我们在这里显示Pak5具有独特的属性,使其区别于Pak家族的所有其他成员。首先, Pak5 Pak1 不同,它不能补充 Saccharomyces cerevisiae 中的 STE20 突变。其次,Pak5与GTPases Cdc42和Rac结合,但是这些GTPases不调节Pak5激酶的活性,该活性比其他任何Pak都强而有力。第三,Pak5通过以不依赖蛋白激酶A的方式磷酸化Ser-112上的BAD来防止喜树碱和C2-神经酰胺诱导的凋亡,并阻止BAD定位于线粒体,从而抑制导致凋亡的凋亡级联反应。最后,我们显示Pak5本身在结构上定位于线粒体,并且该定位独立于激酶活性或Cdc42结合。这些特征使Pak5在Pak家族中独树一帜,表明它在通过BAD磷酸化引起的细胞凋亡中起着重要作用。

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