K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK
K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK
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DOI：
10.1074/jbc.m203428200
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发表时间：
2002-12-20
影响因子：
4.8
通讯作者：
Barker, PA
中科院分区：
文献类型：
--
作者：
Roux, PP;Dorval, G;Barker, PA
K252 a最为人所知的是Trk抑制剂，但也是一种神经保护化合物。CEP 1347是一种K252 a衍生物，保留了神经保护特性，但不抑制TrkA。CEP 1347最近已显示直接抑制NLAPKKK，包括MLK 3，但K252 a对MAPKY.Ks的作用仍不清楚。K252 a和CEP 1347不仅可以防止死亡，而且还可以促进神经突的生长和维持、体细胞肥大和神经递质的合成。这些营养效应的生物化学基础仍然未知。我们比较了CEP 1347和K252 a对MLK和JNK信号传导以及支持存活和生长的神经营养途径的影响。我们的数据表明，K252 a是体内和体外MLK 3活性的有效抑制剂（IC 50类似于5 nm）。然而，我们还发现K252 a和CEP 1347激活Akt和ERK，并显示阻断磷脂酰肌醇3-激酶或MEK活性消除了K252 a和CEP 1347对细胞存活的影响。Akt和ERK的激活通过可能涉及c-Src的MLK非依赖性途径发生。总之，这些数据表明K252 a和CEP 1347的神经保护和神经营养作用涉及几种神经营养信号通路的激活。
K252a is best known as a Trk inhibitor, but is also a neuroprotective compound. CEP1347, a K252a derivative, retains neuroprotective properties, but does not inhibit TrkA. CEP1347 has recently been shown to directly inhibit NLAPKKKs, including MLK3, but the effect of K252a on MAPKY.Ks remains unknown. K252a and CEP1347 not only prevent death, but also facilitate neurite outgrowth and maintenance, somal hypertrophy, and neurotransmitter synthesis. The biochemical basis for these trophic effects remains unknown. We have compared the effects of CEP1347 and K252a on MLK and JNK signaling and on neurotrophic pathways that support survival and growth. Our data show that K252a is a potent inhibitor of MLK3 activity in vivo and in vitro (IC50 similar to 5 nm). However, we also found that K252a and CEP1347 activate Akt and ERK and show that blockade of phosphatidylinositol 3-kinase or MEK activity ablates the effect of K252a and CEP1347 on cell survival. Activation of Akt and ERK occurs through an MLK-independent pathway that may involve c-Src. Together, these data show that the neuroprotective and neurotrophic effects of K252a and CEP1347 involve activation of several neurotrophic signaling pathways.