Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis
Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis
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DOI：
10.1523/jneurosci.22-01-00156.2002
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Yoon, SO
中科院分区：
文献类型：
--
作者：
Harrington, AW;Kim, JY;Yoon, SO
神经营养因子受体p75在体外和体内均可诱导细胞凋亡。p75诱导细胞凋亡的机制仍不清楚。在这里，我们报道p75激活Rac GTPase，而Rac GTPase又以ngf依赖的方式激活c-jun n -末端激酶（JNK），包括损伤特异性JNK3。N17Rac阻断了JNK的激活和随后的ngf依赖性凋亡，表明Rac GTPase的激活是JNK激活和p75诱导的凋亡所必需的。此外，p75介导的Rac激活可通过Trk的协同激活来调节，这表明Rac GTPase是神经营养因子信号传导中对细胞存活和死亡至关重要的关键分子之一。JNK通路在p75信号传导中的关键作用进一步得到证实，通过JNK通路阻断p75信号传导或抑制JNK活性本身可抑制ngf依赖性死亡。总之，这些结果表明p75的凋亡机制包括Rac GTPase和JNK。
The neurotrophin receptor p75 can induce apoptosis both in vitro and in vivo. The mechanisms by which p75 induces apoptosis have remained mostly unknown. Here, we report that p75 activates Rac GTPase, which in turn activates c-jun N-terminal kinase (JNK), including an injury-specific JNK3, in an NGF-dependent manner. N17Rac blocks this JNK activation and subsequent NGF-dependent apoptosis, indicating that activation of Rac GTPase is required for JNK activation and apoptosis induced by p75. In addition, p75-mediated Rac activation is modulated by coactivation of Trk, identifying Rac GTPase as one of the key molecules whose activity is critical for cell survival and death in neurotrophin signaling. The crucial role of the JNK pathway in p75 signaling is further confirmed by the results that blocking p75 from signaling via the JNK pathway or suppressing the JNK activity itself led to inhibition of NGF-dependent death. Together, these results indicate that the apoptotic machinery of p75 comprises Rac GTPase and JNK.