Harrington Anthony W, Kim Ju Young, Yoon Sung Ok
Neurobiotech Center and Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
J Neurosci. 2002 Jan 1;22(1):156-66. doi: 10.1523/JNEUROSCI.22-01-00156.2002.
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.
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大多仍不清楚。在此,我们报告p75激活Rac GTP酶,进而以神经生长因子(NGF)依赖的方式激活c-jun氨基末端激酶(JNK),包括损伤特异性的JNK3。N17Rac可阻断这种JNK激活及随后的NGF依赖的细胞凋亡,表明Rac GTP酶的激活是p75诱导JNK激活和细胞凋亡所必需的。此外,p75介导的Rac激活受Trk共激活的调节,这表明Rac GTP酶是神经营养因子信号传导中其活性对细胞存活和死亡至关重要的关键分子之一。通过JNK途径阻断p75信号传导或抑制JNK活性本身导致NGF依赖的死亡受到抑制,这一结果进一步证实了JNK途径在p75信号传导中的关键作用。总之,这些结果表明p75的凋亡机制包括Rac GTP酶和JNK。