Becker Esther B E, Bonni Azad
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell Cycle. 2007 Jun 1;6(11):1332-5. doi: 10.4161/cc.6.11.4316. Epub 2007 Jun 20.
While the role of the prolyl isomerase Pin1 in dividing cells has long been recognized, Pin1's function in postmitotic neurons is poorly understood. We have identified a novel mechanism by which Pin1 mediates activation of the mitochondrial cell death machinery specifically in neurons. This perspective presents a sophisticated signaling pathway that triggers neuronal apoptosis upon JNK-mediated phosphorylation of the BH3-only protein BIM(EL) at serine 65. Pin1 is enriched at the mitochondria in neurons together with BIM(EL) and components of a neuron-specific JNK signaling complex and functions as a molecular switch that couples the phosphorylation of BIM(EL) by JNK to apoptosis specifically in neurons. We discuss how these findings relate to our understanding of the development of the nervous system and the pathogenesis of neurologic disorders.
虽然脯氨酰异构酶Pin1在分裂细胞中的作用早已为人所知，但Pin1在有丝分裂后神经元中的功能却鲜为人知。我们发现了一种新机制，通过该机制Pin1特异性地在神经元中介导线粒体细胞死亡机制的激活。这一观点提出了一条复杂的信号通路，该通路在仅含BH3结构域的蛋白BIM(EL)丝氨酸65位点发生JNK介导的磷酸化后触发神经元凋亡。Pin1与BIM(EL)以及神经元特异性JNK信号复合体的组分一起在神经元的线粒体中富集，并作为一个分子开关，将JNK介导的BIM(EL)磷酸化与神经元特异性凋亡偶联起来。我们讨论了这些发现与我们对神经系统发育和神经疾病发病机制的理解有何关联。
