Pin1 in neuronal apoptosis.
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.
Becker
Esther B E
EB
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bonni
Azad
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D002451:Cell Compartmentation; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D009422:Nervous System Diseases / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C414604:PDZD2 protein, rat; D011518:Proto-Oncogene Proteins; D010768:Phosphoserine; D048031:JNK Mitogen-Activated Protein Kinases