Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3

• Published in: The EMBO journal Vol. 21; no. 3; pp. 324 - 333
• Main Authors: Li, Bing-Sheng, Zhang, Lei, Takahashi, Satoru, Ma, Wu, Jaffe, Howard, Kulkarni, Ashok B., Pant, Harish C.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.02.2002; Blackwell Publishing Ltd; Oxford University Press
• Subjects: Animals; apoptosis; Apoptosis - physiology; c-Jun; c-Jun amino-terminal kinase 3; Catalysis; cdk5; Cells, Cultured; Cerebral Cortex - pathology; Cerebral Cortex - physiology; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - physiology; Gene Deletion; Irradiation; JNK; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 10; Mitogen-Activated Protein Kinases - physiology; Nerve Tissue Proteins - physiology; Neurons - pathology; Neurons - physiology; Phosphorylation; Protein-Tyrosine Kinases - physiology; Signal Transduction; stress-activated protein kinase; Ultraviolet radiation
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1093/emboj/21.3.324

Cyclin‐dependent kinase 5 (cdk5) is a serine/threonine kinase activated by associating with its neuron‐specific activators p35 and p39. Analysis of cdk5−/− and p35−/− mice has demonstrated that both cdk5 and p35 are essential for neuronal migration, axon pathfinding and the laminar configuration of the cerebral cortex, suggesting that the cdk5–p35 complex may play a role in neuron survival. However, the targets of cdk5 that regulate neuron survival are unknown. Here, we show that cdk5 directly phosphorylates c‐Jun N‐terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c‐Jun phosphorylation. Expression of cdk5 and p35 in HEK293T cells inhibits c‐Jun phosphorylation induced by UV irradiation. These effects can be restored by expression of a catalytically inactive mutant form of cdk5. Moreover, cdk5‐deficient cultured cortical neurons exhibit increased sensitivity to apoptotic stimuli, as well as elevated JNK3 activity and c‐Jun phosphorylation. Taken together, these findings show that cdk5 may exert its role as a key element by negatively regulating the c‐Jun N‐terminal kinase/stress‐activated protein kinase signaling pathway during neuronal apoptosis.