Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3.
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.
Li
Bing-Sheng
BS
Laboratory of Neurochemistry, NINDS, NIH, Bethesda, MD 20892-4130, USA.
Zhang
Lei
L
Takahashi
Satoru
S
Ma
Wu
W
Jaffe
Howard
H
Kulkarni
Ashok B
AB
Pant
Harish C
HC
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002384:Catalysis; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D009474:Neurons / Q000473:pathology* / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction
C108298:Cdk5 activator p39; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases