CDK5 Pathway
Cyclin-dependent kinase-5 (Cdk5) regulates cell differentiation and morphology rather than cell division. Dysfunction of the cdk5 regulation has been linked to Alzheimer’s (AD) and Parkinson's disease (PD). Cdk5 (aka Tau protein kinase II catalytic subunit, TPKII catalytic subunit) is a serine-threonine kinase, expressed primarily in neural cells, that is activated by CDK5 activator proteins: cdk5-activator-1 (CDK5R1p35) (p35); its cleavage product (CDK5R1p25), (p25) and Cdk5-activator-2 (CDK5R2p39) (p39). Heterodimers of cdk5-p35 and cdk5-p39 represent normal physiological complexes in vivo. Whereas, the cdk5-p25 complex historically referred to as Nclk (cdk5-p25/35nck5a)) is a primary mediator of neurotoxicity related to AD and PD.
Alzheimer’s (AD) involves neuronal cell death, the formation of beta-amyloid plaques and neurofibrillary tangles. Parkinson's disease (PD) is characterized by loss of dopaminergic neurons. The p25 regulatory component of the Cdk5.p25 heterodimer (Nclk) has been linked to calcium-dependent cleavage of the p35 Cdk5 activator protein to a p25 protein by calpain. The Nclk form of Cdk5 is displaced from it normal physiological associations and longer acting than the cdk5-p35 heterodimer. Nclk actively hyperphosphoylates tau in neruofibrillary tangles (NFT) and disrupts cytoskeletal structure. PPI inhibitors I-1 and I-2 are phosphorylated and activated by the neuronal kinase, Nclk.
There are many substrates of Cdk-5 associated with its normal activators: p35 and p39. These include: dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP32), a dual-function protein that acts as an inhibitor of protein phosphatase-1 (PPtase-1) when phosphorylated by PKA or PKG and an inhibitor of PKA when phosphorylated by Cdlk5, p35; Rac1-PAK1; beta-catenine; Nudel, Munc18 and amphyphysin.
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References:
- Agarwal-Mawal, A. et. al. (2001) Neuronal Cdc2-like protein kinase (Cdk5/p25) is associated with protein phosphatase 1 and phosphorylates inhibitor-2. J. Biol. Chem. 276, 23712-23718.
- Ko, J. et. al. (2001) p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J. Neurosci. 21, 6758-6771.
- Monaco, E. A. 3rd. (2004) Recent evidence regarding a role for Cdk5 dysregulation in Alzheimer's disease. Curr. Alzheimer Res. 1, 33-38.
- Sobue, K. (2000) Interaction of neuronal Cdc2-like protein kinase with microtubule-associated protein tau. J. Biol. Chem. 275, 16673-16680.
- Svenningsson, P. et. al. (2004) DARPP-32: an integrator of neurotransmission. Annu. Rev, Pharmacol. Toxicol. 44, 269-296.
- Ko, J. et. al. (2001) p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J. Neurosci. 21, 6758-6771.
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Content for this page is provided by Dennis R. Conrad, Ph.D., a Life Science industry consultant with over 25 years of experience in the formulation and optimization of cell culture media. Dr. Conrad's email address is biomediaexpert@earthlink.net
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