CDK5 (Cyclin-dependent Kinase 5)

Definition
Cyclin dependent kinase 5 (CDK5) is a unique member of cyclin dependent kinase family members that is not activated by a cyclin1. Instead it is activated by a kinase, p35. Unlike other CDKs, it plays a major role in cell cell communication, cell morphology and motility1.

Discovery
CDK5 originally named nclk1 was first identified in 1992 in a cDNA library screen of an adult rat brain using mouse cdk1 as a probe2.

Classification
CDK5 belongs to the highly conserved family of Ser/Thr protein kinases2.

Structural Characteristics
CDK5 consists of two lobes, a small N-terminal lobe that binds to cyclin and a large lobe at the C terminus that binds to the substrate3. The ATP binding domain is located in the cleft between the two lobes3. Ser159 in CDK5 is known to be important for its interaction with p353.

Mode of action
CDK5 is abundant in post mitotic neurons4. CDK5 first binds to its regulatory proteins p35/p25/p39 which then triggers its phosphorylation and activation4. Activated CDK5 phosphorylates several proteins in the cell to exert its functions4. The activity of CDK5 is regulated by p35 4.

Functions
CDK5 is important in several aspects of neuronal development3. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases4. CDK5 is also involved in the regulation of exo and endocytosis of synaptic vesicles4. It modulates signal transduction pathways regulating neuronal survival4. CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death5.

References
1.Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH (1992). A family of human cdc2-related protein kinases. Embo J. 11 (8), 2909–17.
2.Hellmich MR, Pant HC, Wada E, Battey JF (1992). Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci, 89(22), 10867-71.
3.Book: Cyclin Dependent Kinase 5 (CDK5), edited by Nancy Y and Tsai LH, 191-211.
4.Maccioni RB, Otth C, Concha II, Muñoz JP (2001). The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer's pathology. Eur J Biochem, 268(6), 1518-27.
5.Dhariwala FA, Rajadhyaksha MS (2008). An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol, 28(3), 351-69.