Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide.

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family that is involved in the regulation of the cell cycle. As their name suggests, the Cdks require association with activator proteins called cyclins for their activity. Cdk5, however, is unique to this family of proline-directed serine/threonine kinases on two accounts. Firstly, Cdk5 has not been found to function in the cell cycle and, although expressed in a number of tissues, its activity is restricted to the nervous system. Secondly, unlike the other members of the Cdk family, Cdk5 is not activated by association with a cyclin, although it can bind them. Instead, Cdk5 is activated by the activator proteins p35 and p39 that are structurally distinct from cyclins and have, for the most part, a neuronal-specific expression pattern. In the past decade of research on Cdk5, it is now established that Cdk5 activity is critical for the proper formation and function of the brain. Moreover, its role as a central kinase, phosphorylating its substrates in its 'cross-talk' control of other kinase and signal transduction pathways, has also been determined. In addition to the normal physiological role of Cdk5, the kinase has been implicated in certain neurodegenerative disorders. For example, Cdk5 associates with the proteolytic, more active p25 fragment that is derived through the cleavage of p35. In turn, the p25/Cdk5 complex aberrantly phosphorylates its substrates tau and neurofilaments, which has been implicated in the pathogenesis of these disorders. Here, we attempt to review the past decade of research on Cdk5 from our laboratory and others, on the roles of Cdk5 in nervous system function. Additionally, our research has recently uncovered a possible therapeutic avenue of research, focusing on inhibition of aberrant Cdk5 hyperactivity which may well be used to treat the symptoms of a number of neurodegenerative diseases. The elucidation of a specific inhibitor of p25/Cdk5, termed CIP, also inhibits p25/Cdk5-mediated tau phosphorylation. This may well provide us with avenues of research focusing on the inhibition of pathologically damaging p25/Cdk5 species.