CDK5: A new lead to survival

The protein kinase CDK5 was originally discovered at a time when cyclin-dependent kinases were thought to be involved exclusively in cell cycle control. The CDK5 catalytic subunit was first identified based on its nucleotide sequence homology to other known CDK family members (cdc2, CDK2), while the enzyme activity was identified by protein purification of a tau kinase relevant to Alzheimer disease and, independently, of a novel kinase exhibiting cdc2-like substrate specificity in brain. These activities were referred to as tau kinase II and brain proline-directed kinase, respectively, which, upon purification were shown to be one and the same enzyme. In addition to isolation of the active form of CDK5, purification revealed a bound p25 regulatory subunit of novel sequence, and molecular cloning revealed the full-length precursor of this subunit, p35. CDK5 has since garnered much attention because of its uniqueness as a CDK in three ways: (1) its association with the non-cyclin-like regulatory subunits p35 and p39; (2) its novel role as a cyclindependent kinase in non-dividing cells and (3) regulation by cleavage of p35 to p25 in vivo. In the first case, early work revealed that p25 displayed little to no homology with cyclins, yet structural analysis revealed that p25 adopted a cyclin-like fold capable of binding to and activating CDK5. Like cyclins, p25 was necessary for activation of the CDK5 catalytic subunit, resulting in virtually identical substrate sequence specificity to that of CDK1/cyclinB and CDK2/cyclinA. Identification of active CDK5/p25 in neurons explained the phosphorylation of neuronal proteins such as neurofilaments at CDK-specific sites, when conventional CDKs were absent from these cells. CDK5 A new lead to survival