Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases which regulate post-mitotic processes such as neuronal activity, neuronal migration during development, and neurite outgrowth. Activation of CDK5 requires its association with a regulatory subunit p35/CDK5R1. p35 is a short-lived protein, and its phosphorylation by CDK5 targets it for ubiquitin-mediated proteolysis. Calpain1 also directly cleaves p35 to release a 25 kD protein product, which causes prolonged activation and mislocalization of CDK5 and hyperphosphorylation of Tau (a neuron-specific MAP), leading to the formation of paired helical filaments and apoptosis. Post-translational modifications, such as phosphorylation by c-Abl (through an Abl-binding adaptor protein called Cables), regulate CDK5 kinase activity...