As an important kinase, CDK5 requires other proteins to activate its kinase activity. Several CDK5 activators have been identified, including p35, p39, and CCN. CDK5 is a widely expressed protein. As a proline-directed serine/threonine kinase, CDK5 is known to phosphorylate a number of cytoskeletal proteins (e.g., MAP1b, tau, neurofilament, nestin, DCX, CRMP2), synaptic proteins (e.g., PSD95, synapsin-I, E-cadherin), and transcription factors (MEF2) in postmitotic neurons (9, 10); its two activator proteins are p35 and p39. p35 and p39 resemble cyclins in their 3D structures and are almost exclusively detected in the nervous system; this restricts CDK5 activity largely to brain . CDK5 plays a pivotal role in neuronal development where its activity is required for normal neuronal migration and differentiation. CDK5 also contributes to neuronal health and survival after the developmental period has ended. Cdk5-deficient neurons are more vulnerable than wild-type cells to Aβ toxicity in culture , more sensitive to DNA-damaging agents (14), and more susceptible to excitotoxic death (15). Our team has also recently reported that cytoplasmic CDK5 can attenuate Aβ-activated cell death (16). Though clearly a positive influence on neurons in many different situations, the full picture of CDK5 action is more complicated because dysregulated CDK5 activity is also believed to contribute to neuronal death. When internal calcium concentrations rise, the calcium-dependent protease calpain is activated, resulting in the cleavage of p35 into p25. Although the levels of p25 are generally low in tissues, interaction with p25 has been reported to promote CDK5 stability and enhance its kinase activity
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