Fig. 1

The regulatory mechanism of Cdk5 in neurons. Cdk5 itself does not own an enzymatic activity. Physiologically Cdk5 is activated by binding with p35 and the complex of Cdk5/p35 is concomitantly recruited to membrane via the myristoylation of p35. p35 is a short-lived protein which is soon degraded by proteasome, resulting in transient activation of Cdk5. When cell faces cell death signals, the NMDAR on cellular membrane is activated and membrane permeability to calcium is increased, leading to activation of calpain protein. Activated Calpain cleaves p35 into p25 fragment, a much more stable protein than p35, resulting in translocation of Cdk5/p25 complex into nucleus and prolonged activation of Cdk5, which induces pathological signaling pathways of cell death