Neuronal Cyclin-dependent Kinase 5(cdk5) and Its Specific Inhibitor (cip): Its Physiological and Pathological Role in the Nervous System

Cdk5, a multifunctional kinase involved in a wide range of neuronal behavior, is regulated by its neuron-specific activators, p35 and p39. It is becoming clear that cdk5, like the MAP kinases, is a key player in signal transduction networks underlying neuronal cell survival, growth and differentiation. Our studies of cdk5 KO mice (-/-) have shown that they express a lethal phenotype with abnormal corticogenesis and embryonic death [1]. Recently, we have also demonstrated that reconstitution of cdk5 expression with a cdk5 transgene under a neuronal specific promoter of p35, completely rescued such null mice; a wild type phenotype was obtained. This clearly demonstrated that neuronal and not glial cdk5 activity is necessary and sufficient for normal development and survival [2]. The p35-/-mouse, which exhibits significant reduced cdk5 activity [3, 4], and a similar disruption of corticogenesis, is not lethal, but develops into a fertile adult with some behavioral abnormalities. However, the p35 and p39 double knockout mice show similar phynotypes as cdk5 [5]. Moreover, in the cdk5-/-mice, we observed the presence of hyperphosphorylated cytoskeletal proteins in swollen brain stem and spinal cord perikarya. This led us to look for other kinases affected by the absence of cdk5 in cdk5-/-mice [6]. Since cdk5 is down regulated in p35-/-mice, we used brain extracts from these mice and found that MAPK (Erk1/2) was hyperactivated. Indeed, we have shown that MEK1 is an in vitro and in vivo target for cdk5/p35 phosphorylation; MEK1 catalytic activity was inhibited by phosphorylation at a specific site, Thr 286. This down regulation of the MAP kinase pathway results sustained MAP (Erk1/2) kinase activity in NGF stimulated PC12. These results suggest that cdk5 is involved in 'cross talk' with other signal transduction and apoptotic pathways. Finally, in an effort to find the other cdk5 targets, we discovered that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on threonine 131 and inhibits its activity, leading to reduced c-jun phosphorylation [7]. In addition, other laboratories have shown that deregulation of cdk5 is involved in neurodegeneration (e.g. AD, ALS) [8-10]. Thus, cdk5 may turn out to function as the "Yin and Yang" in neuronal survival, exhibiting protective or destructive roles, depending on its mechanisms of 'cross talk' and regulation within the network of signal transduction pathways. Cdk5 activity is tightly regulated in the nervous system. Recent studies suggest that the deregulation, (hyperactivation) of cdk5 activity by p25, a proteolytic fragment of p35, …