Cyclin-dependent kinase 5 (Cdk5) is predominantly expressed in the nervous system. Though it is expressed in non- neuronal cell and binds with cyclins but its activity is predominantly found in post mitotic neurons due to its binding to neuron specific molecules P35 and P39. It is involved in neuronal migration, synaptic transmission, and survival.Cdk5,a multifunctional neuronal kinase (targeting proteins from neuronal differentiation to synaptic function), is tightly regulated when complexed with p35, its co-activator. It is one of several kinases that phosphorylate neurofilaments and tau. Its diverse roles stem, in part, from its cross-talk interactions with other kinases in signal transduction networks underlying neuronal cell survival, growth and differentiation. We have shown, for example, that Cdk5 down regulates MAPKs and JNKs and up regulates PI3Ks. These results suggest that Cdk5 normally modulates the intensity of response of other kinases to specific signals underlying neuronal survival. The role of Cdk5 in synaptic transmission is mediated by regulating the cellular functions of presynaptic proteins such as synapsin, Munc18, and dynamin 1. Its multifunctional role at the synapse is complex and probably involves other novel substrates. To explore this possibility, we used a yeast two-hybrid screen of a human cDNA library with p35 as bait and isolated human septin 5 (SEPT5), known also as hCDCrel-1, as an interacting clone. Both,Cdk5 and its activator, p35 associates with SEPT5 in GST (glutathione S-transferase)-pull-down and coimmunoprecipitation assays. We confirmed that Cdk5/p35 phosphorylates SEPT5 in vitro and in vivo and identified S327 of SEPT5 as a major phosphorylation site. A serine (S)-to-alanine (A) 327 mutant of SEPT5 bound syntaxin more efficiently than SEPT5 wild type. Additionally, coimmunoprecipitation from synaptic vesicle fractions and Cdk5 wild-type and knock-out lysates showed that phosphorylation of septin 5 by Cdk5/p35 decreases its binding to syntaxin-1. Moreover, mutant nonphosphorylated SEPT5 potentiated regulated exocytosis more than the wild type when each was expressed in PC12 cells. These data suggest that Cdk5 phosphorylation of human septin SEPT5 at S327 plays a role in modulating exocytotic secretion. When deregulated, however, in stressed neurons, the p35 activator is cleaved by proteases to a truncated fragment, p25, that binds and hyperactivates Cdk5;this abnormal Cdk5/p25 complex contributes to the pathology seen in several neurodegenerative diseases. Most therapeutic approaches targeting the deregulated hyperactive Cdk5/p25 complex, as well as other kinases implicated in neurodegenerative pathology, inhibit activity by interfering with the kinase ATP binding domain. Many drugs like roscovitine, which binds to the Cdk5 ATP site, have been evaluated but lack the specificity required since most cdk kinases (and most kinases) are vulnerable at the ATP binding site. Our study of site specific interactions between Cdk5 and truncated forms of its p35 regulator have revealed a central fragment, 125 amino acids residues (CIP) that has high affinity for and inhibits the in vitro and in situ activity of the Cdk5/p25 complex. We have shown that CIP specifically inhibits Cdk5/p25 (deregulated) activity in transfected cells and also reduces the aberrant and hyperphosphorylation of tau and neurofilament proteins in stressed neurons. It is important to note that CIP does not affect the activity of regulated Cdk5 ( Cdk5/P35). Recently, we have found a much smaller truncated peptide of 24 amino acids derived from p35 that also specifically inhibits Cdk5-deregulated activity. This may provide a possible new and novel therapeutic route for intervention to prevent or reduce the neurodegenerative pathology induced by Cdk5 deregulation. Recently p35 expression and cdk5 activity have been reported in pancreatic beta cells. Chronic exposure to gllucose, as in hyperglycemia, results in hyperactivity of Cdk5 and reduced insulin secretion. Inhibition of Cdk5 activity increases insulin secretion under conditions of high but not low glucose. These studies suggest that inhibition of cdk5/p35 activity may overcome the risks of hypoglycemic episodes induced by the therapeutic use of sulfonylurea for type 2 diabetes. In amyloid stressed neurons we found that p25, a truncated fragment of p35, accumulates and hyperactivates cdk5 and induces apoptosis. Similarly, amyloid deposition within the insulin producing islets of Langerhans in the pancreas, is also pathological. Accordingly, in a recent study we demonstrated that abnormal upregulation of p25 and cdk5/p25 activity induced in a pancreatic beta cell line, resulted in 70% inhibition of insulin secretion in low and high glucose. We also showed that CIP, which inhibits Cdk5/ p25 activity without affecting Cdk5/p35 activity in neurons also inhibited Cdk5/p25 activity in MIN 6 pancreatic cells and in turn, increased insulin secretion. Significantly, as in neurons, CIP had no effect on endogenous Cdk5/p35 activity and insulin secretion. Co-infection of dominant negative Cdk5 (DNCdk5) with p35 or p25 inhibited aberrant activation of Cdk5 activity and insulin secretion levels were increased. These studies indicate that over-activation of Cdk5 deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes. Our results are consistent with the view that AD and type 2 diabetes mellitus (T2DM) are linked metabolically and pathologically in a number of ways. They share such abnormalities as impaired glucose metabolism, increased oxidative stress, amyloid deposition and insulin resistance. The deposition of amyloid within the insulin-producing islets of Langerhans in the pancreas is a common pathological finding in patients with T2DM. Moreover, it has been demonstrated that T2DM is associated with an increased risk of cognitive dysfunction and dementia. Our results, however. go much further in establishing the similarity between neuron and insulin secreting beta cells;they show that deregulation of cdk5 in pancreatic cells follows the pattern of cdk5 deregulation in neurodegenerative disorders and in both cases CIP effectively prevents the pathology and promotes cell survival. These dramatic results are consistent with the suggestion that cdk5 may be a therapeutic target for the treatment of diabetes mellitus and certain neurodegenerative disorders in which cdk5 is deregulated.