The protein kinase Cdk5 - Structural aspects, roles in neurogenesis and involvement in Alzheimer's pathology

A set of different protein kinases have been involved in tau phosphorylatio ns, including glycogen synthase kinase 3 beta (GSK3 beta), MARK kinase, MAP kinase, the cyclin-dependent kinase 5 (Cdk5) system and others. The latter system include the catalytic component Cdk5 and the regulatory proteins p3 5, p25 and p39. Cdk5 and its neuron-specific activator p35 are essential mo lecules for neuronal migration and for the laminar configuration of the cer ebral cortex. Recent evidence that the Cdk5/p35 complex concentrates at the leading edge of axonal growth cones, together with the involvement of this system in the phosphorylation of neuronal microtubule-asociated proteins ( MAPs), provide further support to the role of this protein kinase in regula ting axonal extension in developing brain neurons. Although the aminoacid s equence of p35 has little similarity with those of normal cyclins, studies have shown that its activation domain may adopt a conformation of the cycli n-folded structure. The computed structure for Cdk5 is compatible with expe rimental data obtained from studies on the Cdk5/p35 complex, and has allowe d predictions on the protein interacting domains. This enzyme exhibits a wi de cell distribution, even though a regulated Cdk5 activity has been shown only in neuronal cells. Cdk5 has been characterized as a proline-directed S er/Thr protein kinase, that contributes to phosphorylation of human tau on Ser202, Thr205, Ser235 (and) Ser404. Cdk5 is active in postmitiotic neurons , and it has been implicated in cytoskeleton assembly and its organization during axonal growth. In addition to tau and other MAPs, Cdk5 phosphorylate s the high molecular weight neurofilament proteins at their C-terminal doma in. Moreover, nestin, a protein that regulates cytoskeleton organization of neuronal and muscular cells during development of early embryos, and sever al other regulatory proteins appear to be substrates of Cdk5 and are phosph orylated by this kinase. Studies also suggest, that in addition to Cdk5 inv olvement in neuronal differentiation, its activity is induced during myogen esis, however, the mechanisms of how this activity is regulated during musc ular differentiation has not yet been elucidated. Recent studies have shown that the beta -amyloid peptide (A beta) induces a deregulation of Cdk5 in cultured brain cells, and raises the question on the possible roles of this tau-phosphorylating protein kinase in the sequence of molecular events lea ding to neuronal death triggered by A beta. In this context, there are evid ence that Cdk5 is involved in tau hyperphosphorylation promoted by A beta i n its fibrillary form. Cdk5 inhibitors protect hippocampal neurons against both tau anomalous phosphorylations and neuronal death. The links between t he studies on the Cdk5/p35 system in normal neurogenesis and its claimed pa rticipation in neurodegeneration, provide the framework to understand the r egulatory relevance of this kinase system, and changes in its regulation th at may be implicated in disturbances such as those occurring in Alzheimer d isease.