Phosphorylation of human tau protein by microtubule-associated kinases: GSK3 beta and cdk5 are key participants

Microtubules (MTs), primarily composed of alpha and beta tubulin polymers, must often work in concert with microtubule-associated proteins (MAPs) in o rder to modulate their functional demands. In a mature brain neuron, one of the key MAPs that resides primarily in the axonal compartment is the tau p rotein. Tau, in the adult human brain, is a set of six protein isoforms, wh ose binding affinity to MTs can be modulated by phosphorylation. In additio n to the role that phosphorylation of tau plays in the "normal" physiology of neurons, hyperphosphorylated tau is the primary component of the fibrill ary pathology in Alzheimer's disease (AD). Although many protein kinases ar e known to phosphorylate tau in vitro, the in vivo players contributing to the hyperphosphorylation of tau remain elusive. The experiments in this stu dy attempt to define which protein kinases and protein phosphatases reside in the associated network of microtubules, thereby being strategically posi tioned to influence the phosphorylation of tau. Microtubule fractions are u tilized to determine which of the microtubule-associated kinases most readi ly impacts the phosphorylation of tau at "AD-like" sites. Results from this study indicate that PKA, CK1, GSK3 beta, and cdk5 associate with microtubu les. Among the MT-associated kinases, GSK3 beta and cdk5 most readily contr ibute to the ATP-induced "AD-like" phosphorylation of tau. J. Neurosci. Res . 62:. 463-472, 2000. (C) 2000 Wiley-Liss, Inc.