Kinase-Kinase Interaction and Modulation of Tau Phosphorylation

The microtubule (MT)-associated protein tau attaches to neuronal MT networks and regulates their integrity. The phosphorylation state of tau alters its binding activity. MT integrity is maintained by the phosphorylation state of tau, which is under the control of the kinase-phosphatase balance. This control requires the proper regulation of topographical and temporal characteristics of tau kinases and phosphatases. The tau phosphorylation protein complex (TPPC) anchors tau kinases and phosphatases via scaffold proteins, tau effectors, and tau itself. Targeting these proteins in TPPC fulfills the topographical requirements for maintaining MT functions. The switching of tau kinase activity determines the order of the kinase action. The combined action of kinases is temporally modulated; reversal of the time order of events results in a differential state of tau phosphorylation. Elucidation of protein-protein interaction in the regulation of tau phosphorylation will shed light on the physiology and pathology of tau phosphorylation.