Interaction of neuronal Cdc2-like protein kinase with microtubule-associated protein tau

Neuronal Cdc2-like protein kinase (NCLK), a similar to 58-kDa heterodimer, was isolated from neuronal microtubules (Ishiguro, K., Takamatsu, M., Tomiz awa, K., Omori, A,, Takahashi, M., Arioka, M., Uchida, T. and Imahori, K. ( 1992) J. Biol. Chem. 267, 10897-10901). The biochemical nature of NCLK-micr otubule association is not known. In this study we found that NCLK is relea sed from microtubules upon microtubule disassembly as a 450-kDa species. Th e 450-kDa species is an NCLK tau complex, and NCLK-bound tau is in a nonpho sphorylated state. Tau phosphorylation causes NCLK tau complex dissociation , and phosphorylated tau does not bind to NCLK. In vitro, the Cdk5 subunit of NCLK binds to the microtubule-binding region of tau and NCLK associates with microtubules only in the presence of tau. Our data indicate that in br ain extract NCLK is complexed with tau in a tan phosphorylation-dependent m anner and that tau anchors NCLK to microtubules. Recently NCLK has been sug gested to be aberrantly activated and to hyperphosphorylate tau in Alzheime r's disease brain (Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P, and Tsai, L.-H. (1999) Nature 402, 615-622). Our findings m ay explain why in Alzheimer's disease NCLK specifically hyperphosphorylates tau, although this kinase has a number of protein substrates in the brain.