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J. Biol. Chem., Vol. 276, Issue 13, 10025-10031, March 30, 2001

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Phosphorylation of Tau Is Regulated by PKN^*

Taizo Taniguchi^§, Toshio Kawamata, Hideyuki Mukai^¶, Hiroshi Hasegawa, Takayuki Isagawa^¶, Minoru Yasuda, Takeshi Hashimoto, Akira Terashima, Masamichi Nakai, Yoshitaka Ono^¶, and Chikako Tanaka

From the  Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji 670-0981 and ^¶ Graduate School of Science, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan

For the phosphorylation state of microtubule-associated protein, tau plays a pivotal role in regulating microtubule networks in neurons. Tau promotes the assembly and stabilization of microtubules. The potential for tau to bind to microtubules is down-regulated after local phosphorylation. When we investigated the effects of PKN activation on tau phosphorylation, we found that PKN triggers disruption of the microtubule array both in vitro and in vivo and predominantly phosphorylates tau in microtubule binding domains (MBDs). PKN has a catalytic domain highly homologous to protein kinase C (PKC), a kinase that phosphorylates Ser-313 (= Ser-324, the number used in this study) in MBDs. Thus, we identified the phosphorylation sites of PKN and PKC subtypes (PKC-, -I, -II, -, -, -, -, and -) in MBDs. PKN phosphorylates Ser-258, Ser-320, and Ser-352, although all PKC subtypes phosphorylate Ser-258, Ser-293, Ser-324, and Ser-352. There is a PKN-specific phosphorylation site, Ser-320, in MBDs. HIA3, a novel phosphorylation-dependent antibody recognizing phosphorylated tau at Ser-320, showed immunoreactivity in Chinese hamster ovary cells expressing tau and the active form of PKN, but not in Chinese hamster ovary cells expressing tau and the inactive form of PKN. The immunoreactivity for phosphorylated tau at Ser-320 increased in the presence of a phosphatase inhibitor, FK506 treatment, which means that calcineurin (protein phosphatase 2B) may be involved in dephosphorylating tau at Ser-320 site. We also noted that PKN reduces the phosphorylation recognized by the phosphorylation-dependent antibodies AT8, AT180, and AT270 in vivo. Thus PKN serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly.

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