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Zinc stimulates tau S214 phosphorylation by the activation of Raf/mitogen-activated protein kinase-kinase/extracellular signal-regulated kinase pathway

Kim, Insooka,c; Park, Eun Jia; Seo, Jehoa; Ko, Suk Jina; Lee, Jinud; Kim, Chul Hoona,b

doi: 10.1097/WNR.0b013e32834c0a2d

Hyperphosphorylated tau is a main component of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease (AD). There is evidence that various protein kinases are involved in tau hyperphosphorylation. However, little is known about AD-related stimuli that activates tau kinases. We investigated the role of zinc, a metal involved in AD pathology, in tau phosphorylation. Zinc increased the phosphorylation of serine 214 (S214) in tau protein in human wild-type tau1-441-expressing SH-SY5Y cells. The phosphorylation was inhibited by suppressing the Ras-Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway. Mutation of serine to alanine at residue 214 of tau reduced microtubule polymerization impairment by ERK phosphorylation. These data suggest that zinc induces S214 phosphorylation in tau through ERK activation and interferes with microtubule polymerization.

aDepartment of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science

bSeverance Biomedical Science Institute, Yonsei University College of Medicine, Seoul

cDivision of Metabolic Disease, Department of Biomedical Science, National Institutes of Health, Osong

dYonsei Institute of Pharmaceutical Sciences and College of Pharmacy, Yonsei University, Inchon, Korea

Correspondence to Chul Hoon Kim, MD, PhD, Department of Pharmacology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea Tel: +82 2 2228 1738; fax: +82 2 313 1894; e-mail: and Jinu Lee, Yonsei Institute of Pharmaceutical Sciences and College of Pharmacy, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Inchon 406-840, Korea Tel: +82 32 749 4510; fax: +82 2 2123 8603; e-mail:

Received July 27, 2011

Accepted August 15, 2011

© 2011 Lippincott Williams & Wilkins, Inc.