HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 16, 10513-10521, April 18, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/16/10513    most recent M709852200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chen, S. Articles by Iqbal, K. Search for Related Content PubMed PubMed Citation Articles by Chen, S. Articles by Iqbal, K. Social Bookmarking                      What's this?

I PP2A 1 Affects Tau Phosphorylation via Association with the Catalytic Subunit of Protein Phosphatase 2A^*

From the Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314

In Alzheimer disease (AD) brain, the level of I ^PP2A₁, a 249-amino acid long endogenous inhibitor of protein phosphatase 2A (PP2A), is increased, the activity of the phosphatase is decreased, and the microtubule-associated protein Tau is abnormally hyperphosphorylated. However, little is known about the detailed regulatory mechanism by which PP2A activity is inhibited by I ^PP2A₁ and the consequent events in mammalian cells. In this study, we found that both I ^PP2A₁ and its N-terminal half I ^{PP2A(1–120)}₁, but neither I ^{PP2A(1–163)}₁ nor I ^{PP2A(164–249)}₁, inhibited PP2A activity in vitro, suggesting an autoinhibition by amino acid residues 121–163 and its neutralization by the C-terminal region. Furthermore, transfection of NIH3T3 cells produced a dose-dependent inhibition of PP2A activity by I ^PP2A₁. I ^PP2A₁ and PP2A were found to colocalize in PC12 cells. I ^PP2A₁ could only interact with the catalytic subunit of PP2A (PP2Ac) and had no interaction with the regulatory subunits of PP2A (PP2A-A or PP2A-B) using a glutathione S-transferase-pulldown assay. The interaction was further confirmed by coimmunoprecipitation of I ^PP2A₁ and PP2Ac from lysates of transiently transfected NIH3T3 cells. The N-terminal isotype specific region of I ^PP2A₁ was required for its association with PP2Ac as well as PP2A inhibition. In addition, the phosphorylation of Tau was significantly increased in PC12/Tau441 cells transiently transfected with full-length I ^PP2A₁ and with PP2Ac-interacting I ^PP2A₁ deletion mutant 1–120 (I ^PP2A₁C2). Double immunofluorescence staining showed that I ^PP2A₁ and I ^PP2A₁C2 increased Tau phosphorylation and impaired the microtubule network and neurite outgrowth in PC12 cells treated with nerve growth factor.

Received for publication, December 3, 2007 , and in revised form, January 25, 2008.

^* This work was supported by the New York State Office of Mental Retardation and Developmental Disabilities; by research grants from the Institute for the Study of Aging, New York, and the Alzheimer's Association, Chicago, IL; and by NIA, National Institutes of Health Grant AG-019158. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neurochemistry, New York State Inst. for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314-6399. Tel.: 718-494-5259; Fax: 718-494-1080; E-mail: iqbalk{at}worldnet.att.net.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?