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J. Biol. Chem., Vol. 282, Issue 7, 4748-4756, February 16, 2007

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14-3-3 Protein Interacts with Huntingtin-associated Protein 1 and Regulates Its Trafficking^*

Juan Rong, Shihua Li, Guoqing Sheng, Meng Wu, Brian Coblitz, Min Li, Haian Fu^¶, and Xiao-Jiang Li¹

From the Department of Human Genetics and the ^¶Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322 and the Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

HAP1 (Huntingtin-associated protein 1) consists of two alternately spliced isoforms (HAP1A and HAP1B, which have unique C-terminal sequences) and participates in intracellular trafficking. The C terminus of HAP1A is phosphorylated, and this phosphorylation was found to decrease the association of HAP1A with kinesin light chain, a protein involved in anterograde transport in cells. It remains unclear how this phosphorylation functions to regulate the association of HAP1 with trafficking proteins. Using the yeast two-hybrid system, we found that HAP1 also interacts with 14-3-3 proteins, which are involved in the assembly of protein complexes and the regulation of protein trafficking. The interaction of HAP1 with 14-3-3 is confirmed by their immunoprecipitation and colocalization in mouse brain. Moreover, this interaction is specific to HAP1A and is increased by the phosphorylation of the C terminus of HAP1A. We also found that expression of 14-3-3 decreases the association of HAP1A with kinesin light chain. As a result, there is less HAP1A distributed in neurite tips of PC12 cells that overexpress 14-3-3. Also, overexpression of 14-3-3 reduces the effect of HAP1A in promoting neurite outgrowth of PC12 cells. We propose that the phosphorylation-dependent interaction of HAP1A with 14-3-3 regulates HAP1 function by influencing its association with kinesin light chain and trafficking in neuronal processes.

Received for publication, September 25, 2006 , and in revised form, December 11, 2006.

^* This work was supported by National Institutes of Health Grants NS045016 (to S. H. L.), NS36323, and AG19206 (to X. J. L.) and by a predoctoral training award from the American Heart Association (to B. C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-3290; Fax: 404-727-3949; E-mail: xiaoli{at}genetics.emory.edu.

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