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J. Biol. Chem., Vol. 282, Issue 37, 27171-27180, September 14, 2007

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Treatment of PC12 Cells with Nerve Growth Factor Induces Proteasomal Degradation of T-cadherin That Requires Tyrosine Phosphorylation of Its Cadherin Domain^*

Shoumei Bai¹, Jharna Datta, Samson T. Jacob², and Kalpana Ghoshal

From the Department of Molecular and Cellular Biochemistry, College of Medicine, and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210

T-cadherin (T-Cad), a unique member of the cadherin family of proteins, plays an important role in cell adhesion and cell signaling. Recently, we demonstrated that T-Cad is transcriptionally repressed by DNA methyltransferase 3b during nerve growth factor (NGF)-induced neuronal differentiation of PC12 cells. Here, we show that T-Cad expression is also regulated at the post-translational level by the proteasomal pathway in these cells, which is facilitated upon NGF treatment. Pulse-chase experiments demonstrated that NGF treatment significantly reduced the half-life of T-Cad. Degradation of T-Cad was blocked upon treatment of PC12 cells with the proteasomal inhibitor ZLLL or lactacystin. Ectopic expression of Cdh1 (CDC20 homolog 1), one of the substrate recognition components of anaphase promoting complex (E3 ligase), stimulated T-Cad degradation. Deletion of CD1, one of the five extracellular cadherin domains (CD), promoted degradation of T-Cad, especially in the presence of NGF. On the contrary, deletion of CD2 stabilized this protein maximally. Ubiquitination of different deletion mutants indicates that T-Cad harbors multiple ubiquitination signals. Furthermore, genistein, a protein-tyrosine kinase inhibitor, impeded T-Cad degradation in PC12 cells, implicating requirement of tyrosine phosphorylation in this process. Mutation at tyrosine 327 (Y327F) markedly increased the half-life of T-Cad, suggesting that phosphorylation of this tyrosine residue located within CD2 is critical for this process. These results show that T-cadherin is subject to dual regulation during NGF-induced differentiation of PC12 cells, namely transcriptional repression mediated by Dnmt3b and post-translational degradation through the proteasomal pathway. These data, together with the inhibitory role of T-Cad in neurite outgrowth of PC12 cells upon NGF treatment, underscore the significance of its stringent regulation during this differentiation process.

Received for publication, January 24, 2007 , and in revised form, June 14, 2007.

^* This work was supported in part by National Institutes of Health Grants CA86978 and CA10195. 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 Present address: Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI.

² To whom correspondence should be addressed. Tel.: 614-688-5494; Fax: 614-688-5600; E-mail: jacob.42{at}osu.edu.

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