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J. Biol. Chem., Vol. 281, Issue 36, 26181-26187, September 8, 2006

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Lysine Residues Lys-19 and Lys-49 of -Catenin Regulate Its Levels and Function in T Cell Factor Transcriptional Activation and Neoplastic Transformation^*

Ira S. Winer, Guido T. Bommer, Nathan Gonik, and Eric R. Fearon^¶||**1

From the Cell and Molecular Biology Graduate Program, Division of Molecular Medicine and Genetics, Departments of Internal Medicine, ^¶Human Genetics, and ^||Pathology, and ^**The Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan 48109

Wnt signaling regulates cell fate determination, proliferation, and survival, among other processes. Certain Wnt ligands stabilize the -catenin protein, leading to the ability of -catenin to activate T cell factor-regulated genes. In the absence of Wnts, -catenin is phosphorylated at defined serine and threonine residues in its amino (N) terminus. The phosphorylated -catenin is recognized by a -transducin repeat-containing protein (TrCP) and associated ubiquitin ligase components. The serine/threonine residues and TrCP-binding site in the N-terminal region of -catenin constitute a key regulatory motif targeted by somatic mutations in human cancers, resulting in constitutive stabilization of the mutant -catenin proteins. Structural studies have implicated -catenin lysine 19 as the major target for TrCP-dependent ubiquitination, but Lys-19 mutations in cancer have not been reported. We studied the consequences of single amino acid substitutions of the only 2 lysine residues in the N-terminal 130 amino acids of -catenin. Mutation of Lys-19 minimally affected -catenin levels and functional activity, and mutation of Lys-49 led to reduced -catenin levels and function. In contrast, -catenin proteins with substitutions at both Lys-19 and Lys-49 positions were present at elevated levels and had the ability to potently activate T cell factor-dependent transcription and promote neoplastic transformation. We furthermore demonstrate that the K19/K49 double mutant forms of -catenin are stabilized as a result of reduced TrCP-dependent ubiquitination. Our findings suggest that Lys-19 is a primary in vivo site of TrCP-dependent ubiquitination and Lys-49 may be a secondary or cryptic site. Moreover, our results inform understanding of why single amino acid substitutions at lysine 19 or 49 have not been reported in human cancer.

Received for publication, May 3, 2006

^* This work was supported by National Institutes of Health Grants CA85463, CA46592, and T32GM07863. 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: Division of Molecular Medicine and Genetics, University of Michigan School of Medicine, 109 Zina Pitcher, 1504 BSRB, Ann Arbor, MI 48109-2200. Tel.: 734-764-1549; Fax: 734-647-7950; E-mail: fearon{at}umich.edu.

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