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J. Biol. Chem., Vol. 281, Issue 26, 17751-17757, June 30, 2006

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Adenomatous Polyposis Coli (APC) Differentially Regulates -Catenin Phosphorylation and Ubiquitination in Colon Cancer Cells^*

Jun Yang, Wen Zhang, Paul M. Evans, Xi Chen, Xi He, and Chunming Liu¹

From the Sealy Center for Cancer Cell Biology and Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555 and the Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Most colorectal cancers have mutations of the adenomatous polyposis coli (APC) gene or the -catenin gene that stabilize -catenin and activate -catenin target genes, leading ultimately to cancer. The molecular mechanisms of APC function in -catenin degradation are not completely known. APC binds -catenin and is involved in the Axin complex, suggesting that APC regulates -catenin phosphorylation. Some evidence also suggests that APC regulates -catenin nuclear export. Here, we examine the effects of APC mutations on -catenin phosphorylation, ubiquitination, and degradation in the colon cancer cell lines SW480, DLD-1, and HT29, each of which contains a different APC truncation. Although the current models suggest that -catenin phosphorylation should be inhibited by APC mutations, we detected significant -catenin phosphorylation in these cells. However, -catenin ubiquitination and degradation were inhibited in SW480 but not in DLD-1 and HT29 cells. The ubiquitination of-catenin in SW480 cells can be rescued by exogenous expression of APC. The APC domains required for -catenin ubiquitination were analyzed. Our results suggest that APC regulates -catenin phosphorylation and ubiquitination by distinct domains and by separate molecular mechanisms.

Received for publication, January 26, 2006 , and in revised form, April 24, 2006.

^* 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 Supported by a John Sealy Memorial Fund recruitment award and by Grant R21 CA112007 from the NCI, National Institutes of Health. To whom correspondence should be addressed. Tel.: 409-747-1909; Fax: 409-747-1938; E-mail: chliu{at}utmb.edu.

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