Dual Positive and Negative Regulation of Wingless Signaling by Adenomatous Polyposis Coli

doi:10.1126/science.1151232

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Dual Positive and Negative Regulation of Wingless Signaling by Adenomatous Polyposis Coli

Carter M. Takacs, Jason R. Baird, Edward G. Hughes, Sierra S. Kent, Hassina Benchabane, Raehum Paik, Yashi Ahmed^*

Abstract: The evolutionarily conserved Wnt/Wingless signal transductionpathway directs cell proliferation, cell fate, and cell deathduring development in metazoans and is inappropriately activatedin several types of cancer. The majority of colorectal carcinomascontain truncating mutations in the adenomatous polyposis coli(APC) tumor suppressor, a negative regulator of Wnt/Winglesssignaling. Here, we demonstrate that Drosophila Apc homologsalso have an activating role in both physiological and ectopicWingless signaling. The Apc amino terminus is important forits activating function, whereas the β-catenin bindingsites are dispensable. Apc likely promotes Wingless transductionthrough down-regulation of Axin, a negative regulator of Winglesssignaling. Given the evolutionary conservation of APC in Wntsignal transduction, an activating role may also be presentin vertebrates with relevance to development and cancer.

Department of Genetics and the Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.

^* To whom correspondence should be addressed. E-mail: yfa{at}dartmouth.edu

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