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J. Biol. Chem., Vol. 280, Issue 19, 19027-19035, May 13, 2005

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Integrin 5/1 Expression Mediates HER-2 Down-regulation in Colon Cancer Cells^*

Scott K. Kuwada, Jinqiu Kuang, and Xiufen Li

From the Department of Medicine, Salt Lake City Veterans Administration Health Care System and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112

HER-2 is constitutively activated and overexpressed in many cancers, and its inhibition in colon cancer cells diminishes tumorigenicity and induces apoptosis. Little is known about the regulation of HER-2 signaling in colon cancer cells. Integrin 5/1 expression is frequently lost in colorectal cancer cells compared with normal intestinal epithelium, and colon cancer cells lacking integrin 5/1 expression utilize HER-2 signaling for proliferation and tumorigenicity. Re-expression of integrin 5/1 in colon cancer cells abrogated their tumorigenicity, but how this occurs is not well known. Stable expression of integrin 5/1 in colon cancer cells with little or no detectable integrin 5/1 protein expression resulted in the post-transcriptional down-regulation of HER-2 protein. Integrin 5/1 was found to interact with HER-2, and the cytoplasmic domain of integrin 5/1 was sufficient to mediate HER-2 down-regulation. Integrin 5/1-mediated down-regulation of HER-2 was the result of increased lysosomal targeting. The inhibition of HER-2 signaling represents a potential mechanism by which integrin 5/1 exerts its tumor suppressor-like activity in colon cancer cells. These results also suggest that a novel function for integrin 5/1 is the control of HER-2 expression.

Received for publication, September 13, 2004 , and in revised form, January 10, 2005.

^* 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.

To whom correspondence should be addressed: 2000 Circle of Hope, Salt Lake City, UT 84112.

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