Integrin α5/β1 expression mediates HER-2 down-regulation in colon cancer cells

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 alpha 5/beta 1 expression is frequently lost in colorectal cancer cells compared with normal intestinal epithelium, and colon cancer cells lacking integrin alpha 5/beta 1 expression utilize HER-2 signaling for proliferation and tumorigenicity. Re-expression of integrin alpha 5/beta 1 in colon cancer cells abrogated their tumorigenicity, but how this occurs is not well known. Stable expression of integrin alpha 5/beta 1 in colon cancer cells with little or no detectable integrin alpha 5/beta 1 protein expression resulted in the post-transcriptional down-regulation of HER-2 protein. Integrin alpha 5/beta 1 was found to interact with HER-2, and the cytoplasmic domain of integrin alpha 5/beta 1 was sufficient to mediate HER-2 down-regulation. Integrin alpha 5/beta 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 alpha 5/beta 1 exerts its tumor suppressor-like activity in colon cancer cells. These results also suggest that a novel function for integrin alpha 5/beta 1 is the control of HER-2 expression.