Integrin alpha5/beta1 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 alpha5/beta1 expression is frequently lost in colorectal cancer cells compared with normal intestinal epithelium, and colon cancer cells lacking integrin alpha5/beta1 expression utilize HER-2 signaling for proliferation and tumorigenicity. Re-expression of integrin alpha5/beta1 in colon cancer cells abrogated their tumorigenicity, but how this occurs is not well known. Stable expression of integrin alpha5/beta1 in colon cancer cells with little or no detectable integrin alpha5/beta1 protein expression resulted in the post-transcriptional down-regulation of HER-2 protein. Integrin alpha5/beta1 was found to interact with HER-2, and the cytoplasmic domain of integrin alpha5/beta1 was sufficient to mediate HER-2 down-regulation. Integrin alpha5/beta1-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 alpha5/beta1 exerts its tumor suppressor-like activity in colon cancer cells. These results also suggest that a novel function for integrin alpha5/beta1 is the control of HER-2 expression.
Kuwada
Scott K
SK
Department of Medicine, Salt Lake City Veterans Administration Health Care System and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
Kuang
Jinqiu
J
Li
Xiufen
X
D000362:Agar / Q000737:chemistry; D019921:Biotinylation; D015152:Blotting, Northern; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D039081:Integrin alpha5beta1 / Q000096:biosynthesis*; D008247:Lysosomes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D000362:Agar; D049452:Green Fluorescent Proteins; D039081:Integrin alpha5beta1; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases