| The goal of this study is to elucidate the function of gp38k, a secreted protein thought to participate in tissue remodeling. Gp38k was originally isolated in our laboratory from smooth muscle cells undergoing a phenotypic transition involving cell migration and changes in cell adhesion. Gp38k stimulates migration and reorganization (tube formation) of vascular endothelial cells in vitro, suggesting roles in processes involving cell migration and adhesion. I examined expression of gp38k in mouse tissue sections and discovered that during embryogenesis, gp38k is expressed in the smooth muscle tissue of organs such as the heart, bladder, gut, and lung and in the epithelial tissues lining these organs. Expression of gp38k increases during mammary development and in mammary tumors produced by overexpression of the wnt proto-oncogene. In human tissues, gp38k is expressed in atherosclerotic plaques in cells that express smooth muscle alpha-actin, which are likely smooth muscle cells. Expression of gp38k is more than 2-fold higher in human tumors than in normal tissues. The expression of gp38k in embryonic and diseased tissue is consistent with its proposed role in tissue remodeling. Expression of gp38k mRNA is increased in areas where high levels of gp38k protein are detected, indicating that 38k is produced and secreted locally by cells. Microarray data show that gp38k mRNA expression is elevated in breast tumors with high histologic grade, a predictor of tumor aggressiveness; in tumors from patients whose breast cancer recurred to form distant metastases; and in patients who eventually died from their cancers. Gp38k expression may be regulated by two factors that play important roles in breast cancer, estrogen and BRCA1, the gene whose mutation causes the majority of inherited breast cancers.; To investigate potential mechanisms of gp38k activity, I performed experiments in vitro using vascular smooth muscle and mammary epithelial cells. These cells adhere and spread normally on gp38k, undergoing cytoskeletal reorganization and activating signaling pathways in a manner consistent with integrin-mediated signal transduction. These results, along with the expression pattern of gp38k in tumors, implicate gp38k as a mammalian adhesion and migration factor that may be involved in tumor progression. |
