The Down-Regulated in Adenoma gene (DRA) was originally identified by subtractive hybridization between a colon adenocarcinoma and adjacent, normal mucosa. It was found to be transcriptionally extinguished in the overwhelming majority of colon adenomas and adenocarcinomas. DRA protein is expressed in the terminally differentiated absorptive mucosal epithelium and, to a lesser degree, in the goblet cells, but not in the stem cell population deeper within the crypt. We (and others) have previously demonstrated that DRA is an anion transporter capable of the inward transport of chloride and sulfate ions. Such a function is consistent with its protein localization. However, we, have also discovered another function of DRA that is of more direct interest to the subject of colon tumorigenesis: expression of DRA causes growth suppression. This function is independent of the anion transport function of DRA. In order to determine how DRA causes growth suppression, we have performed a yeast 2-hybrid interaction trap screen and discovered several proteins that interact in vitro and in vivo with a part of DRA required for growth suppression, its C-terminal domain. All of these proteins are found in colon cancer cells that can be growth suppressed by DRA. This proposal will focus on one of the interactive proteins, liprin-alpha1. Liprin-alpha1 function is unclear, but it appears to help localize the protein tyrosine phosphatase LAR-PTP to specific subcellular sites where it acts as a counter-balance to receptor tyrosine kinases involved in signal transduction pathways such as MAP kinase. The goals of this proposal are: 1) to demonstrate a role for liprin in DRA growth suppression, and 2) to identify what signal transduction pathways may be involved.
