MUC1 is a heterodimeric mucin-like glycoprotem expressed by ductal epithelial cells of several organs. MUC1 is overexpressed and differentially glycosylated by many tumors. Results of studies conducted in our laboratory and in other laboratories during the past several years have led us to hypothesize that one major function of the large tandem-repeat containing extracellular fragment of the MUC1 protein is to aid in the configuration of adhesive and anti-adhesive properties of the surface of cells on which it is expressed. On normal epithelial cells, the anti-adhesive properties of MUC1 are predicted to contribute to the maintenance of an apical such that is exposed to a lumenal cavity and is not in association with other cells. It is predicted that MUC1 expression can serve to reconfigure the cell surface adhesion properties with molecular specificity by simultaneously dismupting existing interactions between some adhesion molecules and by confening new adhesive properties through direct adhesion to receptors on other cells or tissues. Experiments proposed in this application will test this hypothesis and investigate the role of MUC1 in tumor invasion and metastasis throughout different organ sites. A second molecular component of cell surface associated heterodimeric MUCI is the integral membrane protein, which contains a cytoplasmic tail, transmembrane domain and a short exiracellular domain that associates with the large extracellular fragment that mediates the adhesion and anti-adhesion functions of this protein. The cytoplasmic tail is phosphorylated and has been implicated as interfacing with beta catenin, GSK3I3, c-Src, EGFR and other ethB receptors, and with Grb2-Sos signal transduction pathways in some cells. The cytoplasmic tail is also believed to associate with cytoskeletal elements including actin, and under some conditions can be recycled from the cell surface to the trans-Golgi network. The precise function of the membrane associated domain of MUC1 and its role in signal transduction has not been established. We propose to test two non-mutually exclusive hypotheses of functions for this component of the MUC1 protein. The first is that the transmembrane and cytoplasmic tail domains function to communicate information about the status of the cell surface to the interior compartments of the cell. In this model we postulate that the exiracellular domain of MUC1 can function as a molecular sensor of certain extracellular conditions (pH and adhesion status) and that alterations in MUC 1 structure or binding status can be communicated to internal compartments of the cell through the transmernbrane domain and cytoplasmic tail. The second hypothesis posits that the transmembrane domain and/or cytoplasmic tail play a structural role that supports the adhesion and anti-adhesion properties of MUC1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Pathology B Study Section (PTHB)
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Ogunbiyi, Peter
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University of Nebraska Medical Center
Internal Medicine/Medicine
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