Interactions of CD147 Involved in MMP Induction

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DESCRIPTION (provided by applicant): The cell surface IgSF protein CD147/EMMPRIN/basigin, binds to peritumor stromal cells or to other tumor cells, leading to MMP production, extracellular matrix degradation, and elevated tumor invasion and metastasis. Despite the growing CD 147 literature (300 papers in Medline), relevant counter-receptors remain to be identified, and mechanisms for MMP induction and tumor regulatory functions need to be established. We now define six molecular targets likely to be important for CD 147 function. These targets include novel CD 147 counter-receptor molecules, the homophilic ligand binding site (within the first Ig domain of CD 147), integrin association site (first Ig domain), the site required for caveolin-1 association (second Ig domain), a potential transmembrane domain interaction site, and a cytoplasmic domain site involved in MMP "induction. We propose to rigorously test the importance of each of these target sites for coordinated associations with other proteins, for MMP production in vitro, and for tumorigenicity in vivo. First, we will identify and characterize the CD 147 counter-receptors utilized during MMP-1 and MMP-2 induction. Second, we will determine CD 147 domain 1 sites required for counter-receptor binding and association with o3j81 integrin, and then we will evaluate the role of these sites during MMP-1 and MMP-2 production. Third, we will utilize domain 2 mutants to test the hypothesis that CD147-caveolin-l complexes suppress MMP induction by preventing CD 147 glycosylation and multimerization. Fourth, we will investigate the role of a highly conserved transmembrane glutamic residue (E218) with respect to protein-protein associations (including monocarboxylate transporter association), and CD147 MMP-inducing functions. Fifth, the CD147 cytoplasmic tail will be used as a probe to search for associated intracellular molecules critical for CD147 functions. Sixth, key mutants defined and characterized in Aims 2-5 will be expressed in breast cancer cell lines and tested for effects on tumor cells in vitro and in orthotopic mouse models in vivo. Our new insights into the coordination of counter-receptor binding, MMP induction, cell adhesion, lactate utilization, and caveolin/microdomain organization should provide an integrated framework in which to better understand the dramatic effects of CD 147 on the invasive behavior of tumor cells.