SMC/MUC4-ErbB2 Complex: Implications on Neoplasia

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The long-term research objectives of this laboratory are centered on elucidating the functions of MUC4 (human)/SMC (rat) in normal epithelial and glandular tissue, and in the neoplastic processes in breast cancer and other cancers. Our short-term aims are focused on the interaction between MUC4/SMC and the receptor tyrosine kinase ErbB2, the consequences of the formation of this complex on localization, phosphorylation and subsequent cell-signaling that may affect cellular mechanisms conducive to breast cancer progression. [unreadable] [unreadable] Over-expression of ErbB2 in cancer tissues is regarded as a major contributor to tumor development, and is specifically considered an indicator of poor prognosis in breast cancer (ErbB2 phosphorylated at tyrosine 1248). Abnormal expression of MUC4 has been implicated in tumor progression in humans particularly in highly aggressive breast tumors. The hypotheses tested in this work are: 1. SMC/MUC4 and ErbB2 interact favorably to form a stable, phosphorylated complex before reaching the cell surface. 2. The formation of the SMC/MUC4-ErbB2 complex, offer a novel origination point that affect ErbB2 signaling pathways. 3. Expression of SMC/MUC4 in polarized epithelial cells has an effect on the localization of ErbB2. [unreadable] [unreadable] Specific aims: 1. To study the biosynthesis and phosphorylation of the complex SMC/MUC4-ErbB2 in insect cells (using histidine-tagged MUC4 and ErbB2, to facilitate purification), SMC transfected, normal mouse polarized epithelial HC11 cells and SMC transfected, non-polarized A375 human melanoma cells, in the presence and in the absence of neuregulin; 2. To investigate the influence of SMC/MUC4 expression on ErbB2 localization and phosphorylation in polarized epithelial cells, using SMC transfected human colon carcinoma CACO-2 cells in the presence and in the absence of neuregulin. [unreadable] [unreadable]