The Coffey lab seeks a comprehensive understanding of the role of EGF receptor (EGFR) and its ligands in epithelial cell growth, differentiation and neoplasia. In vitro, we study spatial compartmentalization of key components of the EGFR axis in the context of polarized epithelial cells. For example, two critical EGFR ligands, TGF-alpha and amphiregulin, are both delivered exclusively to the basolateral surface, cleaved by TACE/ADAM-17, but then interact with basolateral EGFRs in very different ways. Naked2 and MAGI-3 have been identified recently as two proteins that bind the cytoplasmic tail of TGF-alpha and play important roles in the fidelity (former) and efficiency (latter) of TGF-alphas trafficking to the basolateral surface. Naked2 coats exocytic vesicles that contain TGF-alpha and escorts these vesicles to the basolateral surface where they dock and fuse in a Naked2 myristoylation-dependent manner. Naked2 vesicles have been isolated, 389 proteins have been identified by use of fluorescence-activated vesicle sorting (FAVS) and LC/MS-MS. In vivo, mouse models of GI neoplasia are being developed and utilized by Vanderbilt's involvement in the NCI-sponsored Mouse Models of Human Cancers Consortium (of which Dr. Coffey is PI). Innovative therapeutic strategies to disrupt the EGFR axis (ligand cleavage, ligand uptake by receptor, receptor tyrosine kinase activity) in GI neoplasia are fashioned in tissue culture models, refined in mouse models and advanced to clinical trials. A recent example is the successful treatment of a patient with a premalignant disorder of the stomach, Menetrier's disease with EGFR blockade (Erbitux). These efforts have been greatly accelerated by Vanderbilt receiving a 5-year, $13 million GI Special Program of Research Excellence (SPORE) award from the NCI to study colorectal cancer; Dr. Coffey is PI. A major effort is to identify the colonic stem cell using microarray and proteomic profiling. Dr. Coffey also directs the recently-formed VUMC Epithelial Biology Center.
2213 Garland Ave.
10415 MRB IV
Nashville, TN 37232
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Key: MeSH Term Keywordbeta-Galactosidase Cell Line, Tumor Cell Membrane Cell Shape Doxorubicin EGFR epithelial polarity Gelsolin GI cancer Granulosa Cells HCT116 Cells History, 21st Century Intestinal Obstruction Intestine, Small Lasers Menetrier's disease Metaplasia Molecular Conformation Naked2 Nerve Tissue Proteins Proto-Oncogene Proteins p21(ras) Reoviridae Infections TGF-alpha Tristetraprolin Type C Phospholipases Unnecessary Procedures vesicle trafficking