Coralie Carothers Carraway

Professor of Biochemistry and Molecular Biology

Ph.D. (1974) Oklahoma State University.

Signal Transduction, Oncoproteins, Molecular
Mechanisms of Growth Regulation,
Retroviral Gag Protein Interactions
with Signaling and Cytoskeletal Proteins

Tel: (305) 243-5759, Fax: (305) 243-3065

ccarrawa@med.miami.edu

The glycoprotein complex contains several major components, including the oncogenic growth factor receptor p185^neu, which is overexpressed in many human breast and other carcinomas. ErbB2 in these tumor cells is constitutively phosphorylated and activated via an endogenous membrane ligand, and as a consequence the TMC recruits all of the recently described common Ras to MAPK mitogenic pathway components, as well as Src, Abl, PKC, PI-3-kinase, PLC? and other signaling proteins. A cytoplasmic component of the STP, p58, which binds actin, phospholipid and one of the glycoproteins, stabilizes the interaction of microfilaments with the complex. This stability correlates with xenotransplantability of these tumor cells from rats to mice. The sequence of p58 showed that it is a truncated Gag-like protein, suggesting a possible role for these proteins in viral maturation. The microfilament-linked cell-cell interaction protein E-cadherin and associated cytoplasmic proteins a, ß-and ?-catenins are also components of the STP. These observations suggest at least two major cellular roles for the STP, a major membrane-microfilament interaction site: 1) selective linkage of signal transduction pathway components with microfilaments and transduction of growth factor signal to the nucleus and to the cytoskeleton; and 2) integration of multiple signals received by the tumor cell. We have two major ongoing projects in the laboratory. The first is the characterization of the receptor complexes in human normal and breast cancer cells. We are using biochemical, molecular biological and immunological techniques for isolation, characterization of sequence, posttranstranslational modification and interactions, localization and function of the STP glycoprotein components and associated proteins. Its role in organizing the ErbB receptors and of E-cadherin in both normal epithelial and carcinoma cells and its role in transduction in signaling through these receptors is a major focus.

The long-range goal is the elucidation of the roles of these large signaling complexes in both normal differentiation processes, apoptosis and neoplastic transformation. The second project involves potential roles for p58^gag and other Gag proteins in disruption of normal cellular function. p58^gag binds through polyproline motifs to the SH3 domains of both c-Src and c-Abl, activates and is phosphorylated by these kinases. The roles for Gag protein binding to signaling proteins in host cell disruption and in virus maturation are being extended to the AIDS and MAIDS (mouse) Gag proteins, whose sequences have similar Src- and Abl-binding motifs.

Representative Publications

·         Carraway, K.L., Carraway, C.A.C. and Carraway, K.L. III (1998) Signal Transduction and the Cytoskeleton (invited monograph), R.G. Landes Co., Austin, TX.

·         Carraway, K.L., Carraway, C.A.C. and Carraway, K.L. III (1997) Roles of ErbB-3 and ErbB-4 in the Physiology and Pathology of the Mammary Gland. J. Mammary Gland Biol. Neoplasia 2, 187-198.

·         Juang, S.-H., Carvajal, M.E., Whitney, M., Liu, Y. and Carraway, C.A.C. (1996) Tyrosine Phosphorylation at the Membrane-microfilament Interface: A p185^neu-containing Signal Transduction Particle Containing Src, Abl and Phosphorylated p58, a Membrane-and Microfilament-associated Retroviral Gag-like Protein. Oncogene 12, 1033-1042.

·         Carraway, K.L. and Carraway, C.A.C. (1995) Signaling, Mitogenesis and the Cytoskeleton: Where the Action Is. Bioessays 17, 171-175.

·         Carraway, C.A.C., Carvajal, M.E., Li, Y. and Carraway, K.L. (1993) Association of p185^neu with Microfilaments via a Large Glycoprotein Complex in Mammary Carcinoma Microvilli: Evidence for a Microfilament-associated Signal Transduction Particle. J. Biol. Chem. 268, 5582-5587.

Honors and Professional Activities

·         American Society for Biochemistry and Molecular Biology

·         American Society of Cell and Developmental Biology

·         American Association for Cancer Research

·         International Association for Cancer Research

·         International Association for Women Bioscientists