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------------------------------------------------------------------------------------------------- Curriculum Vitae
------------------------------------------------------------------------------------------------- Research Interests For much of the past two decades my primary research effort has been concerned with the role of cell surface glycoproteins in epithelia and cancer, focusing on a particular glycoprotein complex (Muc4, also known as sialomucin complex, SMC) that we discovered about 25 years ago. This complex has both mucin and growth factor subunits and can potentially contribute to two of the major attributes of cancer cells, loss of adhesiveness by steric inhibition and autonomous growth through Muc4 regulation of the receptor tyrosine kinase ErbB2. Our recent studies have implicated Muc4 in epithelial differentiation, control of apoptosis and tumor metastasis. We are primarily concerned with two questions. What is the function of Muc4 in epithelial cells and tumors? How is the expression of Muc4 regulated? The large size of Muc4 allows it to alter cell signaling by effects on both cell-matrix and cell-cell adhesions, thus affecting cell proliferation. An EGF-like domain in Muc4 induces complex formation with ErbB2, regulating both the cellular localization and phosphorylation of this important signaling receptor. In normal polarized epithelial cells, Muc4 localizes ErbB2 to the apical surface and segregates the receptor from other receptors, such as ErbB3, important for transmitting its signals. In contrast, in non-polarized tumor cells Muc4 expression favors ErbB2-ErbB3 complex formation and signaling that promote cell proliferation and repress apoptosis. Thus, Muc4 has a yin-yang effect which can support either differentiation or tumor progression in epithelial cells or carcinomas, respectively.
The effects of Muc4 are determined by regulation of its expression. TGFβ regulates the expression of Muc4 in a number of epithelial cell types by a post-translational mechanism. Muc4 is synthesized as a large precursor, which is cleaved to give two subunits, the mucin and transmembrane subunits. Blockage of that cleavage by TGFβ shunts the Muc4 into the endoplasmic reticulum degradation pathway and proteosome. Tumor cells are resistant to TGFβ and therefore may overexpress Muc4, thus losing their adhesiveness, growth control and susceptibility to apoptosis. Muc4 exerts protective effects in numerous accessible epithelia. In the corneal epithelium we have proposed that Muc4 contributes to cell desquamation and to epithelial homeostasis. In the uterine epithelium Muc4 blocks blastocyst implantation and thus must be down-regulated to permit pregnancy to progress. Soluble forms of Muc4 are secreted into the tear fluid, milk and saliva, as well as onto the surfaces of the airway and reproductive and GI tract, contributing to protection against noxious agents and infection. Thus, Muc4 is a multi-dimensional molecule with functions ranging from protection from infection to regulation of apoptosis. ------------------------------------------------------------------------------------------------- Selected Publications Carraway, K.L. III, Rossi, E.A., Komatsu, M., Price-Schiavi, S.A., Huang, D., Guy, P.M., Carvajal, M.E., Fregien, N., Carraway, C.A.C. and Carraway, K.L. (1999) An intramembrane modulator of the ErbB2 receptor tyrosine kinase that potentiates neuregulin signaling. J. Biol. Chem. 274, 5263-5266. Komatsu, M., Yee, L. and Carraway, K.L. (1999) Overexpression of sialomucin complex, a rat homolog of MUC4, inhibits tumor killing by lymphokine-activated killer cells. Cancer Res.59, 2229-2236. Komatsu, M., Tatum, L., Altman, N.H., Carraway, C.A.C. and Carraway, K.L. (2000) Potentiation of metastasis by cell surface sialomucin complex (rat muc4), a multifunctional anti-adhesive glycoprotein. Int. J. Cancer 87, 480-486. Price-Schiavi, S.A., Zhu, X., Aquinin, R. and Carraway, K.L. (2000) Sialomucin complex (rat muc4) is regulated by transforming growth factor in mammary gland by a novel post-translational mechanism. J. Biol. Chem. 275, 17800-17807. Komatsu, M., Jepson, S., Arango, M.E., Carraway, C.A.C. and Carraway, K.L.(2001) Muc4/Sialomucin Complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor. Oncogene 20, 461-470. Idris, N., Carraway, C.A.C. and Carraway, K.L. 2001. Differential localization of erbb2 in different tissues of the rat female reproductive tract: implications for the use of specific antibodies for ErbB2 analysis. J. Cell. Physiol. 189, 162-170. Arango, M.E., Li, P., Komatsu, M., Montes, C., Carraway, C.A.C. and Carraway, K.L. 2001. Production and localization of Muc4/sialomucin complex and its receptor tyrosine kinase ErbB2 in the rat lacrimal gland. Invest. Ophthalmol. Vis. Sci. 42, 2749-2756. Carraway, K.L., Perez, A., Idris, N., Jepson, S., Arango, M., Komatsu, M., Haq, B., Price-Schiavi, S.A., Zhang, J. and Carraway, C.A.C. 2001. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. Prog. Nucleic Acids Res. Molec. Biol. 171, 149-185. Carraway, K.L., Ramsauer, V.P., Haq, B. and Carraway, C.A.C. 2003. Cell signaling through membrane mucins. BioEssays 25, 66-71. Soto, P., Price-Schiavi, S.A. and Carraway, K.L. 2003. SMAD2 and SMAD7 involvement in the post-translational regulation of Muc4 via the transforming growth factor-beta and interferon-gamma pathways in rat mammary epithelial cells. J. Biol. Chem. 278, 20338-20344. Ramsauer, V.P., Carraway, C.A.C., Salas, P.J.I. and Carraway, K.L. 2003. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized epithelial cells. J. Biol. Chem. 278, 30142-30147. Perez, A., Barco, R., Fernandez, I., Price-Schiavi, S A. and Carraway, K.L. 2003. PEA3 transactivates the Muc4/sialomucin complex promoter in mammary epithelial and tumor cells. J. Biol. Chem. 278, 36942-36952. Lomako, J., Lomako, W., Carraway, C.A.C. and Carraway, K.L. 2005. Non-apoptotic desquamation of cells from corneal epithelium: putative role for Muc4/sialomucin complex in cell release and survival. J Cell Physiol 202: 115-124. Rong, M., Rossi, E.A., Zhang, J., McNeer, R.R., Van Den Brande, J.M.H., Yasin, M., Weed, D. T., Carraway, C.A.C., Thompson, J. F. and Carraway, K.L. 2005. Expression and Localization of Muc4/Sialomucin Complex (SMC) in the Adult and Developing Rat Intestine: Implications for Muc4/SMC Function. J. Cell. Physiol. 202: 275-284. Nagy, P., Friedländer, E., Tanner, M., Kapanen, A.I., Carraway, K.L., Isola, J. and Jovin, T.M. 2005. Decreased accessibility and lack of activation of erbB2 in a Herceptin-resistant, MUC-4-expressing breast cancer cell line. Cancer Res. 65: 473-482. Ramsauer, V.P., Pino, V., Farooq, A., Carraway, C.A.C., Salas, P.J.I. and Carraway, K.L. 2006.Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Mol. Biol. Cell 17: 2931-2941. View published research articles by Dr. Carraway in the National Library of Medicine ------------------------------------------------------------------------------------------------- |
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