The overall goal of this research is to understand the roles of a membrane/soluble glycoprotein complex (Muc4/sialomucin complex, SMC), which is a major contributing mucin at the ocular surface and in the ocular tear film. Muc4/SMC is composed ofa mucin subunit ASGP-1 linked to the plasma membrane via an N-glycosylated transmembrane subunit ASGP-2. The complex is encoded by a single gene, expressed as a 9.2 kb transcript and synthesized as a precursor of approximately 300 kDa. ASGP-1 acts as an anti-recognition factor at cell surfaces. ASGP-2 has two EGF-like domains and can act selectively as a ligand for the receptor tyrosine kinase ErbB2. In addition to the membrane form of Muc4/SMC, corneal epithelia produce a soluble form which is present in tear fluid and loosely associated with the superficial surfaces of the ocular surface epithelia. Our recent studies on transfected cells have shown that Muc4/SMC can act as a repressor of apoptosis and inducer of the cell cycle inhibitor p27kip. Moreover, Muc4/SMC is localized to the most superficial, most differentiated cell layers of the ocular surface epithelia. Our hypothesis is that Muc4/SMC acts to protect ocular surface epithelia by several mechanisms. In recent studies we have established a multilayered cell culture of rat epithelial cells. We will use this culture system to investigate our hypothesis that Muc4/SMC plays an important role in desquamation of cells from the superficial epithelial layer (aim 1). In addition we will develop a transgenic mouse overexpressing and mis-localizing Muc4/SMC in the corneal epithelium to test this hypothesis (aim 1). We will further use a wound healing system and the culture system to investigate the behavior and possible participation of Muc4/SMC in corneal wound healing (aim 2). Finally, we propose to develop a Muc4/SMC knockout mouse for a more comprehensive view of the roles of Muc4/SMC at the ocular surface (aim 3). These combined studies should help to provide us with a more complete picture of the functions of Muc4/SMC at the ocular surface and insights into the roles of this mucin in ocular surface diseases and aberrations.
| Lomako, Joseph; Lomako, Wieslawa M; Carothers Carraway, Coralie A et al. (2010) Regulation of the membrane mucin Muc4 in corneal epithelial cells by proteosomal degradation and TGF-beta. J Cell Physiol 223:209-14 |
| Lomako, Wieslawa M; Lomako, Joseph; Soto, Pedro et al. (2009) TGFbeta regulation of membrane mucin Muc4 via proteosome degradation. J Cell Biochem 107:797-802 |
| Theodoropoulos, George; Carraway, Kermit L (2007) Molecular signaling in the regulation of mucins. J Cell Biochem 102:1103-16 |
| Zhang, Jin; Carraway, Coralie A Carothers; Carraway, Kermit L (2006) Muc4 expression during blood vessel formation in damaged rat cornea. Curr Eye Res 31:1011-4 |
| Lomako, Joseph; Lomako, Wieslawa M; Decker, Susan J et al. (2005) Non-apoptotic desquamation of cells from corneal epithelium: putative role for Muc4/sialomucin complex in cell release and survival. J Cell Physiol 202:115-24 |
| Carraway, Kermit L; Ramsauer, Victoria P; Haq, Bushra et al. (2003) Cell signaling through membrane mucins. Bioessays 25:66-71 |
| Carraway, Kermit L; Perez, Aymee; Idris, Nebila et al. (2002) Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. Prog Nucleic Acid Res Mol Biol 71:149-85 |
| Swan, Jeremy S; Arango, Maria E; Carothers Carraway, Coralie A et al. (2002) An ErbB2-Muc4 complex in rat ocular surface epithelia. Curr Eye Res 24:397-402 |
| Liu, Z; Carvajal, M; Carraway, C A et al. (2001) Expression of the receptor tyrosine kinases, epidermal growth factor receptor, ErbB2, and ErbB3, in human ocular surface epithelia. Cornea 20:81-5 |
| Arango, M E; Li, P; Komatsu, M et al. (2001) Production and localization of Muc4/sialomucin complex and its receptor tyrosine kinase ErbB2 in the rat lacrimal gland. Invest Ophthalmol Vis Sci 42:2749-56 |
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