Investigation of the Role of Sialomucin Complex (SCMC)/Muc4, a Unique Intramembranous HER-2/ErbB-2 Ligand, as a Suppressor of Apoptosis
Abstract
Muc4/sialomucin complex (SMC) is a high Mr heterodimeric glycoprotein complex which was originally observed at the cell surfaces of 13762 rat mammary adenocarcinoma cells and has been more recently found in many accessible and vulnerable epithelia. It is composed of a mucin subunit ASGP-1 and a transmembrane subunit ASGP-2. The latter has two EGF-like domains and can form intramembrane ligand-receptor-type complexes with the receptor tyrosine kinase ErbB2. An important aspect of SMC/Muc4 is its ability to repress apoptosis when transfected into tumor cells. Our hypothesis is that SMC/Muc4 is multifunctional. It acts as an epithelial protective agent by forming a steric barrier at epithelial apical surfaces and by contributing to signaling through ErbB2 involved in epithelial differentiation and repression of apoptosis. Both of these functions may contribute to tumor progression when Muc4/SMC is inappropriately overexpressed. HER-2 (ErbB-2, neu) is a member of the family of epithelial growth factors (EGF), and appears to overexpressed in 25-30 % of human breast carcinomas. Its presence is associated with a poor prognosis. No soluble ligand for HER-2 has been discovered so far, but our research group has shown that the ASGP-2 subunit of Muc4 binds to HER-2 (ErbB-2, neu), and affects its phosphorylation. Muc4 has also shown to suppress apoptosis in A375 human melanoma cells and to upregulate a differentiation-associated protein p27kip1. High levels of expression of p27kip have been seen in some highly proliferative human breast cancer cells. Thus the study of HER-2-Muc4 complex in regards to its suppression of apoptosis will provide us with a more complete understanding of the mechanisms by which these molecules participate in breast cancer; this in turn we hope, will ultimately contribute to the refinement of breast cancer therapies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2005
- Accession Number
- ADA593331
Entities
People
- George Theodore
Organizations
- University of Miami