Preliminary studies indicate that tumor-associated glycosphingolipid (GSL) antigens are clustered and organized with various signal transducer molecules (e.g. c-Src, Ras, FAK, Rho, Cak)as microdomains at the tumor cell surface membrane, termed ÒGSL-enriched microdomains (GEM). GSLs in GEM are involved in cell adhesion or stimulation by antibody, which initiate signal transduction. Thus, tumor-associated GSLs in GEM may play an essential role in defining aberrant adhesion and aberrant signal transduction characteristic of malignant tumor cells. The applicant proposes to study: (1) Organizational status and composition of GEM displaying GSL-dependent cell adhesion coupled with signaling. This includes isolation GEM subfraction, analysis of its chemical composition, association of GSLs with signal transducers, and the role of trans-bilayer lipophilic proteins present in GEM. (2) Functional analysis of GEM and its subfractions, defining GSL-dependent initiation and activation of signaling. This includes observation of activation or inhibition of transducers in whole cells or in subdomain vesicles following stimulation of GSLs. (3) Differences of structure and function of GEM in tumor cells with different grade of malignancy and state of differentiation. (4) Development of reagents which disrupt GSL clustering (uncouplers or inhibit GSL binding to its ligand (anti-ligands), and application of these reagents to disrupt GEM structure and function and thereby inhibit tumor growth and malignancy.
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