Organization and function of glycosphingolipids in membrane

We have characterized novel glycosphingolipids (GSLs) of antigenic or functional importance, including type 3 and type 4 blood group ABH antigens, globo-series gangliosides, sialosyl dimeric Lex, myeloglycan, β1-4GalNAc disialyl-Lc4Cer, etc. Many GSLs have been identified as developmentally-regulated, tumor-associated antigens, suggesting their role in defining stage of development, and tumor cell phenotype. Out of the many types of GSLs, relatively few have been studied and shown to control cellular functions. Our studies indicate that functional effects of these GSLs are based on their interaction with specific target molecules in membrane, including (i) signal transducers (e.g., cSrc, Src family kinases, small G-proteins), to initiate signal transduction; (ii) integrin receptors (e.g., α3β1), to modulate cell adhesion and motility; (iii) growth factor receptors (e.g., for FGF, EGF), to modulate cell growth; (iv) tetraspanins (e.g., proteolipid CD9, CD81, CD82), to affect complex formation with integrin or with growth factor receptor; (v) GSL itself, through GSL-to-GSL interaction; (vi) microbial "adhesin". In many cases, these GSL interactions take place through GSL clusters at GSL-enriched microdomain (GEM). Some GEM show properties similar to those of "lipid rafts", whereas others, particularly those highly enriched in proteolipid/tetraspanin and involved in cell adhesion and cell growth, are distinguishable from "lipid rafts" since they are independent of cholesterol but are non-resistant to (soluble in) 1% Triton X-100. Such microdomains, showing GSL-dependent or -modulated cell adhesion and growth, are termed "glycosynapse". Further studies on GSL structure and function through glycosynapse will help clarify cell social behavior and various disease processes based on malfunction of cellular interaction, or of adhesion with concurrent signaling. (Communicated by Tamio YAMAKAWA, M.J.A.)