Signal transduction through glyco(sphingo)lipids. Introduction and recent studies on glyco(sphingo)lipid-enriched microdomains.
The presence of microdomains enriched in clustered glycosphingolipids (GSLs) at the surface of plasma membranes and liposome membranes, and their functional role in signal transduction, have been suggested by a series of observations, as follows: (1) GSL clusters (patches) are observed by electron microscopy; (2) microvesicles enriched in GSLs and other sphingolipids can be isolated as detergent-insoluble particles by sucrose density gradient ultracentrifugation: (3) such vesicles isolated from B16 melanoma cells contain > 90% of cellular GM3, > 90% of c-Src and Ras, approximately 50% of Rho, and approximately 20 percent of Fak, despite the fact that this vesicle fraction contains only 0.5% of total cellular protein (this fraction is termed "detergent-insoluble GSL-enriched microdomain" (DIGEM)); (4) GM3 in DIGEM can be coimmunoprecipitated with c-Src and Rho, indicating a close association of GM3 with these transducer molecules; (5) stimulation of GM3 in B16 melanoma cells by anti-GM3 antibody or by Gg3 results in change of signal transduction. Thus, GSLs, together with various transducer molecules present at DIGEM, may directly induce signal transduction rather than modulate or modify signal transduction created through receptors of growth factors or hormones as previously observed.
Pacific Northwest Research Foundation, Seattle, Washington 98122, USA. hakomori@u.washington.edu
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D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D005732:Gangliosides / Q000737:chemistry / Q000502:physiology*; D006017:Glycolipids / Q000737:chemistry / Q000502:physiology*; D006028:Glycosphingolipids / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008081:Liposomes; D008546:Melanoma, Experimental / Q000737:chemistry / Q000503:physiopathology; D051379:Mice; D015398:Signal Transduction
D005732:Gangliosides; D006017:Glycolipids; D006028:Glycosphingolipids; D008081:Liposomes