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Functional Role of Glycosphingolipids in Cell Recognition and Signaling

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Functional Role of Glycosphingolipids in Cell Recognition and Signaling JB Review J. Biochem.118, 1091-1103(1995) Functional Role of Glycosphingolipids in Cell Recognition and Signaling Sen-itiroh Hakomori and Yasuyuki Igarashi The Biomembrane Institute, 201 Elliott Ave W, Seattle, WA 98119, USA; and Departments of Pathobiology and Microbiology, University of Washington, Seattle, WA 98195, USA Received for publication, August 4, 1995 Glycosphingolipids (GSLs), cell type-specific markers which change dramatically during ontogenesis and oncogenesis, have been implicated as playing major roles in cellular interactions and control of cell proliferation in multicellular organisms. These functional roles have been partially clarified through two types of studies: (i) Studies of cell recognition mediated by (a) GSL-GSL interaction, (b) GSL-lectin interaction, and (c) GSL-dependent modulation of integrin receptor function. (ii) Studies on control of trans membrane signaling by GSLs and/or sphingosine (Sph) derivatives, with emphasis on effects of these compounds on: (a) signaling pathways initiated by tyrosine kinase-linked receptors; (b) signaling systems mediated by protein kinase C, MAP kinase, other kinases, or cytosolic Ca2+ concentration, leading to changes in cellular phenotypes such as motility, proliferation, differentiation, and apoptosis. Key words: glycosphingolipid-glycosphingolipid interaction, integrin receptors, mitogen activated protein kinase, sphingosine/N, N-dimethylsphingosine-dependent kinase, tyro sine kinase receptor. 1. Introduction: Enigma regarding the function of maintenance of cell recognition, this observation does not glycosphingolipids conflict with the above-mentioned concept of GSL function Great technological advances in separation and charac in multicellular systems in vivo. A potentially more serious terization of glycosphingolipids (GSLs) have been achieved conflict with this concept is presented by the observation over the past three decades. Over 200 variations in carbo that treatment of medaka (fish) embryos with D-1-phenyl hydrate structure, in combination with at least 10 common -2-decanoylamino-3-morpholino-l-propanol (D-PDMP) led molecular species of ceramide (Cer), theoretically create to major reduction or total depletion of various GSLs (e. g. over 2,000 possible molecular species of GSLs. Although depletion of GT3 and GQ1c from brain and neural tube), the functional implications of these structural variations and yet the embryos still developed normally (5). How are largely unknown, some of them are obviously involved ever, the function of the depleted GSLs may have been in defining antigenic specificities of cells. GSLs are effective compensated by the 30-40% of GSLs which were not antigens and immunogens, and have been shown to function depleted by PDMP, or by glycoprotein glycosylation. as (a) cell type-specific and developmental stage-specific A long-standing enigma regarding GSL function exists, antigens, and (b) isogeneic or heterophile antigens (i. e. particularly when cell type-specific patterns are compared histo-blood group antigens) (1, 2). Anachronic or ectopic among different isogenic populations (i. e. histo-blood expression of GSLs in category a or b occurs frequently in groups) or different species. One classic problem is that tumors, and such GSLs are regarded as tumor-associated lifespan and development of individuals with very rare antigens (3). Our knowledge of GSLs as cell type-specific histo-blood groups such as group p (i. e. genotype pp) and antigens increased tremendously through application of Bombay group (genotype hh), who do not synthesize major monoclonal antibody techniques in the late 1970s and early globo-series GSLs or H antigen (respectively) in various 1980s, but the real functions of GSLs remained largely tissues and cells, are indistinguishable from those of the unknown. Functional studies of GSLs have been based on majority population with histo-blood group P (P1and P2) or (i) exogenous addition of GSLs or sphingolipid derivatives; H, who do synthesize these carbohydrates. (ii) effect of GSL synthesis inhibitors on cell phenotype; Expression of certain globo-series structures appears to and (iii) use of GSL expression mutants. Such studies have be essential for development of very early-stage embryos revealed that GSLs are involved in two major cellular (6, 7). We assume that these structures are expressed functions: cell recognition and modulation of transmem during embryogenesis of even individuals with genotype brane signaling. These two functions are interrelated, and pp. Similarly, if H, Leg, and Leb are essential in blastocyst essential for development and homeostasis of multicellular formation and/or the implantation process (8-10), even organisms. Bombay individuals must express these epitopes at early In vitro growth of a tumor cell mutant, totally defective developmental stages. in GSL synthesis, was found to be indistinguishable from Perhaps the most extensively studied species-specific that of parent tumor cells (4). Since GSLs are involved in patterns of GSLs in a single cell type are those in eryth vol. 118, No. 6, 1995 1091 1092 S. Hakomori and Y. Igarashi rocytes (11) and neutrophils (12). Results of such studies glycoproteins (21). Although "galectins" (22) and "selec pose a major, ironic problem in assigning specific functions tins" (23) are capable of binding to GSLs having defined of carbohydrates. For example, sialosyl-Lex (SLex) is carbohydrate structure, the major physiological ligands are claimed to be highly expressed on human neutrophils (12) glycoprotein side chains. However, a few lines of evidence but not on hematopoietic progenitor stem cells (13), and to strongly suggest that GSL-binding lectins do exist. Speci be the binding site for selectins (14). However, neutrophils fi city of such lectins should be analogous to that of bacterial in non-human mammal species so far examined (including "adhesins" which recognize GSL -specific structures such as primates) do not react with any antibodies directed to SLex LacCer and globo-series (17). (12). If this epitope is human neutrophil-specific, it cannot In studies by Schnaar et al. (24, 25), a GTlb-specific be considered as a general epitope interacting with selectins binding molecule (presumably lectin) was detected in rat in non-human neutrophils. The extensive observed varia brain membrane fraction, and was claimed to be essential tion in glycosylation pattern in GSLs and glycoproteins for development of the central nervous system. Fatty acid represents the individuality of a cell type. Although the cell residues of various gangliosides were eliminated, and the biological significance of such individuality remains to be amino group of sphingosine (Sph) residue was coupled to elucidated, one plausible hypothesis is that it represents bovine serum albumin (BSA). Multiple gangliosyl-Sph the "wisdom of a cell" to cope with viral and microbial residues carried by radiolabeled BSA were used as a probe. infections, in which carbohydrates are the target.1 The oligosaccharides without Sph conjugated with BSA In this paper, we will summarize our current concept of were found to be less efficiently bound. Thus, a lectin is the functional role of GSLs in control of two major cell capable of recognizing ganglioside molecules rather than phenotypes: cell recognition2 and transmembrane signal oligosaccharides only. One such molecule was recently control. These two phenomena are, of course, closely identified as an immunoglobulin family receptor present on interrelated. myelin-associated glycoprotein (MAG) which binds sialic acid [Yang, L. J.-S., Zeller, C.B., Shaper, N. L., Kiso, M., 2. Organization of GSLs in membranes, and their role Hasegawa, A., Shapiro, R. E., Schnaar, R. L., unpublished as surface receptors in cell recognition data; presented at the "Sphingo(glyco)lipid Symposium," GSLs have been characterized as cell surface antigens Port Ludlow, WA, USA, August 26-28, 1995]. Amphipa (see preceding section), as binding sites for bacterial toxins thic proteins soluble in chloroform-methanol mixture as (e.g. GM1 for cholera toxin, Gb3Cer for Shigella or ver well as in water were detected in ganglioside fractions otoxin) (15, 16), and as sites for bacterial infection (17). isolated from bovine erythrocyte membrane. One of the Since these established research areas have been well fractions had binding affinity to GM3. Others displayed reviewed as cited above, they will not be discussed here. "Paul -Bunnell" antigenicity which was enhanced by addi Recent studies clearly indicate that GSLs are involved in tion of sialosylparagloboside (26). The physiological role of cell-cell and cell-substratum interaction. The effect of these gangliophilic proteins remains to be elucidated. GSLs in control of cell recognition appears to be exerted Recent studies by Hattori et al. (27) revealed the presence through three different mechanisms: (i) GSLs are recog of GM3-binding lectin at the surface of ovarian immature nized by counterpart lectins (including selectins); (ii) GSLs granulosa cells, which are sensitive to follicle-stimulating (particularly gangliosides) modulate adhesion receptors hormone (FSH) and differentiate into mature follicles. such as integrin; (iii) clusters of specific GSLs interact with These granulosa cells also express GM3, and binding counterpart GSL clusters on the surface of another cell between granulosa cells is thereby mediated by GM3 and (Fig. 1). its specific binding lectin. In order to explain the efficient binding of GSLs to Sulfated
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