Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2002 Jan 8;99(1):225-32.
doi: 10.1073/pnas.012540899. Epub 2002 Jan 2.

The glycosynapse

Sen-itiroh Hakomori Si  1
Affiliations
Review

The glycosynapse

Sen-itiroh Hakomori Si. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A 2002 Mar 5;99(5):3356

Abstract

Physically distinguishable microdomains associated with various functional membrane proteins are one of the major current topics in cell biology. Glycosphingolipids present in such microdomains have been used as "markers;" however, the functional role of glycosyl epitopes in microdomains has received little attention. In this review, I have tried to summarize the evidence that glycosyl epitopes in microdomains mediate cell adhesion and signal transduction events that affect cellular phenotypes. Molecular assemblies that perform such functions are hereby termed "glycosynapse" in analogy to "immunological synapse," the membrane assembly of immunocyte adhesion and signaling. Three types of glycosynapses are so far distinguishable: (i) Glycosphingolipids organized with cytoplasmic signal transducers and proteolipid tetraspanin with or without growth factor receptors; (ii) transmembrane mucin-type glycoproteins with clustered O-linked glycoepitopes for cell adhesion and associated signal transducers at lipid domain; and (iii) N-glycosylated transmembrane adhesion receptors complexed with tetraspanin and gangliosides, as typically seen with the integrin-tetraspanin-ganglioside complex. The possibility is discussed that glycosynapses give rise to a high degree of diversity and complexity of phenotypes.

PubMed Disclaimer

Figures

Figure 1
Figure 1
GSL conformation and organization in membrane. (A) Minimum-energy model of GSL, Gb5 taken as an example, showing that the axis of carbohydrate moiety is perpendicular to the axis of ceramide (133, 134). The surface profile of carbohydrate provides binding sites for Abs, lectins, microbial toxins, and complementary GSLs. (Left) Role of ceramide (Cer) to form microdomain. (Right) Interaction of entire GSLs with key molecules (TSP, tetraspanin; ITR, integrin receptor; GFR, growth factor receptor; SFK, Src family kinase). These molecules, together with Cer or sphingosine (Sph) released from sphingomyelin, activate or modulate their respective kinases and are involved in various ways in control of signal transduction. (B) GSLs are clustered (“GSL patch”) and inserted via ceramide into the outer leaflet of the membrane, without (“2”) or with (“3”) signal transducers (TDa, TDb). GSL clusters organized with signal transducers, PL tetraspanin (PLtsp), and growth factor receptor (GFR) are shown in “4.” Glycoprotein (Gp) clusters (“1”) in many cases may be separated from GSL patches. (Inset) Contrasting properties of glycosignaling domain (GSD), the domain enriched in GSL, TD, and PL, separable from caveolar membrane. Data from refs. and and from K. Handa, D. A. Withers, and S.H. (unpublished data). Cav, caveolin; SaSph, sialyl 2 → 1 sphingosine.
Figure 2
Figure 2
Schematic models of types 1, 2, and 3 glycosynapse. (A) Type 1 glycosynapse with GSL clusters, PL tetraspanin (PLtsp), and growth factor receptor (in this example EGF-R). Clusters of GSLs are organized with signal transducer molecules (TDa, TDb). Stimulation of GSL region “a” causes strong signaling “x” through TDa (19, 20), whereas stimulation of region “b” causes weaker signaling “y” through TDb because of the presence of the blocking factor PLtsp in that region (K. Handa, D. A. Withers, and S.H., unpublished data). When EGF-R is located in a GSL-rich domain, signaling through growth factor (EGF) to activate tyrosine phosphorylation (P-Y) is blocked by the association of EGF-R with GSL (in this example, ganglioside GM3) (48). Binding of GM3 to EGF-R may result from interaction of GM3 with carbohydrate N-linked to EGF-R, as suggested by a previous study (69), and by our studies with N-glycosylation inhibitors (T. Hikita, K. Handa, and S.H., unpublished data). Note that the majority of N-glycosylation (pink oval chains) is localized at the fourth domain from the top (135), close to ganglioside clusters (purple ovals), such that interaction with gangliosides at the membrane surface is favored. (B) Type 2 glycosynapse with mucin-type transmembrane glycoprotein at cholesterol-rich membrane domain. Examples are shown for MUC-1 and PSGL-1. In MUC-1, the number of tandem repeats varies from 20 to 120, and each repeat is a 20-aa sequence. In PSGL-1, the number of tandem repeats is 15, and each repeat is a 10-aa sequence. The units, having multiple O-linked structure with glycosyl adhesion epitope, are organized with various signal transducers (TDa, TDb, TDc). In human and mouse T-cell lines, cSrc, lck56, Lyn, Fyn, and CD45 are detected (73). Both MUC-1 and PSGL-1 are associated with a membrane domain rich in cholesterol (indicated by yellow rods). Cells expressing type 2 glycosynapse are capable of binding to cells expressing P-selectin, E-selectin, or siglecs. A specific structure with three tyrosine phosphates and O-linked glycan to define P-selectin-dependent adhesion in PSGL-1 was recently elucidated (33). (C) Type 3 glycosynapse with integrin receptor (ITR) having α- and β-subunits and tetraspanin (Tsp.). N-glycosylation (pink oval chains) of ITR is essential for connection and stabilization of α5- and β1-subunits (90) and also for interaction of ITR with tetraspanin CD82 (98). Interaction of some tetraspanins (e.g., CD9) with ITR requires GM3 ganglioside (53). The complex is more stable with complete N-glycosylation and is located at a low-density domain showing resistance to β-cyclodextrin.
Figure 3
Figure 3
Models of glycosylation-dependent cell adhesion with signaling. (A) Self-adhesion (autoaggregation) of human teratocarcinoma 2102 cells, with simultaneous signaling to activate transcription factors. The adhesion is mediated by two globo-series (Gb4, Gb5) and one lacto-series GSL (nLc4) based on Gb4–nLc4 or Gb4–Gb5 interaction in type 1 glycosynapse. Structures: Gb4, GalNAcβ3Galα4Galβ4Glcβ1Cer; nLc4, Galβ4GlcNAcβ3Galβ4Glcβ1Cer; Gb5, see Table 1. Adhesion by this process may occur in cooperation with E-cadherin-based homotypic interaction. The former process may be much faster than the latter. The glycosynapse membrane is indicated by a light brown color. Simultaneous with GSL-dependent adhesion, signal transducers (cSrc, RhoA, RasH) present in this glycosynapse may be activated, leading to activation of transcription factors AP-1 (activation protein 1) or CREB (cAMP responsive element binding protein). The adhesion process can be inhibited by Abs directed to Gb4, Gb5, or nLc4. (B) Adhesion of renal cell carcinoma (RCC) to peripheral blood mononuclear cells (PBMC), mediated by clustered disialogangliosides in type 1 glycosynapse, and binding of siglec-7 expressed at the PBMC surface. Three types of disialoganglioside in RCC, indicated by different colors, are organized with signal transducers (cSrc, RhoA, focal adhesion kinase) present in RCC glycosynapse. Disialogangliosides of RCC that bind to siglec-7 are GalNAc-disialyl-Lc4, disialyl-Lc4, and disialyl-Gb5 (see Table 1 for structures). Siglec-7 binds equally well to the three types of disialoganglioside, indicating a lack of binding specificity. Low binding specificity or lack of binding specificity in endogenous lectin is often seen in selectins, siglecs, and galectins. Adhesion of RCC to PBMC causes large-scale aggregation of these two types of cells, which may lead to microembolisms in lung. RCC adhesion to PBMC activates cSrc, followed by signaling (red arrows) to enhance motility and invasiveness. (C) Tumor cell (TC) adhesion to activated ECs, through type 2 glycosynapse in TCs, may activate transducers, followed by signaling to enhance TC motility and invasiveness. Mucin-type transmembrane glycoproteins are organized with signal transducers in glycosynapse (light brown). The majority of glycosyl epitopes in TCs involved in selectin-dependent adhesion are carried by mucin-type glycoproteins in type 2 glycosynapse. The glycosyl epitopes are SLex, SLex-Lex, and SLea, which bind to E-selectin but not to P-selectin unless they are expressed on PSGL-1, and sulfated SLex, which binds to P-selectin. This process, i.e., binding of activated ECs to type 2 glycosynapse of TCs, may activate Src family kinases, RhoA, and Ras present in the glycosynapse, leading to enhanced motility and invasiveness.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Anderson R G W. Annu Rev Biochem. 1998;67:199–225. - PubMed
    1. Brown D A, London E. Annu Rev Cell Dev Biol. 1998;14:111–136. - PubMed
    1. Hakomori S, Handa K, Iwabuchi K, Yamamura S, Prinetti A. Glycobiology. 1998;8:xi–xviii. - PubMed
    1. Horejsí V, Drbal K, Cebecauer M, Cerný J, Brdicka T, Angelisová P, Stockinger H. Immunol Today. 1999;20:356–361. - PubMed
    1. Simons K, Ikonen E. Nature (London) 1997;387:569–572. - PubMed

Publication types

LinkOut - more resources