I-type lectins

Biochimica et Biophysica Acta 1572 (2002) 294 – 316 www.bba-direct.com

Review

I-type lectins Takashi Angata *, Els C.M. Brinkman-Van der Linden * Glycobiology Research and Training Center, University of California, San Diego, 9500 Gilman Drive, 0687, La Jolla, CA 92093-0687, USA Received 21 March 2002; accepted 19 June 2002

Abstract The immunoglobulin superfamily is a large category of proteins defined by their structural similarity to immunoglobulins. The majority of these proteins are involved in protein – protein binding as receptors, antibodies or cell adhesion molecules. The I-type lectins are a subset of the immunoglobulin superfamily that are capable of carbohydrate – protein interactions. There are I-type lectins recognizing sialic acids, other sugars and glycosaminoglycans. The occurrence, structure, binding properties and (potential) biological functions of the I-type lectins are reviewed here. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Lectin; I-type lectin; Siglec; Cell adhesion molecule

1. Introduction ‘‘I-type lectin’’ is a collective term introduced by Powell and Varki [1] to describe carbohydrate-recognizing proteins that belong to the immunoglobulin (Ig) superfamily. This classification is somewhat broader compared with C-type lectins [2– 7] or S-type lectins (or galectins [8 –13]), which are defined by conserved amino acid residues in their carbohydrate-recognition domains (CRDs). Although a small number of proteins with an Ig-like domain (two h-sheets stacked together and cross-linked by a disulfide bond) are found in bacteria [14], Ig superfamily proteins have greatly expanded during the evolution of multicellular animals (metazoa), and acquired great sequence divergence. As a result, it is sometimes difficult to recognize Abbreviations: AIRM1, adhesion inhibitory receptor molecule 1; CRD, carbohydrate-recognition domain; EBV, Epstein – Barr virus; FGF(R), fibroblast growth factor (receptor); FISH, fluorescence in situ hybridization; FNIII, fibronectin type III; GAG, glycosaminoglycan; GPI, glycosylphosphatidylinositol; Ig, immunoglobulin; IgIV, fourth Ig-like domain; ITIM, immunoreceptor tyrosine-based inhibition motif; ITAM, immunoreceptor tyrosine-based activation motif; MAG, myelin-associated glycoprotein; NCAM, neural cell adhesion molecule; NK, natural killer; Neu5Ac, Nacetylneuraminic acid; Neu5Gc, N-glycolylneuraminic acid; OB-BP1, obesity binding protein 1; SMP, Schwann cell myelin protein; Sn, sialoadhesin * Corresponding authors. Tel.: +1-858-534-1346; fax: +1-858-5345611. E-mail addresses: [email protected] (T. Angata), [email protected] (E.C.M. Brinkman-Van der Linden).

by sequence comparison that two randomly selected Ig-like domains are phylogenetically related (the same applies to other ‘‘successful’’ protein structures, such as (h/a)8 barrel structure shared by many enzymes). Many cell adhesion molecules belong to Ig superfamily [15,16], and I-type lectins account for a small fraction of them. However, it is unknown if all I-type lectins have arisen from a recent common ancestor, or if different branches of Ig superfamily proteins have independently acquired lectin functions by functional convergence. Ig-like domains are classified into three different ‘‘sets’’, i.e. V-set, C1-set, and C2-set, based on the number and arrangement of h-strands present in the domain [15]. We followed this traditional classification in this review, but recent studies suggest the presence of ‘‘I-set’’ domains (an intermediate form between V-set and C-set), and many of the Ig-like domains previously classified as C2-set are now reclassified into this I-set [16]. With the advance of threedimensional structural analysis of proteins, further revision of domain classification may be required in the future. In the following section, we will review the properties of Itype lectins. We are deliberately inclusive in the selection of the molecules to be reviewed, i.e. any protein with Ig-like domain and reported lectin-like properties was included, unless its CRD is known not to be in the Ig-like domain. Also, proteins that bind to sulfated glycosaminoglycans are usually not considered as ‘‘lectins’’, but we will provide a brief overview of Ig superfamily proteins that show distinct binding to sulfated glycosaminoglycans.

0304-4165/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 4 - 4 1 6 5 ( 0 2 ) 0 0 3 1 6 - 1

T. Angata, E.C.M. Brinkman-Van der Linden / Biochimica et Biophysica Acta 1572 (2002) 294–316

2. I-type lectins recognizing sialic acids Quite a number of I-type lectins specifically recognize sialic acids. Sialic acids are acidic monosaccharides frequently found at the outer end of secreted and cell surface glycoconjugates, an optimal location for recognition by lectins. More than 40 different forms of sialic acid exist and they can be attached in a variety of linkages to the underlying sugar, creating a huge degree of molecular diversity [17 – 20]. Among the I-type lectins recognizing sialic acids are the Siglecs (Sialic acid-binding Immunoglobulin superfamily lectins), a structurally distinct subclass of I-type lectins [21]. Structurally different than the Siglecs, but also apparently recognizing sialic acids are CD83 [22] and cell adhesion molecule L1 [23,24]. 2.1. Sialic acid-binding immunoglobulin superfamily lectins (Siglecs) The Siglecs are single-pass type 1 transmembrane proteins with extracellular domains that share a high degree of similarity. All contain an N-terminal V-set Ig domain with the sialic acid binding site, followed by variable numbers of C2-set Ig domains. A conserved arginine residue on the F-strand of the V-set domain is essential for sialic acid binding by all Siglecs. The Siglecs contain an unusual arrangement of conserved cysteine residues in

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the V-set domain and adjacent C2-set domains that presumably results in a conventional intrasheet disulfide bond in each domain as well as an unusual interdomain disulfide bond [25]. Most Siglecs have immuno- receptor tyrosine-based motifs in the intracellular domain, suggesting a role for Siglecs in signaling events. A schematic representation of the Siglecs (and other I-type lectins) is given in Fig. 1. Each Siglec has a distinct expression pattern in different cell types, indicating that they perform highly specific functions. To assess the function of sialic acid binding by the Siglecs in intact cells is complicated because the sialic acid binding sites are often masked by endogenous ligands, which can be unmasked by sialidase treatment or sometimes by cellular activation [26 –32]. Table 1 shows an overview of expression pattern and ligand recognition by the Siglecs. More details on sialic acid binding by the Siglecs are summarized in Table 2. Except for Sialoadhesin (Sn)/Siglec-1, all human Siglecencoding genes are found on human chromosome 19q. The gene structures are similar and it is likely that they have arisen by gene duplication. Until 1998, only four members of this family of lectins had been described [21]. Now, in humans, 11 different Siglecs have been characterized, as well as one Siglec-like molecule. The more recently discovered Siglecs form a subset called the CD33/Siglec-3related Siglecs [33,34] (Fig. 1).

Fig. 1. Schematic representation of the I-type lectins. The extracellular domains of the I-type lectins consist of Ig-like domains (V-set and C2-set). L1 and NCAM also contain fibronectin type III (FNIII)-like domains. Many of the Siglecs contain ITIM and putative tyrosine-based motifs in their intracellular domains. Not shown here, but present in many of these molecules, are threonine/serine phosphorylation sites. For comprehensive overview of all animal lectins, see Fig. 4 in Ref. [293]. See also Refs. [294,295].

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Table 1 Tissue distribution and glycan recognition of the I-type lectins Name

Other name

Tissue distribution

Glycan recognized

References

Sialoadhesin CD22 CD33 MAG

Macrophages B cells Myeloid progenitors, mature monocytes Oligodendrocytes, Schwann cells Monocytes, neutrophils B cells, placental trophoblasts NK cells, monocytes

a2-3 Siab>a2-6 SiaHa2-8 Sia a2-6 Sia a2-6 Sia>a2-3 Sia a2-3 Sia a2-3 Sia/a2-6 Sia/a2-8 Sia Siaa2-6GalNAc (sialylTn) a2-6 Sia/a2-8 Sia/a2-3 Sia (3 Ig D) a2-6 Sia>a2-8 Sia>a2-3 Sia (2 Ig D) a2-3 Sia>a2-6 Sia a2-3 Sia/SLeX>a2-6 SiaHa2-8 Sia a2-3 Sia/a2-6 Sia a2-8 Sia

[35 – 48,53,60 – 64] [32,42,46,48,53,65 – 73,75,76,78,79] [28,42,129,137] [29,41,48,98 – 103,105 – 108,113,296] [42,139] [42,140] [143 – 146,152]

a

Siglecs Siglec-1 Siglec-2 Siglec-3 Siglec-4 Siglec-5 Siglec-6 Siglec-7 Siglec-8 Siglec-9 Siglec-10 Siglec-11

OB-BP1 AIRM1 SAF-2

Other I-type lectins CD83 L1 NCAM

CD56

P0

Eosinophils, mast cells Monocytes, neutrophils, NK cells (subset) B cells, eosinophils, monocytes Work in progress

Dendritic cells Neurons, glial cells, CD4 + T cells, monocytes, B cells Neurons, muscles, NK cells Schwann cells

ICAM-1 CD2

CD54

Hemolin

Endothelial cells, lymphocytes, monocytes T cells, NK cells

Hemolymph, hemocytes of insects

[147,148] [150 – 152] [158 – 160] see text

Sia on monocytes and HPB-ALL cells (T cell line) a2-3 Sia on CD24

[22,162 – 164]

High mannose N-linked on L1 (cis) N-linked (phosphacan) Hybrid/complex N-linked HNK-1 on P0 (homophilic) Hyaluronan CD43 N-glycans with fucose (maybe related to Lewis X) GlcNAc and/or Sia containing glycans?

[191 – 194,196]

[23,24,165,166,168 – 171]

[209 – 213,216] [221,222,239,242,243] [244 – 246] [248,249,251,253]

a

Note the following for the Siglecs: most studies on MAG specificities were done on rat MAG (95% identical to human MAG), the other Siglecs mentioned here refer to human Siglecs. Human and mouse Sn show the same specificities. Mouse CD22 shows the same linkage specificity as human CD22, but shows strong preference towards Neu5Gc. See Table 2 for more details on Sia binding specificities. b Sia = Sialic acid.

2.1.1. Sialoadhesin (Sn)/Siglec-1 Sn/Siglec-1 was originally found as a lectin-like adhesion molecule of 185-kDa expressed on specific macrophage

subpopulations. Sn can adhere in a sialic acid dependent manner to various lymphohematopoietic cells [35 –40]. Sn prefers a2-3-sialyllactos(amin)es over a2-6-sialyllactos

Table 2 Summary of recognition specificities of the human Siglecs Sigleca

Ability to recognize

No.

Other name

Siaa2-6 Lac(NAc)

Siaa2-3 Lac(NAc)

1 2 3 4c 5 6 7d 8 9 10 11

Sn CD22 CD33 MAGc

+b ++ ++

++

OB-BP1 AIRM1 SAF-2

a b c d

+

+ + +

++ ++ + +

++ + ++ +

Side chain/Neu5Gc recognition SLeX

Siaa2-6 GalNAc

Siaa2-8 Sia

Glycerol side chain

+/

+ + variable + variable

+ +

+ +/ ++ ?

+ + + ? +/ ?

For references on each Siglec, see Table 1. : No binding; +/ : weak binding; +: binding; ++: strong binding; ?: unknown. Specificity studies on MAG were done on rat MAG (95% identical to human MAG). Specificities for the most common isoform of Siglec-7/AIRM1 with three Ig-like domains.

+ ++ ? +/ ? +

+ ? + ?

Neu5Gc

+ + + + ? ? ? ? ?

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(amin)es and (depending on the assay used) can also bind to a2-8-linked sialic acids on glycolipids [38,41,42] (Table 2). Site-directed mutagenesis, X-ray crystallography and NMR studies have determined the molecular basis for carbohydrate recognition by Sn [43 – 45]. The conserved arginine residue on the F-strand of the V-set domain has been shown to form a salt bridge with the carboxylate of sialic acid [44] and even a conservative substitution with a lysine residue results in a 10-fold decrease in binding affinity for sialic acid [45]. Some modifications of sialic acids can enhance or reduce recognition by the Siglecs, e.g. Sn does not bind to 9-O-acetylated sialic acids [46 – 48]. The importance of the glycerol side chain of sialic acid for binding of Sn is also clear from the abrogation of binding after mild periodate treatment [41], which truncates the side chain [49 – 52]. Furthermore, Sn does not bind to N-glycolylneuraminic acid (Neu5Gc) [46,48,53]. Neu5Gc, a common modification of N-acetylneuraminic acid (Neu5Ac), is found in all mammals studied so far except humans [54 – 57]. The human deficiency in Neu5Gc is due to a frameshift mutation in the gene encoding for the enzyme that generates the N-glycolyl group [58,59]. This could possibly explain the different distribution in the spleen of Sn-positive macrophages between human and chimpanzees: in humans, they are primarily found in the perifollicular zone, whereas in chimpanzees, they also occur in the marginal zone and surrounding the periarteriolar lymphocyte sheets [53]. Initially, studies on Sn were done on the mouse or rat molecules. Human Sn has only recently been characterized and is also expressed only in macrophages and has virtually the same sialic acid binding specificities [42,53,60]. There are several arguments suggesting that Sn has been selected during evolution to mediate extracellular rather than intracellular functions. Firstly, Sn is the largest of the Siglec family, containing 17 Ig-like domains [61] (Fig. 1). The potential function for these multiple extracellular domains is to extend the lectin domain away from the sialylated glyconjugates on the cell surface, thereby constitutively unmasking the sialic acid binding site of Sn [38,40]. Secondly, the Ig-like domains of human- and mouse-Sn are 60 – 80% identical, whereas the intracellular domains are only 30% identical [60]. Thirdly, Sn has a very short cytosolic domain, and is the only human Siglec that lacks tyrosine-based (putative) signaling motifs in the intracellular domain (Fig. 1). Sn may play a role in the development of myeloid cells in the bone marrow because it is highly expressed at contact sites between macrophages and developing myeloid cells [36]. Other studies suggest a role in the trafficking of leukocytes [39,47]. A study using a murine model of allogenic tumor rejections showed that transferred, activated CD4 + and CD8 + T cells can cluster in vivo with Sn positive macrophages, an association that may be important for T cell effector functions [62]. A role in inflammation is indicated by the expression of Sn on inflammatory macrophages found in rheumatoid arthritis [60]. Furthermore, the mucin

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MUC1 on breast cancer cells was found to be a potential counter-receptor for Sn on tumour-infiltrating macrophages [63]. CD43 (leukosialin) was identified as a T cell counterreceptor for Sn and the interaction was proven to be sialic acid-dependent [64]. Although these studies give us some idea of the variety of potential functions for Sn, genetically deficient mice are needed to shed more light on this matter. 2.1.2. CD22/Siglec-2 CD22/Siglec-2 was initially found as a cell surface molecule of 140-kDa that is exclusively expressed on B cells [65,66]. There are two isoforms of CD22. The most common form has seven Ig-like domains (CD22h) and the other form has five Ig-like domains (CD22a), the latter missing domains 3 and 4 due to alternative splicing [65 – 69]. It was subsequently discovered that CD22 binds specifically to the a2-6-linked sialyllactosamines [67,70 – 73] that are commonly found on N-linked glycans of many cell surface glycoproteins [74]. Other a2-6-linkages of sialic acid, such as to GalNAc and GlcNAc, can also be recognized with a lower affinity [42,75]. A conservative substitution of the critical arginine in the V-set domain of CD22 with a lysine results in loss of binding to sialic acid [76]. As with Sn, the side chain of sialic acid is also important for binding: 9-O-acetylation of sialic acid considerably reduces the binding by CD22 [46,48,77] and mild periodate treatment abrogates the binding [71,72]. Unlike Sn, the lack of Neu5Gc in humans has most probably not led to an altered biology of CD22, because both human- and chimpanzeeCD22 can bind equally well to Neu5Ac and Neu5Gc [53,77]. However, mouse CD22 strongly prefers Neu5Gc [46,48,53]. In the last decade, the biology of CD22 has been extensively studied and it has become apparent that it has both extracellular and intracellular functions. On the cell surface of the B cell, the lectin activity of CD22 is normally found in a masked form: a2-6-linked sialylated glycoconjugates on the cell surface occupy the sialic acid binding site of CD22. Experiments using a2-6-sialylated polyacrylamide probes showed that sialidase treatment or cellular activation of human B cells can unmask the lectin activity of CD22 [30]. This is also the case for lectin activity for a23- and a2-6-sialylated glycans on human peripheral blood leukocytes that express many of the Siglec-3-related Siglecs (see below) [31]. It is reasonable to suggest that the extracellular functions that are due to the lectin activity of CD22 are dependent on the status of this masking phenomenon. Murine bone marrow sinusoidal endothelium contains sialylated ligands for CD22 and these may be used for homing of B cells to the bone marrow [32,78,79]. This is indicated by the finding that B cells expressing an unmasked form of CD22 are enriched in the bone marrow compared to those from spleen or mesenteric lymph nodes [32]. This unmasking must be due to decreased activity of ST6Gal-I, the enzyme that generates the sialylated ligands for CD22,

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or the activation of sialidases, or the differential cell surface sorting of CD22 and its cis-ligands. In addition, CD22deficient mice have reduced numbers of mature (IgDhi) B cells in the bone marrow [80]. However, mice deficient for ST6Gal-I have normal numbers of mature B cells in the bone marrow [81]. In this case, the homing may either occur by a compensatory mechanism, or via another sialyltransferase in endothelial cells of the bone marrow that regulates the sialylation of CD22 ligands. A role for CD22 in inflammation is suggested by a study showing that TNFa,LPS and IL-1h upregulate ligands for CD22 on endothelium [82], thus potentially affecting B cell migration. CD22 is noncovalently associated with the B cell receptor (BCR) complex [83,84]. BCR ligation induces tyrosine phosphorylation of the intracellular domain of CD22 by lyn kinase resulting in the recruitment of the tyrosine phosphatase SHP-1 to the three inhibitory tyrosine-based motifs (ITIMs) of the intracellular domain of CD22 [85 – 88], indicating that CD22 may function as a negative regulator of B cell signaling [89]. Other molecules such as Syk, PLCg, PI3 kinase, Grb2, and Shc are also recruited by phosphorylated CD22, suggesting a role in both positive and negative signaling [90 – 92]. These findings are in agreement with the fact that CD22-deficient mice show either B cell hypo- or hyper-responsiveness depending upon the exact experimental conditions used [80,93 –96]. BCR stimulation of B cells from CD22-deficient mice show an elevated calcium influx compared to normal B cells. In addition, the B cells from these CD22-deficient mice show a mildly activated phenotype and with aging produce autoantibodies [97]. ST6Gal-I-deficient mice show a generally similar although more severe phenotype [81], suggesting that a2-6-sialylated glycans are involved in B cell regulation and that other sialic acid-binding proteins on the B cell besides CD22 may be involved as well. Mice expressing CD22 with its critical arginine mutated are needed to show if the lectin activity of CD22 is directly involved in the signaling function of this molecule. In this respect, ligation of CD22 using external multivalent a2-6-sialylated probes may also add more information. In the meantime, the precise role of the sialic acid binding ability of CD22 in its signaling function remains unclear. 2.1.3. Myelin-associated glycoprotein (MAG)/Siglec-4a and Schwann cell myelin protein (SMP)/Siglec-4b Myelin-associated glycoprotein (MAG)/Siglec-4a is a glycoprotein expressed on oligodendrocytes (in central nervous system, CNS) and Schwann cells (in peripheral nervous system, PNS), the cells which form myelin sheaths around neural fibers. MAG is the only Siglec exclusively expressed in the nervous system. MAG is comprised of five Ig-like domains, a transmembrane domain and an intracellular domain. Two major isoforms of MAG, namely L-MAG and S-MAG, have been documented, and the difference in the molecular weight between these two isoforms is explained by the different

length of the intracellular domain, the result of alternative RNA splicing [98]. The property of MAG as a cell adhesion molecule was discovered in 1987 [99], and its ability to recognize glycans containing sialic acids was realized in 1994 [100], when the molecular cloning of Sn [61] led to the detection of the sequence similarity amongst Sn, CD22, CD33, and MAG. The first evidence of sialic acid recognition by MAG was provided by Kelm et al. [100], and the detailed analyses of its binding specificity to various sialylated ligands have been conducted mostly by groups led by Schnaar [29,41,101,102] and Kelm [48,103] in the following years. The minimal structural requirement for robust MAG recognition is Neu5Aca2-3Galh1-3GalNAc (as frequently found in O-linked glycans and complex gangliosides) [41,102], although it also recognizes Neu5Aca2-3Galh14Glc[NAc] (as found in N-linked glycans and ganglioside GM3) [100,103]. Unlike many other Siglecs, ligand recognition is strongly affected by the structural context of the underlying glycan [41]. Thus, in case of glycolipids, efficiency of binding to effective minimal ligand IV3Neu5AcGgOse 4 Cer (Neu5Aca2-3Galh1-3GalNAch1-3Galh14Glc-Cer) is strongly enhanced by substitutions with Neu5Ac residue(s) at positions II (Gal) and III (GalNAc), as in GT1b (Neu5Aca2-3Galh1-3GalNAch1-3[Neu5Aca28Neu5Aca2-3]Galh1-4Glc-Cer) and GQ1ba (Neu5Aca23Galh1-3[Neu5Aca2-6]GalNAch1-3[Neu5Aca2-8Neu5Aca2-3]Galh1-4Glc-Cer), while the addition of Neu5Ac residue on the Neu5Ac at position IV as in GQ1b (Neu5Aca2-8Neu5Aca2-3Galh1-3GalNAch1-3[Neu5Aca28Neu5Aca2-3]Galh1-4Glc-Cer) has strong negative effect on the binding [41]. Further study has revealed that the substitution of underlying sugars at positions II and III with sulfate esters is as efficient as substitution with Neu5Ac [101], suggesting that the presence of negative charges at proper positions is all that is essential for this effect. In contrast, the structure of a2-3-linked sialic acid residue at the terminal position (Neu5Aca2-3Galh1-3GalNAc) has strong influence on the binding affinity. Modification of carboxyl group at C1 position abolishes MAG binding, as does truncation of glycerol-like side chain at C7 –C9 [29]. Neu5Gc does not make as good a ligand as Neu5Ac [29], while KDN (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid) makes even better ligand than Neu5Ac [103], indicating that MAG also recognizes the C5 substitution. Studies using synthetic sialic acid analogs also led to a similar conclusion [48]. Whether the natural ligands in vivo for MAG are glycolipids or glycoproteins remains in question. The evidence in favor of the former is that the mice deficient in GM2/GD2 synthetase (the enzyme required for complex ganglioside biosynthesis) shows similar phenotype as MAG-deficient mice, and the expression level of MAG is reduced in these mice [104]. The evidence in favor of the latter is that several glycoproteins interact with MAG [105 – 107], including fibronectin [108]. Probing of the brain of

T. Angata, E.C.M. Brinkman-Van der Linden / Biochimica et Biophysica Acta 1572 (2002) 294–316

GM2/GD2 synthetase-deficient mice with recombinant MAG protein may provide clues to answer this question. Some studies suggested that there are alternative ligands for MAG other than sialylated glycoconjugates, such as heparin, collagens [109], and tenascin-R [110]. The biological significance of these alternative ligands are yet to be understood. Earlier studies using in vitro systems have suggested that MAG plays critical roles in neural development, such as neural cell adhesion, positive and/or negative regulation of neurite outgrowth, and myelin sheath formation [111]. One study using an arginine point mutant suggested that the neurite inhibition property of MAG was not due to sialic acid recognition [112]. However, a more recent study shows that the mutant MAG can still recognize the core glycan structure of its ligands and that this may be sufficient to carry out this inhibitory function under optimized conditions in vitro [113]. Regardless, it came as a surprise that MAGknockout mice showed rather subtle phenotypes, such as mild delay of myelination in young mice and hypomyelination in adult mice [114,115]. However, the phenotypes observed in these knockout mice were consistent with earlier prediction that MAG is functionally involved in the myelin formation and maintenance, and apparently its function is compensated by other molecules in MAGdeficient mice (for more detailed discussions on the phenotypes of MAG-deficient mice, see review in Ref. [116]). Differential expression of L-MAG (dominant form in early stage of neural development in CNS in rodents) and S-MAG (dominant form in PNS and adult CNS in rodents) suggests different roles of these isoforms, which was verified by the CNS-specific phenotype of L-MAG-specific knockout mice [117]. It is of note that in primates, L-MAG remains the dominant form in adult CNS [118], and is apparently subject to rapid proteolytic release by endogenous protease(s) [119]. The functional significance of such differences between rodents and primates remains unknown. Involvement of MAG in intracellular signaling has been suggested, based on its property to be phosphorylated at serine (both L- and S-MAG), threonine and tyrosine (LMAG only) [120 –122], and to interact with various molecules, including S100h [123], phospholipase Cg [124] and protein tyrosine kinase Fyn [125] at its cytosol. How these molecular interactions affect properties of myelin-forming cells remains to be solved. On the other hand, a recent report suggested MAG binding to GT1b (or glycoprotein with GT1b-like glycan epitope) on opposing (neural) cells induce cellular signaling involving Rho signaling pathway [113], leading to inhibition of neurite outgrowth. Sequence comparison of human and mouse Siglecs suggests that MAG is the most well-conserved member of the Siglec family [126]. A study using a polyclonal antibody has detected MAG-like molecules in all vertebrates tested (except in chondrichtis, or cartilaginous fish) [127], and a MAG-like sequence was also easily identified by a database search of puffer fish genomic DNA database (T. Angata and

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A. Varki, unpublished observation). This is somewhat surprising, given that CD22 (the gene located adjacent to the MAG gene in both human- and mouse-genomes) has diverged to far greater extent [126]. This suggests that the extended recognition specificity of this molecule towards sialylated glycans has restricted the range of permissible mutations. In fact, the highest degree of sequence identity between human- and mouse-MAGs in the extracellular domains is observed in the first Ig-like domain. SMP/Siglec-4b is an avian Siglec expressed on Schwann cells and oligodendrocytes [128]. Molecular cloning of SMP and primary sequence analysis revealed certain degree of sequence similarity between SMP and MAG, particularly in the transmembrane domain (80.0% identity), first Ig-like domain (61.4%), and an eight-amino acid segment at the Cterminal that include a tyrosine residue [128]. It is still not clear if SMP is the avian ortholog of MAG, although the original literature argues against this possibility [128]. Nevertheless, SMP shows near-identical binding specificity towards sialylated glycolipids as MAG [41], suggesting that the molecule is a functional equivalent of MAG in the avian nervous system. 2.1.4. CD33/Siglec-3 and related Siglecs CD33 has been utilized as a useful developmental marker of the myelomonocytic lineage for many years. In human, CD33 is expressed on immature cells of myelomonocytic lineages and on mature monocytes. Molecular cloning of human CD33 [129], CD22 [65,66], and rat MAG [98] originally provided evidence that these proteins belong to a distinct subset of Ig superfamily molecules. Recognition of the capability of CD22 to recognize sialic acid in linkagespecific manner [71,72], and the subsequent molecular cloning of Sn [61] led to the realization that sialic acid binding may be a common property of all these molecules. Proof that CD33 is a sialic acid recognition molecule [28] soon followed. These studies originally led to the proposal to call these and other molecules with distinctive sequence similarity and sialic acid-binding capability as Siglecs [21]. The expansion of Siglec family members in the past few years was facilitated by the increased availability of expressed sequence tag (EST) and genomic DNA sequences. Independent studies to clone inhibitory signaling molecules have also contributed to discover significant number of Siglecs. All of the newly discovered Siglecs (human Siglec-5, -6, -7, -8, -9, -10, -11, and Siglec-L1; mouse Siglec-E and-F) belong to the subgroup of Siglecs called CD33/Siglec-3-related Siglecs. These are defined by close phylogenetic relationship (reflected in their mutual sequence similarity) distinct from other Siglecs (Sn/Siglec-1, CD22/ Siglec-2, and MAG/Siglec-4a). Most members of this subfamily also have tyrosine-based putative signaling motifs in intracellular domain, one of which (membrane-proximal motif) conforms to the canonical immunoreceptor tyrosine-based inhibitory motif (ITIM) [33,34]. The close sequence similarity of CD33/Siglec-3-related Siglecs sug-

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gests that these molecules were generated by repeated gene duplications, and this view is supported by the fact that most of these genes are clustered on a defined chromosomal region ( f 500 kb) on chromosome 19 in humans and the syntenic region of chromosome 7 in mice [126]. In contrast to Sn/Siglec-1, CD22/Siglec-2, and MAG/ Siglec-4a, for which human and mouse orthologs are easily identified, phylogenetic relationships among human- and mouse-CD33/Siglec-3-related genes are difficult to determine. This is partly because CD33/Siglec-3-related gene cluster has undergone different evolutionary paths in primates and rodents, with far more frequent gene duplications (and subsequent inactivations, testified by the presence of numerous Siglec-like pseudogenes) taking place in primate lineage [126]. Adding to the confusion, the degree of sequence conservation between putative human and mouse orthologs are not very high. By combination of phylogenetic analysis, chromosomal localization of genes and overall gene structure, orthologous relationships between mouse and human CD33/Siglec-3-related Siglecs were tentatively identified [126]. In the following sections, CD33/Siglec-3-related Siglecs are classified on the basis of sequence similarity and domain structure of human Siglecs, with reference to putative mouse orthologs. In most cases, the functional link between sialic acid recognition and intracellular signaling by these molecules is not clearly determined. Pursuit of this link should be a major topic of Siglec studies in the future. 2.1.4.1. CD33/Siglec-3. As mentioned above, human CD33 has been used as a useful differentiation marker, without much knowledge of the functional aspects of this protein. Identification of CD33 as a member of Ig-like sialic acid binding proteins, now known as Siglecs, provided the first clue to its function. CD33 consists of two Ig-like domains, a transmembrane domain and an intracellular domain that contains two tyrosine-based putative signaling motifs. Human CD33 shows binding to both a2-3-linked and a2-6-linked sialic acids. An earlier study indicated that CD33 prefers the former [28], while a more recent study indicated otherwise [42]. This apparent discrepancy may be due to the difference in the assay format in these studies: both employed solid-phase binding assay using recombinant CD33 protein, and the former study employed resialylated human erythrocyte as ligands, while the latter employed synthetic oligomeric probes as ligands. Regardless, the ligand recognition specificity of CD33 is not as stringent as those of CD22/Siglec-2 or MAG/Siglec-4a. Evidence for CD33 as an inhibitory signaling molecule was provided by three independent studies [130 – 132]. Molecular interactions with phosphotyrosine phosphatases SHP-1 and SHP-2 were demonstrated, and the binding site for the SHP-1 and SHP-2 was determined to be the phosphotyrosine in the canonical ITIM. Taylor et al. [130] found that point-mutation of the tyrosine residue in the

ITIM (where SHP-1 and SHP-2 docks upon phosphorylation) results in enhancement of CD33 binding to its sialylated ligand, suggesting the involvement of tyrosine phosphorylation in the regulation of ligand binding activity of CD33. Pursuing the prevalent model that inhibitory receptors impose their function by co-localization with activatory receptors, two studies have shown that co-ligation of CD33 and myeloid activatory receptor FcgRI actually reduces activatory signals (calcium mobilization) caused by FcgRI cross-linking [131,132]. Moreover, antibody crosslinking of CD33 alone can induce apoptosis in monocytes [133] and myeloid leukemia cells [134], and inhibit proliferation of normal or leukemic myeloid cells [135]. Utilization of CD33 as a marker for acute myelogenous leukemia has been explored by several groups, and a toxin-conjugated monoclonal anti-CD33 antibody is approved as a chemotherapeutic agent by the Food and Drug Administration [136]. A recent paper by Grobe and Powell [137] described that CD33 is phosphorylated at serine residues by protein kinase C, and the serine phosphorylation and sialic acid binding negatively regulate each other in a reciprocal manner. A putative mouse ortholog of human CD33 was cloned, and mRNA expression pattern appeared to be consistent with the assignment of this molecule as mouse CD33 [138]. Notably, this molecule lacks the ITIM-like putative signaling motif commonly found in CD33/Siglec-3-related Siglecs but maintains the membrane-distal motif. If and how this molecule is involved in cellular signaling is yet to be determined, as is its binding specificity towards sialylated glycans. 2.1.4.2. Siglec-5 and Siglec-6/obesity binding protein 1 (OB-BP1). Siglec-5 consists of four Ig-like domains, a transmembrane domain and an intracellular domain [139], while Siglec-6/OB-BP1 consists of three Ig-like domains, a transmembrane domain and an intracellular domain [140]. Both molecules have two tyrosine-based putative signaling motifs, although the functionality of these motifs have not been examined so far. Sequence similarity between these molecules are not extensive, except for the third Ig-like domain [140], but the presence of exon fossil for the fourth Ig-like domain in Siglec-6 gene, which shows high similarity to that of Siglec-5 [126], suggests that these molecules are evolutionarily closely related. However, such ‘‘patchy’’ sequence similarity between molecules/genes (typically observed in CD33/Siglec-3-related Siglecs) could be the consequence of exon shuffling in the past, and may require cautious interpretation. Siglec-5 is the first Siglec to be cloned on the basis of computer-based sequence similarity search [139]. The molecule was shown to be expressed on monocytes and neutrophils by flow-cytometry. Fluorescence in situ hybridization (FISH) revealed that Siglec-5 gene is located on the human chromosome 19, cytological band 19q13.41 – q13.43, near the CD33 gene locus [139]. This finding was

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the first to suggest the presence of CD33/Siglec-3-related gene cluster on this region. Siglec-6/OB-BP1 was cloned by expression cloning, in search of leptin-binding protein (OB is an abbreviation for ‘‘obesity’’, the name given to the putative gene, mutation of which causes extreme obesity in mice; the gene was identified as leptin, hence OB = leptin) [140]. Siglec-5 was also cloned as a molecule that shows sequence similarity to Siglec-6 in the same study, but the binding of leptin to Siglec-5 was rather unremarkable. Expression of Siglec-6 was observed in placenta (by Northern blotting and immunohistochemistry), and on B cells (by flow-cytometry). The cDNA of Siglec-6 was independently cloned by another group, and its gene was shown to be localized on cytological band 19q13.3 by FISH [141]. Siglec-5 shows relaxed binding specificity towards sialic acids in different linkages, recognizing both a2-3- and a26-linked sialic acids [139], as well as a2-8-linked sialic acids [42]. In contrast, Siglec-6 shows strict binding specificity towards Neu5Aca2-6GalNAca-, or sialyl-Tn antigen [140]. Also, Siglec-6 does not at all require the glycerol-like side chain of sialic acid (C7 – C9) for recognition, while Siglec-5 is more or less sensitive to the truncation of this group by periodate treatment [42]. These differences between the two Siglecs are not too surprising, given the low degree of sequence similarity between the first two Iglike domains of these two molecules. A putative mouse ortholog of Siglec-5, mSiglec-F, was cloned and characterized [126]. From the overall structural similarity of mSiglec-F and Siglec-5 (containing four Ig-like domains), as well as similar expression pattern and position of these genes in the CD33/Siglec-3-related gene cluster, it was tentatively assigned as Siglec-5 ortholog [126]. However, the expression patterns of mSiglec-F and human Siglec-5 are not completely overlapping: the former is predominantly expressed on immature cells of myelomonocytic lineages, while the latter is on mature monocytes and neutrophils [139]. The comparison is further complicated by the fact that mouse and human myeloid cells show significantly different morphology [142], and the lack of definitive developmental markers for mouse myeloid lineage. Unequivocal determination of orthologous relationships of CD33/Siglec-3-related Siglecs in different species will require sequencing of the CD33/Siglec-3-related gene cluster in multiple mammalian species. Notably, mSiglec-F showed strict linkage specificity towards a2-3-linked sialic acids, which is unique among Siglec-3-related Siglecs reported so far. 2.1.4.3. Siglec-7/AIRM1, Siglec-8, Siglec-9 and Siglec-L1/ S2V. Siglec-7/AIRM1, Siglec-8 and Siglec-9 share the same basic architecture, i.e. three Ig-like domains, a transmembrane domain and an intracellular domain with two tyrosine-based putative signaling motifs. They also show distinct mutual sequence similarity, defining a small branch of the phylogenetic tree of the CD33/Siglec-3-related

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Siglecs. The lack of an intron between the coding sequences for the signal peptide and the first Ig-like domain is another unique property among these Siglecs. Siglec-7/AIRM1 (adhesion inhibitory receptor molecule 1) was independently cloned by three groups. The study on the natural killer (NK) cell inhibitory molecule p75/AIRM1, recognized by monoclonal antibody Z176, led to the cloning of a cDNA that resembles CD33/Siglec-3-related Siglecs [143]. The authors demonstrated sialic acid-dependent interaction between p75/AIRM1 and human erythrocytes, its restricted expression on NK cells among lymphocytes, and molecular interaction between this molecule and SHP-1 [143]. Another paper on the cloning of a novel Siglec, Siglec-7, was reported by Crocker’s group, which turned out to be identical to p75/AIRM1 [144]. They reported Siglec-7 recognition of both a2-3- and a2-6-linked sialic acids, its gene localization on cytological band 19q13.3 by FISH, and the protein expression on an NK cell subset, a small subset of CD8 + T cells, monocytes, and granulocytes. Our group’s report describing the cloning and properties of a shorter isoform (lacking the second Ig-like domain) of the same molecule was published later [145]. Interestingly, these two isoforms (with three versus two Ig-like domains) show somewhat different specificity towards sialic acid linkages: the longer (three Ig-like domains) isoform recognize both a2-3- and a2-6-linked sialic acids [144], while the shorter (two Ig-like domains) isoform is specific towards a2-6linked sialic acids [145]. Another report suggested that Siglec-7 shows strong preference towards a2-8-linked sialic acids [146]. Differences in the assay formats makes direct comparison between the studies difficult; however, when polyacrylamide-based polyvalent probe binding to immobilized recombinant proteins was analyzed, the three Ig-like domains isoform showed robust binding to all linkages tested (a2-6 z a2-8 = a2-3), while the two Ig-like domains isoform showed strong preference towards a2-6-linked sialic acids (a2-6>a2-8>a2-3; T. Angata and A. Varki, unpublished results). We also noted that probe binding to the longer isoform was much more robust than that to the shorter isoform. Functional significance of such isoform variation remains speculative. The longer isoform appears to be dominant in most tissues, judging from the mRNA size distribution [144,145]. The property of Siglec-7/AIRM1 as a negative regulatory molecule was further exemplified by the studies showing the cross-linking of this molecule by monoclonal antibody inhibits proliferation and differentiation of normal myeloid cells [133], proliferation of chronic [135] and acute myeloid leukemia cells [134]. Siglec-8 was also cloned by two groups [147,148]. The first report from Crocker’s group described its restricted expression in the eosinophil, gene localization on cytological band 19q13.33 – 13.41 by FISH, and binding to both a2-3- and a2-6-linked sialic acids (a2-3>a2-6) [147]. The other report (calling the molecule SAF-2) showed that Siglec-8/SAF-2 is also expressed on mast cells and baso-

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phils (although the expression on basophils appeared to be marginal) [148]. Notably, cross-linking of this molecule with monoclonal antibodies did not modulate eosinophil activity in either positive or negative way, raising the question regarding the signaling function of Siglec-8 [148]. Nevertheless, Siglec-8 appears to be a useful eosinophil lineage marker. In these original reports, the intracellular domain of Siglec-8 appeared significantly different from those of other CD33/Siglec-3-related Siglecs, being quite short and free of tyrosine-based motifs [147,148]. Later, a Siglec-8 isoform with longer intracellular domain with two tyrosine-based putative signaling motifs (which authors call Siglec8L) was identified by database search and RT-PCR [149]. The originally described Siglec-8 mRNA apparently does not conform to the conventional rules of splicing [149]. This may be explained by the presence of f 80% identical Alu elements in the 3V-end of ‘‘exon 6a’’ and 5V-upstream of ‘‘exon 7a’’ (denomination following Ref. [149]), which might have caused spurious recombination during reverse-transcription or amplification in Escherichia coli. Another (and more interesting) possibility is that this is a naturally occurring polymorphism in the human population. Molecular cloning of Siglec-9 was reported simultaneously by two groups [150,151]. Both papers described its expression on granulocytes and monocytes (the former also found its expression on a subset of NK cells) and binding to both a2-3- and a2-6-linked sialic acids (a2-3 z a2-6). Unlike other Siglecs tested [42], the ligand binding of Siglec-9 is not affected by fucosylation of the underlying GlcNAc (i.e. sialyl LewislNeu5Aca2-3Galh1-4[Fuca13]GlcNAc binds as well as sialyllactosamine Neu5Aca23Galh1-4GlcNAc) [151]. Siglec-9 also has two tyrosinebased putative signaling motifs, but their functionality has not been examined. A recent study [152] has provided more detailed ligand binding specificity of Siglecs-7 and -9, and shown that the putative C –CVloop (the loop connecting h-strands C and CVin the first Ig-like domain) determines the different binding specificity between Siglec-7 (prefers a2-8-linked sialic acids) and Siglec-9 (does not bind a2-8-linked sialic acids). Assuming that all Siglec V-set domains adopt similar threedimensional structure as Sn/Siglec-1 [44], this loop may be a part of glycan binding site determining specificity in other Siglecs as well. There is a mouse Siglec, mSiglec-E/MIS, which shares basic molecular structure with the human Siglecs-7, -8 and 9 [153,154]. A search of Siglec-like molecules in mouse led to the discovery of myeloid inhibitory Siglec (MIS) [154]. An independent study in search of molecules interacting with SHP-1 in humans resulted in the molecular cloning of mSiglec-E [153], which turned out to be identical to MIS (the human cDNA library was apparently contaminated with mouse cDNA). Both studies showed that mSiglec-E/MIS interacts with SHP-1 and SHP-2 in a tyrosine phosphorylation-dependent manner, and that the membrane-proximal

tyrosine residue (in the canonical ITIM) is the docking site for both phosphatases. The latter group showed sialic aciddependent interaction between mSiglec-E and human erythrocytes, although detailed studies on binding specificity are yet to be reported. Phylogenetic relationship of this molecule and human Siglecs was analyzed [126], and it is likely to be the mouse ortholog of human Siglec-9 (or of the common ancestor of human Siglecs-7, -8, and -9), although this assignment is not conclusive. There is another human Siglec (or rather, Siglec-like molecule) showing high similarity to Siglecs-7, -8, and -9. A functional survey of the molecules interacting with SHP-1 in human led to the molecular cloning of S2V, a novel Siglec-like molecule [155]. The molecule has two V-set domains, two C2-set domains, a transmembrane domain and an intracellular domain, which contain two putative tyrosine-based signaling motifs [155]. This molecule is unusual among Siglecs in two aspects: firstly, it has two V-set domains (all other Siglecs have only one V-set domain at the N-terminal); secondly, both V-set domains lack the ‘‘critical arginine’’ residues typically required for sialic acid recognition. The authors reported S2V interaction with SHP-1 and SHP-2 in tyrosine phosphorylation-dependent manner, its phosphorylation by protein tyrosine kinase Src, and identification of membrane-proximal tyrosine (in the canonical ITIM context) as the SHP-1 docking site. These authors proposed a model whereby a glutamine residue in the second domain could substitute for the ‘‘critical arginine’’. Meanwhile, our group independently cloned the same molecule and named it Siglec-L1 (for Siglec-like molecule 1), since we could not observe sialic acid-dependent interaction between this molecule and probes [156]. This appears to contradict with the earlier report, which showed some sialic acid-dependent binding of S2V to human erythrocytes [155]. Perhaps this is due to the difference in the stringency of criteria to define sialic acid-dependent binding in these studies. Our study showed that the orthologs of Siglec-L1/S2V in great apes (chimpanzee, bonobo, gorilla, and orangutan) do have the critical arginine in the first V-set domain (on the other hand, the arginine in the second V-set domain was missing in all great ape orthologs, as in human Siglec-L1/S2V). Moreover, a human Siglec-L1 reverse-mutant, restoring the critical arginine residue in the first V-set domain, and its chimpanzee ortholog robustly bound glycans in sialic acid-dependent manner, and prefers Neu5Gc over Neu5Ac. As mentioned above, Neu5Gc is missing in modern humans due to the human-specific mutation of CMP-Neu5Ac hydroxylase [59] but is expressed abundantly in other mammals, including great apes [57]. Therefore, it seems reasonable to assume an evolutionary link between the loss of sialic acid-binding property of human Siglec-L1 and loss of Neu5Gc in modern humans [156]. It will also be interesting to see if a naturally occurring frameshift mutation of the human Siglec-L1 gene has any functional consequences. Gene organization of Siglec-L1 and Siglec-7 are extremely similar, suggesting

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the common origin of these genes, i.e. Siglec-7 gene contains a relic of an exon (encoding V-set domain) between the first and second functional Ig-like domains, which shows high degree of sequence identity with the second V-set domain of Siglec-L1 [156]. Another study has shown that Siglec-L1/S2V has a splice variant, which lacks the first V-set domain [157]. There does not appear to be an ortholog of Siglec-L1 in the mouse genome [126]. 2.1.4.4. Siglec-10 and Siglec-11. Siglec-10 consists of five Ig-like domains, a transmembrane domain and an intracellular domain, which contains an additional ITIM-like motif in the extended cytosolic section unique to this molecule (Fig. 1). Siglec-10 was independently cloned by three groups [158 –160]. The first paper by Crocker’s group reported its binding to both a2-3- and a2-6-linked sialic acids (a2-6 z a2-3) and protein expression on monocytes, eosinophils, B cells, and CD16 + CD56 lymphocytes by flow cytometry [158]. They also identified its gene localization on the cytological band 19q13.3 by FISH, and its unique position in the Siglec phylogeny, which appears to be in the midpoint between MAG/Siglec-4a and the rest of CD33/Siglec-3-related Siglecs. The second paper was on the cloning of a shorter isoform of Siglec10 (lacking fifth Ig-like domain), showing essentially the same binding preference of this shorter isoform to sialylated ligands as the full-length isoform, and its expression in monocytes and dendritic cells [159]. Interestingly, their Northern blotting analysis indicates that mRNA of Siglec10 is differently processed in different tissues; for example, peripheral blood leucocytes exclusively express f 3.3 kb mRNA (presumably the full-length), while f 1.8 kb mRNA was predominant in spleen and liver [159]. (It should be noted that they used a probe that anneals to the 3V-end of the coding sequence.) The nature of this short isoform is yet to be determined. The third paper provided insight into the molecular interaction between Siglec-10 and protein tyrosine kinases and phosphatases [160]. The study showed that Siglec-10 can be phosphorylated at Tyr-597 and Tyr-667 (the tyrosine residues in the ITIM context; the first ITIM is unique to Siglec-10, while the second ITIM is common among CD33/Siglec-3-related Siglecs), and possibly at Tyr-691 (the tyrosine in the membrane-distal putative signaling motif) by Lck, Jak3, and Emt, representatives of three of the four major families of protein tyrosine kinases. Phosphotyrosine phosphatases SHP-1 and SHP-2 interact with the intracellular domain of Siglec-10 in phosphorylation-dependent manner, and SHP-1 interacts preferentially with the second ITIM, while SHP-2 appears to interact with both the first and second ITIMs [160]. The presence of three splice variants of Siglec-10 was also reported [161]. Analysis of mouse genomic DNA sequence suggests that there is a well-conserved putative ortholog of human Siglec-

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10 in mouse, which was tentatively denoted mSiglec-G [126]. Siglec-11 is a recently cloned molecule with five Ig-like domains, a transmembrane domain and an intracellular domain, which shows high degree of sequence similarity with Siglec-10 at the extracellular domain. The intracellular domain contains two tyrosine-based putative signaling motifs, as in other typical CD33/Siglec-3-related molecules. It shows weak but specific binding to a2-8-linked sialic acids [297]. 2.2. CD83 CD83 is a 45 kDa glycoprotein expressed on mature dendritic cells [162 –164]. It consists of a single V-set Iglike domain, a transmembrane domain, and a short intracellular domain of 39 amino acids [162]. Recently, it has been shown that a soluble CD83 – Ig fusion protein binds to monocytes, to a fraction of activated CD8 + T cells or stressed CD8 + T cells, and to the leukemia T cell lines Jurkat and HPB-ALL [22]. Furthermore, a carcinoma cell line transfected with CD83 bound to HPB-ALL cells. Binding to monocytes and HPB-ALL cells was determined to be sialic acid-dependent, based on sialidase treatment of the target cells, thus including CD83 into the family of I-type lectins. Because CD83 does not contain the typical V-set and C2-set Ig-like domains representative of the known Siglecs, it was decided not to classify this molecule as a true Siglec. The counter-receptor on HPB-ALL cells was shown to be a glycoprotein of 72 kDa [22]. These findings indicate that CD83 may be involved in the interaction between dendritic cells and circulating monocytes as well as activated and/or stressed T cells. The potential cell adhesive function of CD83 (and the importance of the sialic acidbinding activity of CD83 for its function) needs to be further explored. 2.3. Cell adhesion molecule L1 L1 is a homophilic and heterophilic adhesion molecule of 200 kDa that was originally found in the nervous system where it plays an important role in axon guidance and cell migration. L1 was later also found on CD4 + T cells, monocytes, and B cells [165]. It has an extracellular domain consisting of six Ig-like domains and five fibronectin type III (FNIII)-like domains, a transmembrane domain and an intracellular domain [166]. (For reviews on L1, see Refs. [167 –175].) L1 contains multiple binding sites and these are involved in homophilic interactions, in assisted homophilic interactions between L1 and L1/neural cell adhesion molecule (NCAM) complexes at the surface of adjacent cells (see below), and in heterophilic interactions with integrins [165,176,177]. The importance of L1 for neurogenesis is clear from disorders in humans with L1 defects. Disorders caused by mutations in the L1 gene include X-linked hydrocephalus, MASA syndrome (mental retardation, apha-

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sia, shuffling gait, adducted thumbs), spastic paraparesis type 1 and X-linked agenesis of corpus callosum [175,178]. Interestingly, L1-deficient mice show many phenotypic similarities with humans that have L1 disease [171,174, 179 – 181]. It is known that L1 can bind to CD24 [23,182], a highly glycosylated mucin linked to the cell surface membrane with a glycosylphosphatidylinositol (GPI)-anchor, which is, like L1, found in the nervous system and on immune cells. CD24 can also be recognized by P-selectin [23], a member of the selectin family [4]. The interaction between L1 and CD24 on neurons appears to modulate the signal transduction functions of L1 [182]. Further studies indicated that this interaction is mediated by the O-linked glycans on CD24 and may be dependent on sialic acid [23]. A more recent study demonstrated that sialic acids in an a2-3linkage on CD24 are essential for the interaction between L1 and CD24 [24]. Interestingly, CD24-induced effects on neurite outgrowth are mediated via L1 and depend on a2-3linked sialic acid residues on CD24 [24]. Although the first FNIII domain of L1 contains a putative sialic acid binding site, the true sialic acid binding site has not been determined [24].

3. I-type lectins recognizing other sugars Several Ig superfamily proteins reportedly recognize glyococonjugates in a sialic acid-independent manner. These molecules lack a recognizable common sequence motif defining carbohydrate binding, and do not share binding specificity either, hence not to be considered as a cohesive subfamily of I-type lectins. It is tempting to include the Receptor for Advanced Glycation Endproducts (RAGE) [183] in this group of molecules, because of the fact that probes used in the search of binding proteins for Advanced Glycation Endproducts (AGEs) are prepared via spontaneous coupling between the aldehyde group of free monosaccharides (typically glucose or glucose-6-phosphate) and the q-amino group of lysines in proteins (typically bovine serum albumin). However, the Schiff base formed between the aldehyde group of free sugar and the amino group of lysine further undergoes complex chemical reactions, and the true end-products are rather poorly characterized mixture of compounds which do not fit the definition ‘‘carbohydrate’’ very well [184]. Therefore, we are not including this molecule in this review. It would be interesting to know if RAGE recognizes glucose– lysine Schiff base, rather than true advanced glycation end products, such as N q-carboxymethyl lysine. 3.1. Neural cell adhesion molecule NCAM is one of the first cell-adhesion molecules to be identified and among the most extensively studied. NCAM is expressed in many tissues, but the most conspicuous

expression is found in the brain. NCAM is highly conserved among vertebrates, and molecules of similar architecture can be found even in fruit fly (fasciclin-II), suggesting the universal functional significance of NCAM-like molecules in neural development. The extracellular domain of NCAM consists of five Iglike domains (C2-set) and two FNIII-like domains. Of three major isoforms of NCAM polypeptides identified in brain, the short isoform (f120 kDa) is attached to cell membrane by a GPI-anchor, while intermediate (f140 kDa) and long (f180 kDa) isoforms have a common transmembrane domain and intracellular domain of different lengths. These and other isoforms, of which some are considered tissuespecific, are created by alternative splicing of mRNA [185]. Addition of polysialic acid (PSA) to one (or more) of Nlinked glycans in the fifth Ig-like domain accounts for the major difference between embryonic and adult forms of NCAMs [186]. For more detailed discussions, on the PSA and NCAM functions, see reviews in Refs. [186 –188]. NCAM shows both homophilic (NCAM to NCAM) and heterophilic (NCAM to other molecule) interactions. Homophilic interaction is mediated by protein – protein interaction, and negatively affected by the presence of PSA [189,190], which explains the different adhesive properties of embryonic form (less adhesive) and adult form (more adhesive) of NCAM. Many examples of heterophilic interaction of NCAM have been documented, and some of these involve NCAM – glycan interaction. An example of heterophilic interaction involving NCAM – glycan interaction is the complex formation between NCAM and cell adhesion molecule L1 (L1) via cis-interaction (i.e. between NCAM and L1 expressed on the same cell) [191]. It was shown that NCAM recognizes high-mannose type N-linked glycan(s) on L1, and that this interaction appears to be mediated by the fourth Ig-like domain (IgIV) of NCAM, which contains a sequence motif somewhat similar to Ctype lectins [192]. At high concentration (2 mg/ml), a 19amino-acid peptide fragment of the IgIV can significantly inhibit binding between NCAM and L1 [192]. Since it is somewhat questionable if this ‘‘C-type lectin-like’’ motif actually assumes C-type lectin-like folding (C-type lectin domain and Ig-like domain are structurally very different), the mode of interaction between high-mannose oligosaccharide and NCAM may be different from that of C-type lectin and glycans. Nevertheless, the biological significance of this NCAM interaction with L1 via high-mannose type oligosaccharides appears to be verified by the experiments in which high-mannose type oligosaccharides inhibit phosphorylation of L1 [193] and hippocampal long-term potentiation (leading to the formation of memory) [194], presumably via inhibition of NCAM– L1 complex formation. Of note, IgIV is alternatively spliced to include or exclude a 30-nucleotide length exon named VASE or k [195], possibly influencing the heterologous interaction of NCAM via IgIV. Another example of NCAM recognition

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of a heterophilic ligand via N-linked glycans was reported, in which phosphacan/protein tyrosine phosphatase ~/h are recognized via complex type N-linked glycans on these molecules [196]. The domain of NCAM involved in this interaction is not yet determined. A third example of NCAM– glycan interaction is recognition of heparin/heparan sulfate [197 – 200]. A series of studies identified a 17-amino-acid segment of NCAM in the second Ig-like domain that specifically binds heparin/heparan sulfate [199]. This peptide fragment contains six basic amino acid residues (lysine and arginine), suggesting the involvement of salt bridge between these positively charged residues and negatively charged heparin/heparan sulfate. However, this interaction appears to be specific, and not a simple charge-interaction: this 17-amino-acid segment does not interact with chondroitin sulfate (which is also heavily negatively charged), and a scrambled peptide with the same amino acid composition does not bind heparin/heparan sulfate [199]. Crystal structure of the first and second Iglike domains of NCAM shows that this heparin-binding segment is not involved in the homophilic binding [201]. Notably, NCAM is recently found to be a cellular receptor for rabies virus, and this NCAM– virus interaction is disrupted by the presence of heparin [202]. It is not yet known if the heparin-binding site is directly involved in viral recognition, or if the heparin binding just sterically hinders the NCAM– virus interaction. NCAM appears to interact with yet another type of glycosaminoglycan, chondroitin sulfate [203,204], although earlier studies stated otherwise. A brain-specific chondroitin sulfate proteoglycan neurocan can interact with NCAM, and this interaction appears to involve both protein backbone and chondroitin sulfate [204]. There are also some other reported heterophilic ligands for NCAM, such as collagens and fibroblast growth factor receptor (FGFR). A recent report suggested that NCAM and collagen do not interact directly but can be bridged by heparin/heparan sulfate [205]. Two different types of mice with NCAM deficiency have been created so far [206,207]. One of these was a selective disruption of the longest isoform of NCAM, NCAM180 [207]. Another group created a complete knockout of all isoforms of NCAM [206]. Both lines showed surprisingly mild phenotypes, most pronounced of which was the reduction of the size of olfactory bulb. Minor abnormalities in cerebellum, retina, and hippocampus were also noted in the NCAM180-knockout mice [207]. An abnormality in the hippocampus was also found in complete NCAM knockout mice, and linked to the impairment of these mice in spatial learning [206]. Another attempt for specific NCAM gene modification, i.e. removal of transmembrane domain (NCAM is expressed only in unnatural soluble form), resulted in dominant embryonic lethality, the most drastic phenotype of all experimental NCAM mutants [208]. The reason for this much-enhanced phenotype in this NCAM mutant compared with others is not clear. Contribution of glycan-binding activity of NCAM to the phenotypes of

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these mutant mice is not evident and will require more focused analysis. 3.2. Myelin protein zero (P0) Myelin protein zero (P0 or MPZ) is a glycoprotein expressed in vertebrate peripheral nerve myelin, and accounts for over 50% of all proteins expressed in Schwann cells. P0 is expressed in myelin of all vertebrates, including that of cartilaginous fish [209]. P0 has an extracellular domain consisting of only one Ig-like domain (V-set), a transmembrane domain and an intracellular domain [209]. The property of P0 as a homophilic adhesion molecule was demonstrated in 1990 [210]. This homophilic interaction apparently involves the N-linked glycan chain of P0, as demonstrated by the loss of aggregation of P0-transfected cells by introduction of a point-mutation at the unique Nglycosylation site of P0 [211]. Moreover, when P0 was expressed on mutant CHO cells that only express highmannose type N-linked glycans, P0-mediated cell – cell aggregation was severely attenuated [212]. These results point to the P0 homophilic binding via recognition of hybrid and/or complex type N-linked glycan. In accordance with this model, a study using purified and recombinant P0 protein [213] showed direct evidence that P0 specifically recognize HNK-1 antigen (SO 4 – 3GlcAh1 – 3Galh1 – 4GlcNAc), which is expressed on hybrid and complex type glycans of P0 [214,215]. Interestingly, the effect of N-glycan loss by the point mutation has a dominant-negative effect, i.e. cells expressing a mixture of wild-type (with N linked glycan) and mutant (without N linked glycan) P0 cannot form cell aggregates normally observed among P0 expressing cells [216]. Therefore, N glycan recognition may not be directly involved in the intercellular (trans) interaction, but rather P0 homo oligomer formation on the same cell surface (cis-interaction) which facilitates cell – cell interaction. The crystal structure of the extracellular domain of P0 has been determined, and the N-glycosylation site (Asn-93) is found near the membrane-proximal base of the domain [217]. It is of note that the N-glycosylation site of P0 is conserved throughout vertebrate evolution from cartilaginous fish to mammals [209], suggesting its significance in the biological function of P0. Mice lacking P0 were created by targeted gene disruption, and shows severe and progressive phenotypes (deficiency in motor coordination, tremors, etc.) caused by the hypomyelination of peripheral nerves and axonal degeneration thereof [218,219]. Some mutations in P0 gene result in various neurodegenerative disorders in humans characterized by the demyelination/hypomyelination of peripheral neurons, such as Charcott –Marie– Tooth neuropathy type 1B, Dejerine– Sottas syndrome, and congenital hypomyelination [220]. Since various mutations in this single gene can cause such a wide spectrum of diseases, some in heterozygous individuals and some in homozygous individuals, it was suggested

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that P0 gene mutation results in diseases both via loss-offunction (in homozygous individuals) and via dominantnegative effects (in heterozygous individuals), depending on the nature of the mutation. Again, it is notable that some patients with Charcott–Marie– Tooth neuropathy type 1B patients have a mutation at Asn-93, where N-linked glycan is attached in wild-type molecule [220]. 3.3. ICAM-1/CD54 ICAM-1/CD54 is a glycoprotein of the Ig superfamily of 80 to 114 kDa. It is expressed only at low levels on vascular endothelium, certain lymphocytes and monocytes, but is up-regulated in inflamed and malignant tissues. ICAM-1 contains five extracellular Ig-like domains, a transmembrane domain, and a short intracellular domain. For reviews on ICAM-1, see Refs. [221,222]. ICAM-1 is one of the main ligands for the leukocyte h2-integrins, i.e. lymphocyte function-associated antigen-1 (CD11a/CD18) and macrophage-associated Mac-1 (CD11b/CD18) [223 – 225]. Several studies have shown the importance of ICAM-1– integrin interaction for transmigration of neutrophils to inflamed tissue [226 – 228]. This was further demonstrated in ICAM-1 knockout mice [229]. In addition, ICAM-1 functions as a costimulatory molecule on antigen-presenting cells to activate T cells [230]. ICAM-1 is also a receptor for various pathogens, such as rhinoviruses, some members of the Coxsackievirus A family and for erythrocytes infected by the malarial parasite Plasmodium falciparum [231 – 235]. The heavily sialylated plasma protein fibrinogen can interact with ICAM-1 [236] and is a bridging molecule between leukocytes and endothelium [237]. This interaction is not due to the glycosylation of fibrinogen but seems to occur between the g chain of fibrinogen and ICAM-1 [238]. It has been described that ICAM-1 binds to the anionic polysaccharide hyaluronan [239], thus including ICAM-1 into the family of I-type lectins. Hyaluronan is mainly found in connective tissues and performs a variety of physiological and cell biological functions, such as lubrication and providing a matrix for cell migration [240]. The level of hyaluronan is increased at pathological sites in disease states such as inflammation, atherosclerosis, and cancer and it was postulated that this increase may be the result of increased ICAM-1 expression [239]. The interaction between ICAM-1 and hyaluronan may also explain some of the beneficial effects of hyaluronan on inflammation and wound healing and thus deserves further study. The Ig domain of ICAM-1 involved in binding hyaluronan is unknown. The heavily sialylated glycoprotein CD43, expressed on human leukocytes [241], is also reported to be another ligand for ICAM-1 [242]. It is not known if the sialylation is important for this interaction. However, glycosylation of CD43 per se may be involved in this interaction, since studies with transgenic mice overexpressing core 2 branched

O-glycans in T cells show reduced immune responses associated with decreased adhesion of T cells to ICAM-1 [243]. 3.4. CD2 CD2 is a f 50 kDa glycoprotein expressed on T cells and NK cells. Its extracellular domain consists of two Iglike domains, although the first Ig-like domain (V-set) lacks canonical cysteines involved in inter-sheet disulfide bond. CD2 is known to interact with CD48 (in rodents) or CD58 (in human) [244]. In search of alternative CD2 ligands, a group found that the recombinant CD2 binding to K562 (human erythroleukemic cell line) was reduced by preculture of the cells in the presence of tunicamycin, an N-glycosylation inhibitor [245]. In a follow-up study, the same group found that a-Lfucosidase treatment of K562 cells or presence of fucose (50 mM) in the assay system reduced recombinant CD2 binding to K562, suggesting that this alternative CD2 ligand contains fucose [246]. They also presented data suggesting that this ligand may be involved in NK cell recognition of target cells via CD2. The precise structure of this ligand is not yet determined, but may be related to Lewislstructure (Galh1-4[Fuca1-3]GlcNAc) [246]. CD2 was assumed to be an important signaling molecule involved in the T cell development, from the fact that antiCD2 antibodies can induce T cell activation in vitro. However, studies using CD2 knockout mice showed that CD2 may be dispensable in the T cell development [247]. 3.5. Hemolin Hemolin is an insect member of the immunoglobulin superfamily of 48– 52 kDa containing four Ig-like domains [248,249]. It is present in low amounts in the hemolymph (the insect’s blood equivalent) and increases after bacterial infection, suggesting a role in the insect’s defense system [249]. Hemolin binds to hemocytes (the insect’s blood cells), inhibits their aggregation, and induces their phagocytic activity [249,250]. In addition, hemolin appears to be involved in the regulation of the cellular immune responses through a pathway that includes protein kinase C activation and protein phosphorylation [250]. Besides the soluble form of hemolin (48 kDa), there is a membrane bound form (52 kDa) expressed on hemocytes [251], that may be involved in homophilic interaction resulting in aggregation of hemocytes [251]. Hemolin binds to lipopolysaccharide (LPS) and it was demonstrated that the lipid A moiety of LPS is responsible for this interaction [252]. A first indication that hemolin may be an I-type lectin was found only recently in a study showing the importance for GlcNAc and sialic acid in the binding of hemolin to hemocytes [253]. This demonstrates that recognition of glycans by Ig superfamily molecules (the definition of I-type lectins) is an evolutionarily old idea.

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4. Immunoglobulin superfamily proteins that recognize sulfated glycosaminoglycans As mentioned earlier, proteins interacting with sulfated glycosaminoglycans (GAGs) are generally not considered as ‘‘lectins’’, perhaps because the binding is dictated predominantly by charge interactions. However, some proteins show selectivity towards the type of GAGs they interact with (in many cases heparin/heparan sulfate are the favored ligands). Hence, we include a brief overview of this class of molecules. Platelet – endothelial cell adhesion molecule-1 (PECAM-1) was also considered as one of the Ig superfamily proteins recognizing heparan sulfate [254], but a recent literature from the same group which originally reported GAG – PECAM-1 interaction provided a strong argument against it [255], hence we excluded it from the following section. 4.1. Fibroblast growth factor receptors Vertebrates have four FGFRs (FGFR-1-4) that share a common molecular architecture, i.e. an extracellular domain composed of three Ig-like domains (C2-set) followed by a transmembrane domain and an intracellular protein tyrosine kinase domain. Many splicing variants affecting protein structure are known, which in turn affect their function, such as binding specificity towards different FGFs ( f 20 of them are currently recognized) [256]. FGFR-like molecules are also present in fruit fly (Drosophila melanogaster Heartless and Breathless) and nematode (Caenorhabditis elegans Egl-15) [257]. Interaction of FGF and FGFR requires cell surface heparan sulfate proteoglycans (HSPG) [258,259]. These three components form a stable ternary complex (two FGFs and two FGFRs tethered by a heparan sulfate chain), leading to mutual tyrosine phosphorylation of FGFRs and intracellular signaling thereof. The precise order of events leading to the formation of this ternary complex is still not fully resolved [257,260]. Heparin/heparan sulfate and FGFR can directly interact [261 – 264], although the affinity of this interaction (Kd = 104 AM) is much lower than that for FGF –heparin (Kd = 470 nM) or FGF –FGFR (Kd = 41 nM) interactions [262]. Notably, crystal structures of FGF – FGFR complex are different in the absence [265,266] or presence [267] of heparin in the complex. Although FGF and FGFR can form a complex without heparin/heparan sulfate, the relevance of heparan sulfate in the FGF –FGFR signaling under biological conditions was evident from the phenotypical similarities between Drosophila mutants in FGFRs and in the heparan sulfate biosynthesis enzymes [268]. The importance of FGFRs in the normal development of vertebrates is unequivocally established by the embryonic lethality of FGFR-1 [269,270] and FGFR-2 [271,272] knockout mice and bone malformation in FGFR-3 knockout mice [273,274]. It is also notable that several bone malfor-

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mation disorders in humans are caused by dominant-negative mutations of FGFR-1, -2, or -3, most prevalent of which is achondroplasia (the most common form of dwarfism) caused by mutations in FGFR-3 [275,276]. 4.2. Perlecan (heparan sulfate proteoglycan-2/HSPG2) Perlecan is a large ( f 400 kDa) heparan sulfate proteoglycan found in extracellular matrix, particularly in basement membrane. This molecule consists of numerous domains, including 21 (human) or 14 (mouse) tandem Iglike domains (C2-set). Perlecan has been shown to interact with numerous ligands via protein core and heparan sulfate chains [277]. A study showed interaction between heparin and recombinant Ig-like domains of mouse perlecan [278]. A follow-up study showed that the heparin binding is mediated by the fifth Ig-like domain, and this domain can also bind to sulfatide [279]. Early lethality (due to failure of basement membrane development, exencephaly, and condrodysplasia) of perlecan knockout mice clearly indicates that this molecule is essential to mammalian embryonic development [280,281]. More detailed studies (controlled deletion of particular domains, etc.) will be required to dissect which interaction is essential for each particular phenotype displayed by the whole-sale knockout mice. Human mutations in perlecan have been identified in dyssegmental dysplasia, Silverman – Handmaker type [282] and Schwartz – Jampel syndrome (chondrodystrophic myotonia) [283]. 4.3. CD48 CD48 is a GPI-anchored protein with two Ig-like domains (first: V-set, second: C2-set). The first Ig-like domain lacks canonical disulfide bond, as in CD2. CD48 is expressed on the cells of lymphoid and myeloid lineages, and is greatly up-regulated in Epstein– Barr virus (EBV)-infected B cells [284]. CD48 in rodents is a counter-receptor of CD2, while human CD48 shows very weak, if any, interaction with CD2 [244]. It was recently shown that both human and rodent CD48 interact with another Ig superfamily molecule called 2B4, which is expressed on NK cells and T cells [285 – 287]. The intracellular signaling pathway from 2B4 involves signaling lymphocyte activation molecule (SLAM)-associated protein, deficiency of which causes X-linked lymphoproliferative disorder (XLP), a human disease characterized by the uncontrolled proliferation of EBV-infected B cells [288]. Biological significance of the CD48 –2B4 interaction in the context of XLP has been demonstrated [289,290]. CD48 knockout mice show a defect in CD4 + T cell activation [291]. In search of human CD48 ligands on epithelial cells, a group identified heparin/heparan sulfate as a ligand for CD48 [292]. How this interaction relates to in vivo function of CD48 remains to be determined.

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5. Concluding remarks Many Ig superfamily proteins have been shown to interact with carbohydrates in the past decade, and new members will undoubtedly join this family of I-type lectins in the future. Finding new members of I-type lectins, as well as discovering carbohydrate binding properties of known Ig superfamily proteins, will continue to be important aspects of glycobiology. However, the relevance of carbohydrate recognition in the biological functions of these molecules has not been extensively studied so far. To further extend our understanding of the significance of carbohydrate – protein interactions, we would have to devote our efforts to find out the precise mechanisms of these interactions, and the consequences of disrupting such interactions. For example, we should identify exact structures of carbohydrate ligands for these lectins, determine amino acid residues of lectins involved in the ligand recognition (through sitedirected mutagenesis and/or X-ray crystallography), and study in vivo effects of introducing point-mutation(s) in these residues (e.g. targeted mutagenesis via homologous recombination in mouse). Along with these efforts, the studies of enzymes involved in the biosynthesis of carbohydrate ligands for these lectins, especially those using knockout approach, will continue to be essential to understand the functions of animal lectins, I-type or else.

Acknowledgements We thank Dr. Ajit Varki for valuable discussions and comments on the manuscript.

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