Nectins are Ca2+-independent immunoglobulin (Ig) superfamily cell adhesion molecules constituting a family with four members, all of which have three Ig-like loops at their extracellular regions. Nectins play roles in the formation of a variety of cell–cell adhesion apparatuses. There are at least three types of nectin-mediated cell adhesions: afadin- and cadherin-dependent, afadin-dependent and cadherin-independent, and afadin- and cadherin-independent. In addition, nectins trans-interact with nectin-like molecules (Necls) with three Ig-like loops and other Ig-like molecules with one to three Ig-like loops. Furthermore, nectins and Necls cis-interact with membrane receptors and integrins, some of which are associated with the nectin-mediated cell adhesions, and play roles in the regulation of many cellular functions, such as cell polarization, movement, proliferation, differentiation, and survival, co-operatively with these cell surface proteins. The nectin-mediated cell adhesions are implicated in a variety of diseases, including genetic disorders, neural disorders, and cancers. Of the three types of nectin-mediated cell adhesions, the afadin- and cadherin-dependent apparatus has been most extensively investigated, but the examples of the third type of apparatus independent of afadin and cadherin are recently increasing and its morphological and functional properties have been well characterized. We review here recent advances in research on this type of nectin-mediated cell adhesion apparatus, which is named nectin spot.

Introduction

Multicellular organisms are organized by cell–cell and cell–matrix adhesions (Figure 1A), which are essential for the ontogenesis and the regeneration and maintenance of tissues and organs. Cell–cell and cell–matrix adhesions are involved in fundamental cellular activities, including not only adhesion but also polarization, movement, proliferation, differentiation, and survival. Cell–cell adhesions are categorized into two major groups: one is homotypic and the other is heterotypic (Figure 1B). In homotypic adhesion, the same type of adjacent cells adheres each other, whereas in heterotypic adhesion, the different types of adjacent cells adhere each other. Many cell–cell adhesion apparatuses have been identified and characterized: cell–cell adhesion apparatuses include the adherens junction (AJ), the tight junction (TJ), the desmosome, and the gap junction, whereas cell–matrix adhesion apparatuses include the hemidesmosome, the focal complex, and the focal adhesion (Figure 1C). The AJ plays a role in mechanically connecting adjacent cells to resist strong contractile forces [1]; the TJ functions as a barrier that prevents the passage of soluble molecules through the gaps between cells [2]; the desmosome resists shearing forces of attached cells [3]; the gap junction is a channel that provides direct intercellular communication pathways allowing rapid exchange of ions and metabolites [4]; the hemidesmosome connects the basal face of the cell to the basement membrane and inhibits detachment and movement of the cells from it [5]; the focal complex and the focal adhesion are formed between cells and extracellular matrix and involved in cell movement: the former is formed at the leading edge of the moving cell, whereas the latter is formed at the rear side of the moving cell [6].

Cell–cell and cell–matrix adhesion apparatuses.

Figure 1.
Cell–cell and cell–matrix adhesion apparatuses.

(A) Cell–cell and cell–matrix adhesion. (B) Homotypic and heterotypic cell adhesion. In homotypic adhesion, the same type of adjacent cells adheres each other. In heterotypic adhesion, the different types of adjacent cells adhere each other. (C) Cell–cell and cell–matrix adhesion apparatuses. Cell–cell adhesion apparatuses include the adherens junction, the tight junction, the desmosome, and the gap junction. Cell–matrix adhesion apparatuses include the hemidesmosome, the focal complex, and the focal adhesion.

Figure 1.
Cell–cell and cell–matrix adhesion apparatuses.

(A) Cell–cell and cell–matrix adhesion. (B) Homotypic and heterotypic cell adhesion. In homotypic adhesion, the same type of adjacent cells adheres each other. In heterotypic adhesion, the different types of adjacent cells adhere each other. (C) Cell–cell and cell–matrix adhesion apparatuses. Cell–cell adhesion apparatuses include the adherens junction, the tight junction, the desmosome, and the gap junction. Cell–matrix adhesion apparatuses include the hemidesmosome, the focal complex, and the focal adhesion.

Many cell adhesion molecules (CAMs) have been identified and characterized at these cell adhesion apparatuses. The major CAMs at the AJ are cadherins and nectins [1,7]; those at the TJ are claudins, occludin, tricellulin, and junction adhesion molecules (JAMs) [2]; those at the desmosome are desmosomal cadherins, which belong to the cadherin superfamily [3]; and those at the gap junction are connexins [4]. The major CAMs at the cell–matrix adhesion apparatuses are integrins [8].

Nectins are Ca2+-independent immunoglobulin (Ig)-like CAMs, of which family comprises of four protein members, nectin-1, nectin-2, nectin-3, and nectin-4, encoded by the Pvrl1, Pvrl2, Pvrl3, and Pvrl4 genes, respectively [9,10]. Nectin-1, nectin-2, and nectin-3 are also called CD111, CD112, and CD113, respectively. Nectin-1 and nectin-2 are known to be herpes simplex virus receptors [1114] and nectin-4 is known to be a measles virus receptor [15,16]. No viruses using nectin-3 as a receptor have not been identified yet. Each nectin family member consists of two or three splice variants [9]. All nectins, apart from the secreted nectin-1γ, have an extracellular region with three Ig-like loops (one V-type and two C2-types), a single membrane-spanning region, and a cytoplasmic tail (Figure 2Aa). Nectins are able to trans-interact with each other through their extracellular regions and form cell–cell adhesion (Figure 2Ba). They are able to interact with the actin filament (F-actin)-binding protein afadin through their cytoplasmic tails (Figure 2Aa,c).

Structures, binding proteins, and functions of nectins.

Figure 2.
Structures, binding proteins, and functions of nectins.

(A) Domain structures of nectins and afadin and their binding proteins. (Aa) Structures of nectins and their binding proteins. (Ab) Ribbon diagram of the V-shaped extracellular region of nectin-1 dimer (Protein Databank Code, 3ALP). Structure image was reconstituted using JMol application, an open-source Java viewer for chemical structures in 3D (http://www.jmol.org). Each molecule is colored in magenta and light blue, respectively. The Ig-like domains (first, second, and third) are labeled. The figure and legend are modified from an article by Narita et al. [56]. (Ac) Structure of afadin and its binding proteins. RA1, RA2, Ras-associated domain-1 and -2; FHA, forkhead-associated domain; DIL, dilute domain; PDZ, PDZ domain; PR1, PR2, PR3, proline-rich domain-1 to -3; FAB, F-actin-binding domain. (B) trans-Interaction properties of nectins and cadherins. (Ba) Homophilic and heterophilic trans-interactions between nectins. Nectins are able to trans-interact with the same and different nectin family members to form homophilic and heterophilic trans-interactions through their extracellular regions. Because of this property, cells expressing different nectins tend to be arranged in a mosaic pattern. Known dissociation constants are shown to indicate variations in affinity. (Bb) Homophilic trans-interactions between same cadherins. Cadherins are able to trans-interact with the same cadherin family members to form homophilic trans-interactions through their extracellular regions. Because of this property, cells expressing different cadherins tend to segregate.

Figure 2.
Structures, binding proteins, and functions of nectins.

(A) Domain structures of nectins and afadin and their binding proteins. (Aa) Structures of nectins and their binding proteins. (Ab) Ribbon diagram of the V-shaped extracellular region of nectin-1 dimer (Protein Databank Code, 3ALP). Structure image was reconstituted using JMol application, an open-source Java viewer for chemical structures in 3D (http://www.jmol.org). Each molecule is colored in magenta and light blue, respectively. The Ig-like domains (first, second, and third) are labeled. The figure and legend are modified from an article by Narita et al. [56]. (Ac) Structure of afadin and its binding proteins. RA1, RA2, Ras-associated domain-1 and -2; FHA, forkhead-associated domain; DIL, dilute domain; PDZ, PDZ domain; PR1, PR2, PR3, proline-rich domain-1 to -3; FAB, F-actin-binding domain. (B) trans-Interaction properties of nectins and cadherins. (Ba) Homophilic and heterophilic trans-interactions between nectins. Nectins are able to trans-interact with the same and different nectin family members to form homophilic and heterophilic trans-interactions through their extracellular regions. Because of this property, cells expressing different nectins tend to be arranged in a mosaic pattern. Known dissociation constants are shown to indicate variations in affinity. (Bb) Homophilic trans-interactions between same cadherins. Cadherins are able to trans-interact with the same cadherin family members to form homophilic trans-interactions through their extracellular regions. Because of this property, cells expressing different cadherins tend to segregate.

Nectins form at least three types of cell–cell adhesion apparatuses depending on the involvement of afadin and cadherins: afadin- and cadherin-dependent; afadin-dependent and cadherin-independent; and afadin- and cadherin-independent (Figure 3). Of these three types of nectin-mediated cell adhesion apparatuses, the afadin- and cadherin-dependent apparatus constitutes the structures of the AJ, which was originally identified electron microscopically in the absorptive intestinal epithelium [17], of the AJ in endothelial cells and fibroblasts, and of the synaptic puncta adherentia junction (PAJ) in neurons [18,19]. The structural and functional properties of this type of the apparatus have been most extensively investigated, and many reviews on this type have been published [9,2042]. The second type is found at the adhesion between spermatids and Sertoli cells in the testis [4245]. The third type is first found at the adhesion between commissural axons and floor plate basal cell processes in developing neural tube [46], then at the adhesion between mitral cell lateral dendrites in the olfactory bulb [47,48], and recently at the adhesion between the luminal and basal cells in the mammary gland epithelium [49]. The type similar to the third type may be present at the adhesion between leukocytes in immune responses and between leukocytes and vascular endothelial cells during their transendothelial migration (TEM) [5053]. Thus, the examples of the third type of apparatus are increasing, and its structural and functional properties have recently been well characterized. We review here recent advances in research on this type of nectin-mediated cell adhesion apparatus, which is named nectin spot.

Three types of nectin-mediated cell adhesion apparatuses.

Figure 3.
Three types of nectin-mediated cell adhesion apparatuses.

Afadin- and cadherin-dependent cell adhesion apparatus is observed at the AJ between epithelial cells or at the PAJ between axons and dendrites. Afadin-dependent and cadherin-independent cell adhesion apparatus is observed at Sertoli cell–spermatid junctions. A novel type of afadin- and cadherin-independent cell adhesion apparatus, nectin spot, is observed at dendro-dendrotic appositions in the olfactory bulb, at the boundary between the luminal and basal cells in the mammary gland, or at the contact between the commissural axons and floor plate cell basal processes in the neural tube.

Figure 3.
Three types of nectin-mediated cell adhesion apparatuses.

Afadin- and cadherin-dependent cell adhesion apparatus is observed at the AJ between epithelial cells or at the PAJ between axons and dendrites. Afadin-dependent and cadherin-independent cell adhesion apparatus is observed at Sertoli cell–spermatid junctions. A novel type of afadin- and cadherin-independent cell adhesion apparatus, nectin spot, is observed at dendro-dendrotic appositions in the olfactory bulb, at the boundary between the luminal and basal cells in the mammary gland, or at the contact between the commissural axons and floor plate cell basal processes in the neural tube.

General properties of nectins

Homophilic and heterophilic trans-interactions

Physical properties of nectins are summarized in comparison with those of cadherins in Table 1 [37]. Nectins are able to trans-interact with the same and different nectin family members to form homophilic and heterophilic trans-interactions through their extracellular regions, whereas cadherins are able to trans-interact with the same cadherin family members to form homophilic trans-interactions through their extracellular regions (Figure 2Ba,b). Nectins first form homo-cis-dimers, which then undergo lateral cluster formation on the cell surface [18]. Then, the lateral clusters of the homo-cis-dimers are suggested to trans-interact with those on the opposing cell surface. In this trans-interactions, the clusters of nectins are able to homophilically and heterophilically trans-interact with each other [10,18]. The V-type Ig-like loop in the extracellular region of nectins is necessary for the formation of trans-dimers [10]. Studies performed initially suggested that the first C2-type Ig-like loop in the extracellular region contributes to the formation of cis-dimers [54,55].

Table 1
General properties of nectins and cadherins
Properties Classical cadherins Nectins Functions of nectins 
Family1 E-, N-, P-, R-, VE- -1, -2, -3, -4  
Adhesion strength1 Strong Weak  
Affinity2 Low High Initiation of cell–cell adhesion 
Lateral diffusion speed3 Slow Fast  
Binding Mode1 Homophilic Homophilic Homotypic cell–cell adhesion 
Heterophilic Heterotypic cell–cell adhesion 
Properties Classical cadherins Nectins Functions of nectins 
Family1 E-, N-, P-, R-, VE- -1, -2, -3, -4  
Adhesion strength1 Strong Weak  
Affinity2 Low High Initiation of cell–cell adhesion 
Lateral diffusion speed3 Slow Fast  
Binding Mode1 Homophilic Homophilic Homotypic cell–cell adhesion 
Heterophilic Heterotypic cell–cell adhesion 
1

General properties of cadherins are reviewed in ref. [7], and nectins are reviewed in ref. [41].

2

Dissociation constants between E-cadherins were determined by Koch et al. [68] and between nectins and Necls were determined by Ikeda et al. [60] and Harrison et al. [57].

3

Lateral diffusion speed of E-cadherin and nectin-2 were determined by Troyanovsky et al. [69].

The crystallographic structures of all four nectins are now resolved. Nectins form a homo-trans-dimer in the crystal lattice, which is consistent with the behavior in solution [5658]. The V-type Ig-like loop in the extracellular region exhibits a two-layered β-sheet sandwich topology, which is present in other V-type Ig-like loop structures, and contains the front and back sheets composed of 5 and 4 strands, respectively (Figure 2Ab). The trans-dimer interface is formed by nearly orthogonal association of the front 5-stranded β-sheets of two engaging V-type Ig-like loops to organize the nectin homo-trans-dimers similar to the quaternary structure observed in a number of other physiologically relevant dimers in the Ig superfamily. In mouse nectin-2, F136 residue resides in the V-type Ig-like loop and is buried at the trans-dimer interface, which is important for the interaction between nectin-2 [57,59]. Point mutation, F136D, in the V-type Ig-like loop of nectin-2 inactivates homo-trans-dimerization and severely attenuates recruitment of nectin-2 to the cell–cell adhesion sites, indicating that the dimerization interface observed in the crystal structures is required for the recruitment of nectins to the cell–cell contact sites. Targeted cross-linking experiments with nectin-2 suggest that the crystallographically observed dimers common to all nectins are in a trans manner, implicating that the V-type Ig-like loop is the adhesive domain of nectins to achieve both cis- and trans-interactions.

Heterophilic trans-interactions and implication in heterotypic cell adhesion

The heterophilic trans-interactions between different nectin family members are stronger than the homophilic trans-interactions [41,57,60]. Ranging from the strongest to the weakest interaction, the strength decreases as follows: nectin-1/nectin-3, nectin-2/nectin-3, and the homophilic trans-interactions between nectin-1/nectin-1, nectin-2/nectin-2, and nectin-3/nectin-3. The dissociation constant values for the interaction between nectin-1/nectin-3 and between nectin-2/nectin-3 are 2.3 and 360 nM, respectively.

These properties of nectins confer them to mediate the adhesion between heterotypic cells, which express different nectin family members and play critical roles in hererotypic cell–cell adhesion apparatuses [37,41,42]. For instance, at the adhesion between Sertoli cells and spermatids during spermatid differentiation in the testis, nectin-2 and nectin-3 are differentially expressed in Sertoli cells and spermatids, respectively, and the trans-interaction between nectin-2 and nectin-3 is involved in this heterotypic cell adhesion [4345]. Similarly, at the adhesion between commissural axons and floor plate cell basal processes in the developing neural tube, nectin-1 and nectin-3 are differentially expressed in commissural axons and floor plate cell basal processes, respectively, and the trans-interaction between nectin-1 and nectin-3 is involved in this heterotypic cell adhesion [46] (see ‘Nectin-1/nectin-3 spot in commissural axons’). At the apex–apex adhesion between the pigment and non-pigment cells of the ciliary epithelium in the eye, nectin-1 and nectin-3 are differentially expressed in the pigment and non-pigment cells, respectively, and the trans-interaction between nectin-1 and nectin-3 is involved in this heterotypic cell adhesion [61]. In the mouse tooth, nectin-1 and nectin-2 are expressed in ameloblasts and nectin-3 and nectin-4 are expressed in the neighboring stratum intermedium cells [62]. Nectin-1 and nectin-3 are involved in the formation of desmosomes between ameloblasts and stratum intermedium cells. Besides the trans-interaction between nectin-1 and nectin-3, the trans-interactions between nectin-1 and nectin-4 and/or between nectin-2 and nectin-3 may be also involved in this heterotypic cell adhesion.

In contrast to the AJ in epithelial and endothelial cells and fibroblasts, the neuronal synapses formed between axons and dendrites are homotypic but asymmetric cell adhesion. At the mossy fiber–CA3 pyramidal cell synapses in the hippocampus, nectin-1 and nectin-3 are asymmetrically distributed, being localized exclusively at the pre- and postsynaptic sides of the PAJ, respectively [19]. This asymmetric localization of nectin-1 and nectin-3 and the strong heterophilic trans-interaction between them are involved in the selective interaction between axons and dendrites [63].

Heterophilic trans-interactions and implication in cellular mosaic patterning

In the auditory epithelium of the cochlea, hair and supporting cells are arranged into highly ordered rows and are interdigitated to form a checkerboard-like mosaic pattern [64]. Nectin-1 and nectin-3 are differentially expressed in hair and supporting cells, respectively, and nectin-2 is expressed in both hair and supporting cells [65]. The trans-interaction between nectin-1 and nectin-3 mediates the heterotypic cell adhesion and the establishment of the checkerboard pattering of these two types of cells. In the olfactory epithelium, olfactory and supporting cells, which express different cadherins, are arranged in a characteristic mosaic pattern, in which olfactory cells are enclosed by supporting cells [66]. Nectin-2 and N-cadherin are expressed in olfactory cells, and nectin-2, nectin-3, E-cadherin, and N-cadherin are expressed in supporting cells [67]. The heterophilic trans-interaction between nectin-2 in olfactory cells and nectin-3 in supporting cells preferentially recruits cadherins to this heterotypic cell junction, and the differential distributions of cadherins between junctions promote cellular intercalations, resulting in the formation of the mosaic pattern. Thus, the synergistic action of nectins and cadherins generates mosaic pattern in the olfactory epithelium. In the auditory epithelium and, though slightly lesser extent, in the olfactory epithelium, different types of cells are arranged in well-ordered mosaic pattern. However, in many other tissues, such as the retina of the eye, the oviductal epithelium, and the intestinal epithelium, different types of cells are arranged in irregular mosaic patterns. Differential expression of different nectins in the cells constituting these tissues may also contribute to these irregular mosaic cellular patterning.

Weak but rapid trans-interactions

The dissociation constant values of the homophilic and heterophilic trans-interactions of nectins are far smaller than those that have been measured for the trans-interaction between E-cadherin molecules (∼80 μM) [41,57,60,68]. Compared with the strong trans-interactive property of E-cadherin, which is able to facilitate long-term cell–cell adhesion, the weak trans-interactive property of nectins is more suitable for the formation of transient cell–cell adhesions and the repeated turnover of these adhesions. trans-Interaction strength depends at least on the plasmalemmal concentration and trans-interaction affinity. In general, the combination of high plasmalemmal concentration and high trans-interaction affinity generates the strongest trans-interaction strength, whereas the combination of low plasmalemmal concentration and low trans-interaction affinity generates the weakest trans-interaction strength. Plasmalemmal concentration of CAMs is determined by the speed of lateral diffusion. In the case of cadherins and nectins, cadherins show low affinity for trans-interactions with cadherins of opposing cell surfaces and slow lateral diffusion on the cell surface, whereas nectins show high affinity for trans-interactions and rapid lateral diffusion [69]. Owing to these properties of nectins, they are able to initiate cell–cell adhesion, which is followed by the recruitment of cadherins to stabilize cell–cell adhesion, resulting in the establishment of the AJ and the PAJ [41]. Furthermore, cells expressing different nectins can be arranged in mosaic patterns, whereas cells expressing different cadherins segregate separately [37].

Heterophilic trans-interactions with other CAMs

Nectins are further able to trans-interact with nectin-like molecules (Necls), Necl-1, Necl-2, Necl-3, Necl-4, and Necl-5, all of which show domain structures similar to those of nectins [41,42] (Figure 4Aa). Necl-1 is also named CADM3, TSLL1, and SynCAM3; Necl-2, CADM1, IGSF4, RA175, SgIGSF, TSLC1, and SynCAM1; Necl-3, CADM2, SynCAM2; Necl-4, CADM4, TSLL2, and SynCAM4; and Necl-5, Tage4, polyovirus receptor (PVR), and CD155. They have an extracellular region with three Ig-like loops (one V-type and two C2-types), a single membrane-spanning region, and a cytoplasmic tail. Some of them have a consensus motif for the binding to the PSD95–DLG1–ZO-1 (PDZ) domain, but they are not able to interact with afadin. Furthermore, nectins are able to trans-interact with other Ig-like CAMs with one to three Ig-like loops: nectin-1 with Tactile (also known as CD96) with three Ig-like loops [51]; nectin-2 with DNAX accessory molecule 1 (DNAM-1, also known as CD226) with two Ig-like loops [50] and with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) with one Ig-like loop [52]; and nectin-3 with TIGIT [70] (see ‘Transiently formed cell–cell contacts’).

trans- and cis-Interactions among nectins, Necls, receptors, and integrins and their roles in the regulation of cell signaling.
Figure 4.
trans- and cis-Interactions among nectins, Necls, receptors, and integrins and their roles in the regulation of cell signaling.

(A) trans- and cis-interactions among nectins, Necls, receptors, and integrins. (Aa) Domain structure of Necls and trans-interactions of nectins, Necls, and other Ig-like molecules. Known dissociation constants are shown to indicate variations in affinity. (Ab) cis-Interactions of nectins, Necls, receptors, and integrins. (B) Stimulatory and inhibitory effects of nectins and Necls on receptors and integrins. Nectins and Necls stimulate and inhibit, respectively, the signaling of these receptors and integrins, and play roles in the regulation of many cellular functions.

Figure 4.
trans- and cis-Interactions among nectins, Necls, receptors, and integrins and their roles in the regulation of cell signaling.

(A) trans- and cis-interactions among nectins, Necls, receptors, and integrins. (Aa) Domain structure of Necls and trans-interactions of nectins, Necls, and other Ig-like molecules. Known dissociation constants are shown to indicate variations in affinity. (Ab) cis-Interactions of nectins, Necls, receptors, and integrins. (B) Stimulatory and inhibitory effects of nectins and Necls on receptors and integrins. Nectins and Necls stimulate and inhibit, respectively, the signaling of these receptors and integrins, and play roles in the regulation of many cellular functions.

cis-Interactions with membrane receptors and integrins

Nectins and Necls are further able to cis-interact with membrane receptors and integrins: nectin-1 with the fibroblast growth factor (FGF) receptor [71] and integrin αvβ3 [72]; nectin-3 with the platelet-derived growth factor (PDGF) receptor [73] and integrin αvβ3 [72]; and nectin-4 with the prolactin receptor [49] (Figure 4Ab). Necl-2 interacts with ErbB3, ErbB4, and integrin α6β4 [7476]; Necl-4 interacts with ErbB3, the vascular endothelial growth factor (VEGF) receptor, and integrin α6β4 [77,78]; and Necl-5 cis-interacts with the PDGF receptor [79], the VEGF receptor [80], and integrin αvβ3 [81] (Figure 4Ab). Nectins and Necls stimulate and inhibit, respectively, the signaling of these receptors and integrins and play roles in the regulation of many cellular functions, such as cell polarization, movement, proliferation, differentiation, and survival, co-operatively with these cell surface proteins (Figure 4B). In contrast to the inhibitory effects of other Necls, Necl-5 stimulates the signaling of these receptors and integrin αvβ3. Although Necls are categorized according to their inability to interact with afadin, Necl-5 is structurally similar to nectins and functionally more similar to nectins than to other Necls, according to their phylogenetic trees.

Binding of many peripheral membrane proteins

Nectins directly bind many peripheral membrane proteins, including afadin, through their cytoplasmic tails [10,18,41,42,82] (Figure 2Aa). All nectins, with the exception of nectin-1β, nectin-3γ, and nectin-4, contain a conserved motif (E/A-X-Y-V, where X represents any amino acid) at their carboxyl termini, which serves as a binding motif for the PDZ domain of afadin. Despite lacking this conserved motif, nectin-4 is able to interact with the PDZ domain of afadin through its carboxyl terminus [10]. Some, but not all, members of the nectin family are able to bind various peripheral membrane proteins in addition to afadin, through their cytoplasmic tails, including partitioning defective 3 homolog (Par-3, also known as PARD3) [83], protein interacting with PRKCA1 [84], multiple PDZ domain protein (MUPP1, also known as MPDZ), Pals1-associated TJ protein [85], membrane palmitoylated protein 3 [86], zyxin [87], and Willin [88] (Figure 2Aa). Of these nectin-binding proteins, the F-actin-binding protein afadin further binds many proteins, such as Rap1 small G-protein, ADIP, ZO-1, α-catenin, LMO-7, and ponsin, in this order from the N-terminus [38] (Figure 2Ac).

One role of afadin is that it binds to the cytoplasmic tails of nectins and facilitates their trans-interactions through their extracellular regions [89]. Another role is that it binds to many proteins that directly or indirectly interact with cadherins, such as α-catenin, ADIP, LMO-7, and ponsin, and recruits cadherins to the nectin-based cell–cell adhesion sites through these proteins to form the AJ and the PAJ [41]. Nectins may trans-interact with each other to form microclusters as described for E-cadherin microclusters [90]. The peripheral nectin molecules of this microclusters recruit the cadherin molecules to the peripheral regions of the nectin microclusters to induce their clustering, forming the mosaic of these two species of microclusters eventually to establish the AJ. In contrast to this model, another model has recently been proposed [69,91,92]. In the latter model, E-cadherin microclusters are independently formed prior to or concomitantly with the clustering of nectin-2 and recruit the nectin-2 molecules to this E-cadherin-based microclusters to form the mosaic of these two species of microclusters. The binding of α-catenin to E-cadherin via β-catenin and its F-actin-binding activity are required for this mosaic formation. The order of the formation of the nectin and cadherin microclusters is apparently opposite, but the former model is obtained mainly by using Madin–Darby canine kidney cells that endogenously express E-cadherin and nectin-1 and nectin-2 and exogenously overexpress nectin-1 [93], whereas the latter model is obtained by using A431D cells that endogenously express nectin-2, but not any cadherin, and exogenously express E-cadherin [69,91,92]. Therefore, depending on the expression levels and the trans-interaction strength levels of nectins and cadherins, these apparently inconsistent results might be obtained. It is not evident which is the case under physiological conditions, but both mechanisms may operate depending on cell types that express endogenously nectins and cadherins to different levels, and nectins play a crucial role in forming the AJ and the PAJ, co-operatively with afadin and cadherins (Figure 3).

Implications in diseases

Nectins are associated with onsets and progression of a variety of diseases listed in Table 2 [41,42]. These include cancer [94101], ectodermal dysplasia [102106], Alzheimer's disease [107109], stress-related mental disorders [110112], viral infection [1116], and cataract [113]. Several diagnosis and treatment methods using nectins are being developed. Thus, evidence is accumulating that nectins play crucial roles not only in a variety of physiological but also in a variety of pathological context.

Table 2
Implication of nectins in diseases
Member Related disease References 
Nectin-1 Cancer (overexpression) [94
Ectodermal dysplasia (mutation) [102,103
Stress-related mental disorders (mouse model) [112
Virus infection (receptor) [11,12,14
Nectin-2 Cancer (overexpression) [95
Alzheimer's disease (SNPs) [107109
Virus infection (receptor) [13
Nectin-3 Cancer (overexpression) [96,97
Stress-related mental disorders (mouse model) [110,111
Cataract (down-regulation) [113
Nectin-4 Cancer (overexpression) [98101
Ectodermal dysplasia (mutation) [104106
Virus infection (receptor) [15,16
Member Related disease References 
Nectin-1 Cancer (overexpression) [94
Ectodermal dysplasia (mutation) [102,103
Stress-related mental disorders (mouse model) [112
Virus infection (receptor) [11,12,14
Nectin-2 Cancer (overexpression) [95
Alzheimer's disease (SNPs) [107109
Virus infection (receptor) [13
Nectin-3 Cancer (overexpression) [96,97
Stress-related mental disorders (mouse model) [110,111
Cataract (down-regulation) [113
Nectin-4 Cancer (overexpression) [98101
Ectodermal dysplasia (mutation) [104106
Virus infection (receptor) [15,16

Nectin-1 spot in the olfactory bulb

A novel type of nectin-mediated cell adhesion apparatus named nectin-1 spot is found at the adhesion between mitral cell lateral dendrites in the olfactory bulb, and its structural and functional properties are studied [47,48].

The cellular structure and the function of the olfactory bulb

The olfactory bulb is composed of a few thousand glomerular modules, each of which receives converging axonal inputs from olfactory sensory neurons expressing the same type of odorant receptor [114116]. An individual mitral cell projects an apical dendrite to a single glomerulus, receives olfactory sensory inputs within the glomerulus, and projects an axon to the olfactory cortex [117]. Individual mitral cells project several long lateral dendrites tangentially with appropriate branching patterns, which are in direct apposition with the lateral and apical dendrites of other mitral cells and connected with granule cell dendritic spines to form dendro-dendritic reciprocal synapses. In response to odor stimulation, mitral cells, belonging to different, but co-activated glomerular modules, show synchronized spike activities at γ-range frequency (40–100 Hz), which are thought to play important roles in the olfactory cortex for the perception, learning, and memory of the odor objects [117119]. Proper dendritic connections lead to the formation of dendro-dendritic reciprocal synapses between mitral cell dendrites and granule cell dendrites in the deep sublamina of the external plexiform layer (EPL) that are responsible for the generation of γ-synchronized outputs from mitral cells [119]. The lateral extent of dendritic trees from a single mitral cell is much wider than that from a single granule cell. Thus, the arrangement and extent of overlapping of mitral cell lateral dendrites as well as dendro-dendritic synapses formed between mitral cell lateral dendrites and granule cell dendrites are key determinants for efficient odor information processing derived from many co-activated glomerular modules.

Dendro-dendritic appositions

In addition to axon-dendritic synapses, dendro-dendritic reciprocal synapses, and gap junctions, appositions are observed between dendrites of one neuron and those of other neurons. The first example was observed electron microscopically between mitral cell lateral dendrites and between mitral cell primary and lateral dendrites in the EPL of the adult rat olfactory bulb [120]. Subsequently, similar appositions between dendrites were identified in many other brain regions, including the retina and hippocampus [121,122].

Nectin-1 spot as a cell adhesion apparatus of dendro-dendritic appositions

Nectin-1 is concentrated at the contacts between mitral cell lateral dendrites, between mitral cell lateral and apical dendrites, and between mitral cell lateral dendrites and granule cell dendritic spine necks in the deep sublamina of the EPL in the developing mouse olfactory bulb [47] (Figure 5Aa). Other CAMs, such as nectin-2, nectin-3, and N-cadherin, or their associating peripheral membrane proteins, such as afadin, β-catenin, α-actinin, and vinculin, are not co-localized with nectin-1 in the EPL. Nectin-1 is symmetrically localized on the plasma membranes at the contacts between mitral cell lateral dendrites. These contacts where nectin-1 is symmetrically localized are named nectin-1 spot. The nectin-1 spot is 0.21 μm in length on average and the distance between the plasma membranes is 20.8 nm on average. The plasma membranes are bilaterally darkened without cytoskeletal undercoats at the nectin-1 spot. In three-dimensional reconstruction of serial sections, clusters of the nectin-1 spot form a disc-like structure (Figure 5Ab). The electron microscopic ultrastructures of the nectin-1 spots are different from those of other adhesion apparatuses, such as the PAJ, the excitatory synaptic junction, and the inhibitory synaptic junction in neurons and those of the AJ, the TJ, and the desmosome in non-neural cells, such as epithelial and endothelial cells. At the contacts between mitral cell lateral dendrites in the nectin-1-knockout (KO) mouse olfactory bulb, the nectin-1 spot is undetectable and the bilateral plasma membranes are normalized in darkness but partly separated from each other, and their contacts become irregular. Thus, the nectin-1 spot constitutes a novel adhesion apparatus at the contacts between mitral cell lateral dendrites, between mitral cell lateral and apical dendrites, and between mitral cell lateral dendrites and granule cell dendritic spine necks in the deep sublamina of the EPL in the olfactory bulb.

Nectin-1 spot in the olfactory bulb.
Figure 5.
Nectin-1 spot in the olfactory bulb.

(A) Nectin-1 spot as a cell adhesion apparatus of dendro-dendritic appositions. (Aa) Schematic representation of the symmetric localization of nectin-1 (red dots, nectin-1 spots) between mitral cell lateral dendrites, mitral cell lateral, and apical dendrites, and between mitral cell lateral dendrites and granule cell dendrites in the deep sublamina of the external plexiform layer. Green ellipsoid and rectangles show clusters of the nectin-1 spots. (Ab) Three-dimensional reconstitution of the nectin-1 spots between mitral cell lateral dendrites and localization of the nectin-1 spots in the tangentially cut section. Red dots, immunogold particles for nectin-1; yellow polygonals, clusters of the nectin-1 spots. Each mitral cell lateral dendrite is distinguished by different colors. To show nectin-1-positive red dots more clearly, another image that all the mitral cell lateral dendrites colored in black is also shown. Localization of the nectin-1 spots is demonstrated by immunoelectron microscopy in the tangentially cut ultrathin section. Gl, glomeruli; MC, mitral cell; Md, mitral cell dendrite; Gds, granule cell dendritic spine. The figure and legend are modified from an article by Inoue et al. [47].

Figure 5.
Nectin-1 spot in the olfactory bulb.

(A) Nectin-1 spot as a cell adhesion apparatus of dendro-dendritic appositions. (Aa) Schematic representation of the symmetric localization of nectin-1 (red dots, nectin-1 spots) between mitral cell lateral dendrites, mitral cell lateral, and apical dendrites, and between mitral cell lateral dendrites and granule cell dendrites in the deep sublamina of the external plexiform layer. Green ellipsoid and rectangles show clusters of the nectin-1 spots. (Ab) Three-dimensional reconstitution of the nectin-1 spots between mitral cell lateral dendrites and localization of the nectin-1 spots in the tangentially cut section. Red dots, immunogold particles for nectin-1; yellow polygonals, clusters of the nectin-1 spots. Each mitral cell lateral dendrite is distinguished by different colors. To show nectin-1-positive red dots more clearly, another image that all the mitral cell lateral dendrites colored in black is also shown. Localization of the nectin-1 spots is demonstrated by immunoelectron microscopy in the tangentially cut ultrathin section. Gl, glomeruli; MC, mitral cell; Md, mitral cell dendrite; Gds, granule cell dendritic spine. The figure and legend are modified from an article by Inoue et al. [47].

Development-dependent expression of nectin-1

Mitral cells start to project primary and lateral dendrites to form a dendritic meshwork structure at embryonic day 15–16 and the projection complete by 4 weeks after birth [123,124]. Most of granule cells are acquired postnatally during the first 3 weeks, but they are renewed every day throughout adulthood [125,126], and appropriate insertion of their dendrites into the pre-existing meshwork of mitral cell lateral dendrites is essential for the maintenance of olfaction. In immunofluorescence microscopy, nectin-1 at the nectin-1 spot is observed at P5, the highest at P10, and thereafter reduced at P70. In Western blotting, nectin-1 is detected at P5, the highest at P10, and thereafter reduced at P70. These results indicate that the expression of nectin-1 in the deep sublamina of the EPL changes in a development-dependent manner.

Function of nectin-1 spot

In cultured nectin-1-KO mitral cells, the number of the branches of mitral cell dendrites is reduced compared with that in the control cells [48]. Juxtacellular labeling of mitral cell lateral dendrites in the deep sublamina of the EPL in the control and the nectin-1-KO olfactory bulb has revealed that the total number of branching points of mitral cell lateral dendrites in the deep sublamina of the EPL is reduced in the nectin-1-KO olfactory bulb compared with that in the control olfactory bulb [47]. These results indicate that the nectin-1 spot regulates the mitral cell dendritic branching in the deep sublamina of the EPL and suggest that the nectin-1 spot is required for odor information processing in the olfactory bulb. Two distinct mechanisms for the regulation of the branching of mitral cell lateral dendrites are conceivable: nectin-1 spot-independent regulation of the branching of dendrites near the soma (distance from the soma <200 μm) and nectin-1 spot-dependent regulation of the branching of dendrites distant from the soma (distance from the soma >200 μm). It still remains unknown why there are two mechanisms for the regulation of the branching of mitral cell lateral dendrites. It is also unknown which nectin-1 spot, that between mitral cell lateral dendrites and/or those between mitral cell lateral and apical dendrites, affects the branching of mitral cell lateral dendrites observed in the nectin-1-KO olfactory bulb, but taken together the results of the cultured mitral cells, it is likely that at least the nectin-1 spot between mitral cell lateral dendrites is responsible for the regulation of their branching in the deep sublamina of the EPL.

It is unknown how the deficiency of nectin-1 reduces the number of branching points of mitral cell lateral dendrites. The adhesion affinity of the homophilic trans-interaction of nectin-1 is more than 103-fold lower than that of the heterophilic trans-interaction between nectin-1 and nectin-3 [41,57]. In addition, the expression of nectin-1 in the olfactory bulb is highest at postnatal day 10 during development [47]. Taken together, it can be speculated that the nectin-1 spot helps to fasten together mitral cell lateral dendrites during the course of dendritic differentiation and also helps to suppress the retraction of formed dendritic branches. Consequently, the nectin-1 deficiency may lead to the retraction of dendritic branches, resulting in a reduction in the number of branching points of mitral cell lateral dendrites. The nectin-1 spot is likely an adhesion apparatus suitable for transient use at specific stages of dendritic development; however, further studies are needed to elucidate the function of the nectin-1 spot in the branching of mitral and tufted cell dendrites, which is critical for odor information processing in the olfactory bulb.

Dendro-dendritic reciprocal synapses are formed between mitral cell lateral dendrites and granule cell dendrites in the deep sublamina of the EPL. In the lateral dendritic field, the excitatory signals from mitral cells are transmitted to granule cells via mitral-to-granule dendro-dendritic synapses. Granule cells then serve to inhibit and synchronize mitral cell activity through granule-to-mitral dendro-dendritic inhibitory synapses [127]. The number of these dendro-dendritic reciprocal synapses in the deep sublamina of the EPL is reduced in the nectin-1-KO olfactory bulb compared with that in the control olfactory bulb. The molecular mechanism underlying this reduction of the number of reciprocal synapses between mitral cell lateral dendrites and granule cell dendrites is not known. One possible mechanism may be that this reduction is just caused by the reduced number of the branches of mitral cell lateral dendrites in the nectin-1-KO olfactory bulb. The second is that the nectin-1 spot between mitral cell lateral dendrites and granule cell dendritic spine necks regulates the formation of reciprocal synapses. The third is that the nectin-1 spot in the developing olfactory bulb may predominantly regulate the formation of dendro-dendritic reciprocal synapses, which promotes the stabilization of mitral cell lateral dendrites and results in up-regulation of the number of dendritic branches, because it has been shown that the formation of synapses on nascent dendritic branches promotes the stabilization of dendrites [128]. In this case, the nectin-1 deficiency may lead to the reduction in the number of reciprocal synapses between mitral cell lateral dendrites and granule cell dendrites and contribute to the reduction in the number of branches of mitral cell lateral dendrites. A decrease in the dendro-dendritic reciprocal synapse formation with granule cell dendrites may lead to a change in the pattern of inhibitory inputs to mitral cell lateral dendrites.

cis-Interaction of nectin-1 with the FGF receptor

Nectin-1 cis-interacts with the FGF receptor through their extracellular regions [71]. The first and second Ig-like loops of nectins are involved in their trans-interaction and cis-interactions, respectively [5458]. The third Ig-like loop of nectin-1 cis-interacts with all the isoforms of the FGF receptor [71]. The recombinant protein of the third Ig-like loop of nectin-1 induces neurite outgrowth in primary cultures of hippocampal and cerebellar granule neurons, and this effect is abolished by treatment with the FGF receptor inhibitor SU5402 or by transfection with a dominant-negative FGF receptor 1 construct. The third Ig-like loop of nectin-1 induces the phosphorylation of FGF receptor 1c in the same manner as the whole extracellular region of nectin-1 and promotes the survival of cerebellar granule neurons. A peptide, nectide, constructed by employing in silico modeling of various FGF receptor ligand-binding sites mimics all the effects of the third Ig-like loop of nectin-1. These results imply that the nectin-1 spot is associated with the FGF receptor and regulates the mitral cell dendritic branching co-operatively with this receptor.

Nectin-1/nectin-4 spot in the mammary gland epithelium

Nectin-1/nectin-4 spot is identified at the adhesion between the luminal and basal cells of the mammary gland epithelium [49]. This spot is associated with the prolactin receptor and stimulates its activation and signaling, although the electron microscopic structure of this spot remains unknown.

Development of the mammary gland

The mammary gland develops from a thickening in the ventral skin during embryogenesis that grows into a rudimentary ductal tree before birth [129] (Figure 6Aa). The female mammary gland continues to develop in a hormone-independent manner until puberty, following which hormones induce ductal elongation and branching. Elongation and branching of ducts, along with alveolar development with lactogenic differentiation, are induced by pregnancy. This development of the mammary gland during puberty and pregnancy is regulated by hormones, including estrogen, progesterone, and prolactin, and growth factors and cytokines, such as growth hormone, insulin-like growth factor-1, epidermal growth factor, FGF, Wnt, and receptor activator of nuclear factor κ-B ligand [129]. It is known that each stage of ductal morphogenesis depends on a specific extracellular signaling pathway; however, the roles of the cell adhesion apparatuses in the regulation of the mammary gland development remained largely unknown.

Nectin-1/nectin-4 spot in the mammary gland epithelium.
Figure 6.
Nectin-1/nectin-4 spot in the mammary gland epithelium.

(A) Development and cellular structure of the mammary gland. (Aa) Schematic representation of the stages of the mammary gland development from newborn, puberty, pregnancy, and lactation. EGF, epidermal growth factor; IGF, insulin-like growth factor; RANKL, receptor activator of nuclear factor κ-B ligand. (Ab) Schematic representation of the mammary gland. The adult mammary gland, consisting of collecting ducts and alveoli, is composed of a bilayer structure of inner luminal cells surrounded by outer basal myoepithelial cells with the outermost side ensheathed by the basement membrane. (B) Nectin-1/nectin-4 spot as a novel adhesion apparatus in the mammary gland epithelium. The nectin-1/nectin-4 spot is found at the boundary between the luminal and basal cells and serves as a platform for cellular signaling. The figure and legend are modified from an article by Kitayama et al. [49].

Figure 6.
Nectin-1/nectin-4 spot in the mammary gland epithelium.

(A) Development and cellular structure of the mammary gland. (Aa) Schematic representation of the stages of the mammary gland development from newborn, puberty, pregnancy, and lactation. EGF, epidermal growth factor; IGF, insulin-like growth factor; RANKL, receptor activator of nuclear factor κ-B ligand. (Ab) Schematic representation of the mammary gland. The adult mammary gland, consisting of collecting ducts and alveoli, is composed of a bilayer structure of inner luminal cells surrounded by outer basal myoepithelial cells with the outermost side ensheathed by the basement membrane. (B) Nectin-1/nectin-4 spot as a novel adhesion apparatus in the mammary gland epithelium. The nectin-1/nectin-4 spot is found at the boundary between the luminal and basal cells and serves as a platform for cellular signaling. The figure and legend are modified from an article by Kitayama et al. [49].

Cellular structure of the mammary gland and adhesion apparatuses

The adult mammary gland, consisting of collecting ducts and alveoli, is arranged in a bilayer structure of inner luminal cells surrounded by basal myoepithelial cells, with the outermost side ensheathed by the basement membrane [130] (Figure 6Ab). The luminal cells form a sheet by adhering to adjacent cells through cell adhesion apparatuses, including the TJ, the AJ, the desmosome, and the gap junction. The TJ is located at the most apical side of the lateral membranes of the luminal cells and the AJ is located at the basal side of the TJ. The desmosome and the gap junction are randomly located along the basolateral plasma membranes. The basal cells attach to each other by the AJ, the desmosome, and the gap junction. The luminal and basal cells attach to each other through the desmosome. The presence of the gap junction between the luminal and basal cells is controversial [131]. In addition, the basal cells attach to the basement membrane through the hemidesmosome.

Nectin-1/nectin-4 spot as a novel adhesion apparatus in the mammary gland epithelium

In addition to these known cell adhesion apparatuses, a cell adhesion apparatus mediated by nectin-1 and nectin-4 is localized at the boundary between the luminal and basal cells in the mammary gland [49] (Figure 6B). This apparatus, named the nectin-1/nectin-4 spot, is mainly formed and/or maintained by the trans-interaction between nectin-4 in the luminal cells and nectin-1 in the basal cells. None of the components of the AJ and the TJ, such as nectin-2, afadin, E-cadherin, β-catenin, occludin, and ZO-1, or none of the F-actin-binding proteins that directly or indirectly bind to nectins and E-cadherin, such as l-afadin, are co-localized at the nectin-1/nectin-4 spot. Moreover, neither desmoplakin, a component of the desmosome, nor connexin 43, a component of the gap junction, is co-localized at the nectin-1/nectin-4 spot. Thus, the nectin-1/nectin-4 spot is a novel type of cell adhesion apparatus that is different from the AJ, the TJ, the desmosome, and the gap junction. In the nectin-1-KO mammary gland, the nectin-1/nectin-4 spot disappears, but these other cell adhesion apparatuses are not impaired, indicating that the nectin-1/nectin-4 spot does not affect the formation and/or maintenance of these other cell adhesion apparatuses. At the boundary between the luminal and basal cells, only the desmosome was previously known to be located, although the presence of the gap junction has been controversial. However, the presence of the gap junction at this boundary is confirmed [49]. Therefore, at least three types of cell adhesion apparatuses are located at this boundary, namely the desmosome, the gap junction, and the nectin-1/nectin-4 spot.

Physical and functional interaction of the nectin-1/nectin-4 spot with the prolactin receptor

The nectin-1-KO female mice fail to breast feed their pups [49]. The pregnant nectin-1-KO mammary gland shows the insufficient alveolar development, including a suppression of alveolar development, abnormal morphologies of the ducts and alveoli, and reduces de novo synthesis of the milk protein, indicating that nectin-1 is involved in alveolar development with lactogenic differentiation. This impairment in lactation explains why the nectin-1-KO female mice fails to breast feed their pups.

A major hormone involved in the pregnancy-induced alveolar development with lactogenic differentiation is prolactin [132]. Prolactin binds to its receptor in the luminal cells and induces the JAK2 tyrosine kinase activation, which tyrosine phosphorylates STAT5 [133]. STAT5 then induces the transcription of many genes, including β-casein, which is necessary for alveolar development [133]. Both nectin-1 and nectin-4 cis-interact with the prolactin receptor to enhance its signaling for alveolar development with lactogenic differentiation in vivo [49]. However, the prolactin receptor is expressed in the luminal cells, and nectin-4, but not nectin-1, in the luminal cells is mainly involved in the formation of a novel apparatus by trans-interacting with nectin-1 in the basal cells at the boundary between two cell types in vivo. Therefore, nectin-4 of the nectin-1/nectin-4 spot is most likely to cis-interact with the prolactin receptor in the luminal cells in vivo. Taken together, it is likely that nectin-1 in the basal cells is involved in the formation of a novel apparatus by trans-interacting with nectin-4 in the luminal cells, and that nectin-4 of this apparatus cis-interacts with the prolactin receptor in the luminal cells and regulates its signaling for alveolar development with lactogenic differentiation (Figure 6B). In the nectin-1-KO mice mammary gland, it is likely that not only nectin-4 but also the prolactin receptor in the luminal cells is no longer concentrated at the nectin-1/nectin-4 spot, thereby sufficient signaling for alveolar development with lactogenic differentiation could not be transduced. Thus, this apparatus may serve as a platform for the prolactin receptor signaling. However, the detailed electron microscopic structure of the nectin-1/nectin-4 spot remains unknown.

Possible interactions of the nectin-1/nectin-4 spot with the FGF receptor and integrin αvβ3

Nectin-1 cis-interacts with the FGF receptor and enhances its receptor signaling for neural process outgrowth and neural survival [71], although it remained to be elucidated whether nectin-4 cis-interacts with the FGF receptor. Both the FGF receptor 1 and the FGF receptor 2 are expressed in both the luminal and basal cells in the mammary gland [134]. The genetic deletion of the FGF receptor 2 results only in transient developmental defects in branching morphogenesis. The genetic deletion of the FGF receptor 1 results in an early, yet transient delay in development. However, no reduction in functional outgrowth potential is observed following limiting dilution transplantation analysis. In contrast, a significant reduction in outgrowth potential is observed upon the deletion of both the FGF receptor 1 and the FGF receptor 2 in the luminal and basal cells. Although the phonotype of the mammary gland in the nectin-1-KO is mainly the impairment of alveolar differentiation and not that of ductal outgrowth, it could be speculated that nectin-1 affects this action of the FGF receptors and impairs the mammary gland development during pregnancy in the nectin-1-KO mammary gland co-operatively with these receptors. Further studies are necessary for the elucidation of the functional relationship between the nectin-1/nectin-4 spot and the FGF receptor.

It is shown that integrin αvβ3 plays a critical role in adult mammary stem cells during pregnancy [135]. Whereas integrin αvβ3 is a luminal progenitor marker in the virgin gland, it is expressed in mammary stem cells at midpregnancy. Accordingly, mice lacking integrin αvβ3 shows defective mammary gland morphogenesis during pregnancy. This is associated with decreased mammary stem cell expansion, clonogenicity, and expression of Slug, a master regulator of mammary stem cells. In contrast, mice lacking integrin αvβ3 display normal development of the mammary gland with no effect on luminal progenitors before puberty. Nectin-1 cis-interacts with integrin αvβ3 [72], although it is unknown whether nectin-4 cis-interacts with integrin αvβ3. However, it could be speculated that nectin-1 affects this action of integrin αvβ3 and impairs the mammary gland development during pregnancy in the nectin-1-KO mammary gland co-operatively with integrin αvβ3. Further studies are necessary for the elucidation of the functional relationship between the nectin-1/nectin-4 spot and integrin αvβ3.

Nectin-1/nectin-3 spot in commissural axons

Nectin spot is first found at the adhesion between commissural axons and floor plate cell basal processes in developing neural tube [46] before the identification of the nectin-1 spot in the olfactory bulb and the nectin-1/nectin-4 spot in the mammary gland. This spot is similar to these nectin spots and hereafter named nectin-1/nectin-3 spot, although the cis-interacting receptors and integrins remain unidentified.

Regulation of elongation and path-finding of commissural axons by soluble cues

In the developing neural tube, commissural axons grow toward the ventral midline, cross the floor plate, and then abruptly change their trajectory from the circumferential to the longitudinal axis [136,137] (Figure 7A). This commissural axon guidance is regulated by many soluble cues and contacts between commissural axons and floor plate cell basal processes. The axons of commissural neurons are initially drawn to the ventral midline by attractive forces represented by netrin 1 and sonic hedgehog (Shh), which are secreted from the floor plate [138,139]. Commissural axons leave the floor plate on the contralateral side owing to a change in responsiveness to repulsive cues, mainly because of the expression of Robo receptors that recognize midline-associated repellents, the Slit proteins [140,141].

Nectin-1/nectin-3 spot in commissural axons.
Figure 7.
Nectin-1/nectin-3 spot in commissural axons.

(A) Commissural axon growth in the developing neural tube. (B) Vital contacts between commissural axons and floor plate cell basal processes. (C) Localization and roles of nectins and Necls at the contacts between commissural axons and floor plate cell processes in the neural tube. Nectin-3 and Necl-3 on extending axons interact with nectin-1 and Necl-2 on dendrites of the floor plate cells, respectively.

Figure 7.
Nectin-1/nectin-3 spot in commissural axons.

(A) Commissural axon growth in the developing neural tube. (B) Vital contacts between commissural axons and floor plate cell basal processes. (C) Localization and roles of nectins and Necls at the contacts between commissural axons and floor plate cell processes in the neural tube. Nectin-3 and Necl-3 on extending axons interact with nectin-1 and Necl-2 on dendrites of the floor plate cells, respectively.

Role of CAMs in the trajectory of commissural axons

The Ig-like CAMs provide vital contacts between commissural axons and floor plate cell basal processes [142] (Figure 7B). The interaction between axonin-1/TAG1 expressed on the surface of commissural growth cones and NrCAM expressed in floor plate cell basal processes is required for axons to cross the midline. Thus, midline crossing by commissural axons is regulated by a balance between positive axonin-1/NrCAM and negative Robo/Slit signals. After midline crossing, dorsal commissural axons turn rostrally into the longitudinal axis and extend along floor plate basal cell process border [143]. In mouse, this is mediated by an attractive rostral high to caudal low Wnt4 gradient in the floor plate [144]. In contrast, in chick, Shh expressed in a rostral low to caudal high gradient in floor plate cells has been identified as a repellent for post-crossing commissural axons in a subtractive hybridization screen [145].

Nectin-1/nectin-3 spot and its function in the trajectory of commissural axons

In addition to these CAMs, nectins have an important role in mediating the contacts between commissural axons and floor plate cell basal processes (Figure 7C). Nectin-1 and nectin-3 are asymmetrically localized at commissural axons and floor plate cell basal processes, respectively [46]. None of the components of the AJ, including N-cadherin, β-catenin, α-actinin, vinculin, ZO-1, and l-afadin, are concentrated at the contacts where nectin-1 and nectin-3 are localized. Electron microscopically, these contacts are not undercoated with the actin cytoskeleton [46,146,147]. These results indicate that the contacts between the commissural axons and floor plate cell basal processes mediated by nectin-1 and nectin-3 are different from the classically categorized AJ, similar to the nectin-1 spot in the olfactory bulb and the nectin-1/nectin-4 spot in the mammary gland, and named nectin-1/nectin-3 spot.

The nectin-1/nectin-3 spot regulates the commissural neuron axon guidance, because glycoprotein D, a HSV1 protein that binds to nectin-1 and inhibits its trans-interaction with other nectins and Necls [19], disturbs the trajectory of the commissural axons after middle crossing [46]. The weak attachment that is mediated by the trans-interaction between nectin-1 and nectin-3 is crucially involved in the determination of the axonal guidance and this weak trans-interaction, instead of the strong adhesion mediated by cadherins, might be advantageous when commissural axons continuously elongate while being attached to floor plate cell basal processes. Because commissural axons communicate with or transfer signals to floor plate cells through these contact sites [142], the nectin-1/nectin-3 spot may be associated with soluble cues. Both weak signal communication and weak mechanical contacts between commissural axons and floor plate cell basal processes that are mediated by the nectin-1/nectin-3 spot may be involved in the regulation of the axonal guidance.

Necl-2/Necl-3 spots in the commissural axons

In addition to the nectin-1/nectin-3 spot, Necl-2 is expressed in floor plate cells, and Necl-2 and Necl-3 are expressed in the growth cone of the commissural axons and the trans-interactions of Necl-2 with Necl-2 and Necl-3 are involved in the trajectory of the commissural axons [148] (Figure 7C). The cis-interaction between Necl-2 and Necl-3 forms a receptor complex that mediates the activity of floor plate cell-derived Necl-3. After down-regulation of Necl-3 in floor plate cells, growth cones fail to turn rostrally after midline crossing. The directionality of growth along the floor plate cell border is also determined by gradients of Shh and Wnt proteins. It remains unknown whether these two guidance systems are linked, whether they act in parallel in a redundant manner, or whether these two guidance systems are associated with the nectin-1/nectin-3 spot.

Transiently formed cell–cell contacts

In addition to the expression of nectins and their trans-interacting molecules in tissues and organs, they are also expressed in leukocytes which transiently attach to other leukocytes and other cells including vascular endothelial cells, virally transfected cells, and cancer cells [149]. Nectin-2, nectin-3, Necl-2, Necl-5, Tactile, DNAM-1, CRTAM, and TIGIT are expressed in leukocytes: nectin-2 is in dendritic cells and monocytes; nectin-3 in T cells; Necl-2 in mast cells; Necl-5 in dendritic cells and monocytes; Tactile in T-cells and NK cells [150]; DNAM-1 in T-cells, B-cells, NK cells, monocytes, macrophages, megakaryocytes, and platelets [151]; CRTAM in T-cells and NK cells [152]; and TIGIT in T-cells and NK cells [52]. The interactions in trans between these molecules may form a cell adhesion apparatus similar to nectin spots and regulate the activation of leukocytes. The trans-interactions of these CAMs may constitute transient nectin-like spots and regulate leukocyte functions in immune responses and TEM.

Immune responses

NK cells are innate lymphocytes that play important roles in the immune defense against virus-infected cells and cancer cells. The Ig-like molecules, such as nectin-2, Necl-5, Tactile, DNAM-1, CRTAM, and TIGIT, are involved in these processes [153]. Tactile trans-interacts with nectin-1 and Necl-5, DNAM-1 with nectin-2 and Necl-5, CRTAM with Necl-2, and TIGIT with nectin-2, nectin-3, and Necl-5 on their target cells, such as cancers cells (Figure 8A). NK cells are endowed with two functionally different types of cell surface receptors, activating and inhibitory receptors, allowing them to discriminate between normal cells and virus-infected or cancer cells [154]. Activating receptors are specific for cell surface molecules that are up-regulated in virally infected and cancer cells, but absent from the cell surface of healthy cells. These receptors transmit activating signals upon engagement with their respective ligands, stimulating NK cell cytotoxicity toward the ligand-expressing cell. Inhibitory receptors detect cell surface molecules expressed on normal cells and transmit inhibitory signals to spare normal cells from NK cell attack. Most known NK cell inhibitory receptors are specific for classical or nonclassical MHC class I molecules expressed by normal cells. DNAM-1 and CRTAM serve as stimulatory co-receptors for the activating receptors, whereas Tactile and TIGIT serve as inhibitory co-receptors for the inhibitory receptors [149]. Nectin-1, nectin-2, and Necl-5 are up-regulated in a variety of cancer cells and the interaction of these molecules with DNAM-1 further enhances the activation of NK cells, whereas the interaction of these molecules with Tactile and TIGIT further suppresses the activation of NK cells [155]. The affinity between DNAM-1 and Necl-5 is 114 nM, that between Tactile and Necl-5 is 37.6 nM; and that between TIGIT and Necl-5 is 3.15 nM [70]. These results suggest that Necl-5 up-regulated in cancer cells first suppresses and then enhances the activation of NK cells depending on its expression level. Necl-2 is in general down-regulated in a variety of cancer cells, but Necl-5, which is not down-regulated in cancer cells, enhances the activation of NK cells. However, it still remains unknown how these Necls regulate the activity of these interacting molecules in NK cells. Cytotoxic T lymphocytes (CTLs) are T lymphocytes that kill virus-infected cells and cancer cells. Most CTLs express the T-cell receptor (TCR) that can recognize a specific antigen. CTLs express nectin-2, Necl-5, and DNAM-1, which play similar roles to those of NK cells in killing virus-infected cells and cancer cells [156].

Transiently formed cell–cell contacts.
Figure 8.
Transiently formed cell–cell contacts.

(A) Activation and inhibition signals mediated by trans-interactions of nectins, Necls, and other Ig-like molecules. DNAM-1/CD226 and CRTAM/CD355 transduce activation signals, whereas TIGIT and Tactile/CD96 transduce inhibition signals upon engagement of their ligands. (B) Schematic representation of the distinct steps during the transendothelial migration mediated by trans-interactions of nectin, Necls, and other Ig-like molecules.

Figure 8.
Transiently formed cell–cell contacts.

(A) Activation and inhibition signals mediated by trans-interactions of nectins, Necls, and other Ig-like molecules. DNAM-1/CD226 and CRTAM/CD355 transduce activation signals, whereas TIGIT and Tactile/CD96 transduce inhibition signals upon engagement of their ligands. (B) Schematic representation of the distinct steps during the transendothelial migration mediated by trans-interactions of nectin, Necls, and other Ig-like molecules.

NK cells activated in response to IL-2 efficiently lyse autologous and allogeneic mesenchymal stem cells (MSCs) and inversely, MSCs inhibit the IL-2-induced proliferation of resting NK cells [157]. MSCs are multipotent stem cells that are able to form bone, cartilage, and other mesenchymal tissues. MSCs serve as bone marrow stroma that support hemopoiesis by providing suitable cytokines and growth factors. MSCs express nectin-2 and Necl-5 as well as UL16-binding protein, and the inhibition by the anti-DNAM-1 antibody (Ab) reduces the lysis of MSCs and cytokine production by NK cells, suggesting that the trans-interaction between DNAM-1 in NK cells and nectin-2 or Necl-5 in MSCs is involved in these reactions [157].

Dendritic cells are the most potent antigen-presenting cells of the immune system and express nectin-2, Necl-5, and DNAM-1 [158]. Depending on their maturation status, they prime T-cells to induce adaptive immunity or tolerance. The trans-interactions of DNAM-1 with nectin-2 and Necl-5 contribute to the NK cell-mediated lysis of immature and mature dendritic cells [158]. Analogously, mature dendritic cells are protected from the NK cell-mediated lysis by high surface expression of HLA class I molecules on mature dendritic cells; these act as ligands for inhibitory receptors on NK cells. Immature dendritic cells are efficiently killed by NK cells due to DNAM-1 function [158]. Therefore, DNAM-1 might play a role in NK-mediated ‘quality control’ of dendritic cell maturation by selecting those dendritic cells that show a high expression of HLA class I molecules and costimulatory ligands, optimizing their ability to prime T-cells.

Mast cells show critical effector functions in various immune reactions. In allergic inflammation, mast cells interact with tissue-infiltrating eosinophils, forming a regulatory unit in the late and chronic phases of the allergic process. Mast cells express nectin-2, Necl-2, and DNAM-1 [159161]. DNAM-1 synergizes with FcεRI on mast cells, and its engagement augments degranulation through a pathway involving Fyn, linker of activation of T-cells, phospholipase Cγ2, and CD18 [160]. This pathway is subject to negative interference by inhibitory receptors and is completely inhibited by linking IgE with IRp60 (CD300a) using a bispecific Ab [160]. Moreover, a blocking Ab against nectin-2 expressed on eosinophils normalizes the hyperactivity resulting from IgE-dependent activation of mast cells co-cultured with eosinophils, indicating that a novel interface between these two effector cells implicates relevance for in vivo allergic states.

Transendothelial migration

Another example of transiently formed cell–cell contacts is observed during TEM. The vascular endothelium consists of a continuous monolayer of cells that lines the entire vascular system. Leukocytes leave the bloodstream by attaching to vascular endothelial cells through a well-characterized multistep adhesion molecule cascade, including tethering, rolling, firm adhesion, and TEM [162] (Figure 8B). Endothelial cells have cell junction apparatuses essentially similar to those in epithelial cells and regulate TEM of a variety of cells, including leukocytes and cancer cells. Vascular endothelial cells express many CAMs, including VE-cadherin, nectin-1, nectin-2, nectin-3, JAM-A, JAM-B, JAM-C, occludin, claudin-1, claudin-3, claudin-5, claudin-12, Necl-4, Necl-5, platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), and CD99, suggesting that these CAMs regulate TEM. Among these CAMs, nectin-2 and Necl-5, as well as PECAM-1, JAMs, CD99, and VE-cadherin, have been shown to regulate TEM of leukocytes [163].

Monocytes express DNAM-1 and its trans-interaction with Necl-5 expressed in endothelial cells is involved in their TEM [164]. Nectin-2 and Necl-5 are concentrated at cell junctions of primary vascular endothelial cells and the specific binding of a soluble DNAM-1-Fc molecule is detected at this junctions. This binding is inhibited by an anti-Necl-5 monoclonal Ab, but not modified by an anti-nectin-2 monoclonal Ab, indicating that Necl-5 is the major DNAM-1 ligand in endothelial cells. Both anti-DNAM-1 and anti-Necl-5 monoclonal Abs block the TEM of monocytes. Moreover, after the treatment with the anti-DNAM-1 or anti-PVR monoclonal Ab, monocytes are arrested at the apical surface of the endothelium over intercellular junctions, suggesting that the DNAM-1–Necl-5 interaction occurs during the diapedesis step. Thus, Necl-5 regulates monocyte extravasation via its interaction with DNAM-1 expressed in monocytes (Figure 8B).

Human CD4+ T lymphocytes can rapidly transmigrate across the endothelial cell monolayer in response to either chemokine or the TCR-activating signals displayed by human dermal microvascular endothelial cells under conditions of venular shear stress. The TCR-stimulated TEM depends on fractalkine (also known as CX3CL1), PECAM-1, intercellular adhesion molecule-1 (ICAM-1, also known as CD54), and CD99 expression in the endothelial cells [165]. In addition, it depends on nectin-2 and Necl-5 in the endothelial cells [163]. ICAM-1 in the endothelial cells trans-interacts with lymphocyte function-associated antigen 1 (also known as CD11a/CD18) in the CD4+ T cells, whereas nectin-2 and Necl-5 trans-interact with DNAM-1 and Tactile. Blocking Abs against these molecules inhibit these interactions and TCR-dependent TEM of the CD4+ T cells (Figure 8B).

Nectin-3 is the only nectin of the nectin and Necl superfamily expressed in the CD4+ T cells and trans-interacts with nectin-2 expressed in endothelial cells, and this interaction is required for the TEM of lymphocytes [53]. A soluble form of nectin-3 binds to nectin-2 localized at endothelial cell junctions and a blocking monoclonal Ab against nectin-2 abolishes this binding of soluble nectin-3 to endothelial cells. Nectin-2 is expressed on high endothelial venules, where lymphocyte homing occurs in vivo. A blocking monoclonal Ab either against nectin-3 expressed on lymphocytes or nectin-2 expressed on endothelial cells inhibits the lymphocyte extravasation. Thus, nectin-3 trans-interacts with nectin-2 to promote lymphocyte extravasation (Figure 8B).

Nectin microclusters and assembly of other membrane protein microclusters

It has recently been shown that about five non-trans-interacting E-cadherin molecules form microclusters and that the E-cadherin molecules in this microclusters trans-interact with each other to form primordial cell–cell adhesive spots that are delimited by F-actin [90]. The trans-interacting E-cadherin molecules in this microclusters are assembled to form the AJ. It is not known whether non-trans-interacting nectin molecules are assembled to their microclusters or how many trans-interacting nectin molecules are assembled to their microclusters at the AJ, but immunoelectron microscopy analysis shows that nectin-1 molecules are found in their microclusters and that these microclusters are assembled to form the nectin-1 spots in the olfactory bulb [47]. Although the nectin-1 spot in the olfactory bulb is not associated with F-actin, these results have raised the possibility that the nectin microclusters, which may be present at the AJ, are similar to those of the E-cadherin microclusters. In the initial AJ formation, nectin microclusters may facilitate the assembly of the E-cadherin microclusters, co-operatively with F-actin associated with these two CAMs.

It is not known how membrane receptors and integrins cis-interact with nectins and Necls, but they may cis-interact with the peripheral nectin molecules at nectin spots. Many membrane receptors and integrins are known to cis-interact with cadherins [166]. At the AJ, these membrane receptors and integrins cis-interact with both the peripheral nectin and cadherin molecules at their respective microclusters to form the complicated mosaics. The cis-interactions of membrane receptors are effectively concentrated and become more sensitive to lower concentrations of their ligands by cis-interacting with these nectin microclusters.

Conclusions and perspectives

Nectins form not only afadin- and cadherin-dependent and afadin-dependent and cadherin-independent cell adhesion apparatuses but also afadin- and cadherin-independent cell adhesion apparatus, and examples of this apparatus are increasing. The structural property of this apparatus is that it is not associated with any cytoskeleton. This apparatus is observed as dots or short lines by immunofluorescence microscopy and electron microscopy and are named nectin spots. Consistent with these structural properties, the functional property of nectin spots is that their cell–cell adhesions and contacts seem to be weak and transient. The inability of nectin spots to interact with cadherins and cytoskeleton is due to their inability to bind afadin, but the mechanism for this inability is unknown. The C-termini of nectins at these spots may be occupied by an unidentified molecule that prevents afadin from binding to them. Identification of these molecules is needed for our understanding of the mechanism for the formation of nectin spots. At nectin spots, the trans-interacting nectin molecules are clustered to form a microdomain on the plasma membrane of apposing cells. Clustering of CAMs, in general, is induced by their trans-interactions through their extracellular regions and further enhanced by their association with the cytoskeletons through their intracellular tails. Although the typical cytoskeleton associated with the known cell adhesion apparatuses, such as the AJ, the PAJ, the TJ, and the desmosome, is not observed at nectin spots, electron microscopy shows that the bilateral plasma membranes of nectin spots are slightly thickened. One possible mechanism of this slight thickening at nectin spots is that some unidentified peripheral membrane proteins are associated with the cytoplasmic tails of nectins or some unidentified transmembrane proteins are cis-interacted with the extracellular region and/or the cytoplasmic region of nectins on the same plasma membrane, and these proteins may bind some peripheral membrane proteins. In fact, the nectin-1/nectin-4 spot cis-interacts with the prolactin receptor. It could be speculated that other nectin spots may also cis-interact with other membrane receptors, causing co-clustering of these cis-interacting molecules and thickening the plasma membranes to slight extents. Thus, nectin spots as well as other nectin-mediated cell adhesion apparatuses may serve as not only cell adhesion apparatuses but also signaling platforms for membrane receptors. Only three examples of nectin spots have thus far been identified, namely in the olfactory bulb, in the mammary gland, and in the commissural axons. Although the expression of afadin in transiently formed nectin-mediated cell–cell contacts of leukocytes remains unclear, this contacts in which many membrane receptors are colocalized with nectins, Necls, and other Ig-like CAMs in leukocytes could be classified into nectin spot. Nectin spots may be also identified in other tissues and organs at their developing stages and reorganizing conditions, where they might play roles in the organization and reorganizations of these tissues and organs co-operatively with membrane receptors and integrins. The adhesion apparatus at the internodes between an axon and a Schwann cell is formed by the trans-interaction of Necl-1 in an axon and Necl-4 in a Schwann cell and the adhesion apparatus at the Schmidt-Lanterman incisure is formed by the trans-interaction of Necl-4, Necl-1, and Necl-2 in a sheet of a Schwann cell and Necl-1, Necl-2, and Necl-2 in an opposing sheet of the same Schwann cell, respectively [167,168]. It is unknown whether these apparatuses are similar to nectin spots and future studies are needed to elucidate whether they belong to the entity of nectin spots.

Abbreviations

Ab, antibody; AJ, adherens junction; CAM, cell adhesion molecule; CTL, cytotoxic T lymphocyte; DNAM-1, DNAX accessory molecule 1; EPL, external plexiform layer; F-actin, actin filament; FGF, fibroblast growth factor; ICAM-1, intercellular adhesion molecule-1; Ig, immunoglobulin; JAM, junctional adhesion molecule; KO, knockout; MSC, mesenchymal stem cell; Necl, nectin-like molecule; PAJ, puncta adherentia junction; PDGF, platelet-derived growth factor; PDZ, PSD95–DLG1–ZO-1; PECAM-1, platelet endothelial cell adhesion molecule-1; PVR, polyovirus receptor; Shh, sonic hedgehog; TCR, T-cell receptor; TEM, transendothelial migration; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TJ, tight junction; VEGF, vascular endothelial growth factor.

Funding

This work of our laboratory is supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science [21227005 and 26251013 to Y.T.] and [26860190 to K.M.], by Grants-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology [26114007 to Y.T.], and Japan Foundation for Applied Enzymology (to Y.T.).

Acknowledgments

The authors thank all co-workers and collaborators for their outstanding contributions. We apologize to many authors whose excellent papers we could not cite owing to space limitations.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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