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J. Biol. Chem., Vol. 278, Issue 37, 35421-35427, September 12, 2003
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From the
Department of Molecular Biology and
Biochemistry and Department of Surgery and
Clinical Oncology, Osaka University Graduate School of Medicine/Faculty of
Medicine, Suita 565-0871, Osaka, Japan and ¶KAN
Research Institute Inc., 93 Chudoji-Awatamachi, Shimogyo-ku, Kyoto 600-8815,
Japan
Received for publication, May 22, 2003 , and in revised form, June 13, 2003.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
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Nectins are emerging cell-cell adhesion molecules that play roles in the organization of a variety of cell-cell junctions, such as AJs and TJs in epithelial cells, synaptic junctions in neurons, and heterotypic junctions formed between the Sertoli cells and spermatids in the testis, in cooperation with or independently of cadherins (5). Although cadherins are Ca2+-dependent cell-cell adhesion molecules, nectins are Ca2+-independent cell-cell adhesion molecules that comprise a family of four members, nectin-1, -2, -3, and -4 (5). All nectins have one extracellular region with three Ig-like loops, one transmembrane region, and one cytoplasmic region (5). Each nectin forms homo-cis-dimers followed by formation of homo-trans-dimers, causing cell-cell adhesion (5). Nectin-3 furthermore forms hetero-trans-dimers with either nectin-1 or -2, and the adhesion activity of each hetero-trans-dimers is stronger than that of each homo-trans-dimers (5). Nectin-4 also forms hetero-trans-dimers with nectin-1 (5). Nectins except nectin-4 have a C-terminal conserved motif of four amino acid (aa) residues that interacts with the PDZ domain of afadin (5). Nectin-4 does not have this consensus motif but binds afadin. Afadin is an F-actin-binding protein with one PDZ domain and three other domains and connects nectins to the actin cytoskeleton (5).
Five molecules with one extracellular region containing three Ig-like loops, one transmembrane region, and one cytoplasmic region have thus far been identified. We have proposed, based on their domain structures which are similar to those of nectins, that these molecules are called nectin-like molecules (Necls) (6). These include Necl-1/TSLL1/SynCAM3 (7, 8), Necl-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 (8–12), Necl-3/similar to Necl-3/SynCAM2 (8), Necl-4/TSLL2/Syn-CAM4 (7, 8), and Necl-5/Tage4/PVR/CD155 (6, 13–16). Of these, we focus here on Necl-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1. Necl-2 was directly submitted to GenBankTM (GenBankTM/EMBL/DDBJ accession number AF061260 [GenBank] (1998); GenBankTM/EMBL/DDBJ accession number AF132811 [GenBank] (1999)); IGSF4 was identified as a candidate for a tumor suppressor gene associated with loss of heterozygosity of chromosome 11q23.2 (9); RA175 was identified to be a gene highly expressed during neuronal differentiation of embryonic carcinoma cells (10); SgIGSF was identified to be a gene expressed in spermatogenic cells during earlier stages of spermatogenesis (11); and TSLC1 was identified to be a tumor suppressor in human non-small cell lung cancer (12). TSLC1 shows Ca2+-independent homophilic cell-cell adhesion activity (17). TSLC1 has a band 4.1-binding motif at the juxtamembrane region and binds tumor suppressor DAL-1, one of the band 4.1 family members, which connects TSLC1 to the actin cytoskeleton (18); SynCAM1 was identified to be a brain-specific synaptic adhesion molecule (8). SynCAM1 shows Ca2+-independent homophilic cell-cell adhesion activity (8). SynCAM1 forms synapses between HEK293 cells expressing exogenous SynCAM1 and primary cultured hippocampal neurons in vitro (8). SynCAM1 has been shown to be specifically expressed in mouse brain as estimated by Western blotting (8), but TSLC1 and SgIGSF have been shown to be expressed ubiquitously as estimated by Northern blotting (11, 19). This molecule with six different nomenclatures is referred to Necl-2.
We have studied the properties of Necl-2, including its cell-cell adhesion activity, its localization, and its binding protein. We have found that Necl-2 localizes at the extra-junctional region of the basolateral plasma membrane of epithelial cells and directly binds Pals2. Pals2 was originally isolated as a Lin-7-binding protein (20). Lin-7 is a PDZ domain-containing protein that forms a heterotrimeric complex with Lin-2 and -10. This Lin-2·Lin-7·Lin-10 protein complex is involved in organization of epithelial and neuronal junctions in Caenorhabditis elegans and mammals (21). Pals2 belongs to the membrane-associated guanylate kinase family and consists of two Lin-2/-7 homology domains, one PDZ domain, one Src-homology 3 domain, and one guanylate kinase domain. Pals2 as well as Pals1 and Lin-2 constitutes a subfamily that binds to Lin-7 (20). Here we describe these novel properties of Necl-2.
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EXPERIMENTAL PROCEDURES |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
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Construction of Plasmids—Expression vectors were constructed
in pFLAG-CMV1 (Sigma), pCAGIPuro
(22), pCAGIZeo
(23), pGBD-C1
(24), pGEX4T-1 (Amersham
Biosciences), pMAL-C2 (New England Biolabs Inc.), pGAD424-HA
(25), pFastBac1-Msp-Fc
(26), and pCMV-HA
(27). Various constructs of
Necl-1 and -2 contained the following aa: pFLAG-CMV1-Necl-1, aa 20–396
(deleting the signal peptide); pCAGI-Puro-FLAG-Necl-1, aa 20–396
(including the preprotrypsin signal peptide); pCAGIZeo-Necl-2, aa 1–417
(full-length); pFLAG-CMV1-Necl-2, aa 43–417 (deleting the signal
peptide); pCAGIPuro-FLAG-Necl-2, aa 43–417 (including the preprotrypsin
signal peptide); pCAGIPuro-Necl-2-
C, aa 1–413 (deleting the
C-terminal 4 aa); pFastBac1-Msp-Fc-Necl-2-EC, aa 43–348 (the
extracellular region deleting the signal peptide); pGBD-C1-Necl-2-EC,
aa 335–417 (deleting the extracellular region); pGEX4T-1-Necl-2-CP, aa
372–417 (the cytoplasmic region); pGEX4T-1-Necl-2-CPC, aa
372–413 (the cytoplasmic region deleting the C-terminal 4 aa). The cDNA
of mouse Pals2 was kindly provided by Dr. B. Margolis (University of Michigan
Medical Center, Ann Arbor, MI). Constructs of mouse Pals2 contained the
following aa: pCMV-HA-Pals2, aa 1–539 (full-length); pMAL-C2-Pals2, aa
1–539 (full-length); pMAL-C2-Pals2-PDZ, aa 361–639 (PDZ domain).
Various constructs of nectin-2
and l-afadin contained the following aa:
pGEX4T-1-nectin-2-CP, aa 387–467 (the cytoplasmic region);
pGBD-C1-nectin-2-CP, aa 387–467 (the cytoplasmic region);
pMAL-C2-afadin-PDZ, aa 1007–1125 (PDZ domain); and pGAD424-HA-l-afadin,
aa 1–1829 (full-length)
(25,
28). The IgG Fc fusion
proteins were prepared as a secreted protein from the baculovirus transfer
system (Invitrogen) and purified by use of protein A-Sepharose beads (Amersham
Biosciences) as described
(26). The glutathione
S-transferase (GST) and maltose-binding protein (MBP) fusion proteins
were purified by use of glutathione-Sepharose beads (Amersham Biosciences) and
amylose resin beads (New England Biolabs, Inc.), respectively.
Cell Culture and Establishment of Transfectants—L and MTD-1A
cells were kindly supplied by Dr. S. Tsukita (Kyoto University, Kyoto, Japan).
L and MTD-1A cells were maintained in Dulbecco's modified Eagle's medium
supplemented with 10% fetal calf serum. L cell lines stably expressing human
nectin-1, mouse nectin-2, mouse nectin-3, or mouse Necl-5
(nectin-1-L, -2-L, -3-L, and Necl-5-L cells, respectively) were prepared as
described (6,
22,
28,
29). An L cell line stably
expressing FLAG-Necl-1 (Necl-1-L cells), full-length Necl-2
(non-tagged-Necl2-L cells), FLAG-Necl-2 (Necl-2-L cells), or Necl-2-C
(Necl-2-C-L cells) was obtained by transfection with
pCAGIPuro-FLAG-Necl-1, pCAGIZeo-Necl-2, pCAGIPuro-FLAG-Necl-2, or
pCAGIPuro-Necl-2-C, respectively, using LipofectAMINE PLUS reagent
(Invitrogen). We mostly used Necl-2-L cells (FLAG-tagged Necl-2) in the
present study, but the essentially similar results were obtained with
non-tagged Necl-2-L cells.
Antibodies—A rat anti-Necl-2 monoclonal Ab (mAb) (1C4-2) was raised against the fusion protein of the extracellular region of Necl-2 (aa 43–348) with IgG Fc. The anti-Necl-2 mAb was used for both Western blotting and immunostaining. An anti-l-afadin polyclonal antibody (pAb) was prepared as described (30). An anti-FLAG mAb (M1) and pAb were purchased from Sigma. An anti-ZO-1 mAb (AB01003) and pAb (61–7300) were purchased from Sanko Junyaku Co. and Zymed Laboratories Inc., respectively. An anti-HA mAb was purchased from Berkeley Antibody Co.
Yeast Two-hybrid Screening—The yeast two-hybrid library
constructed from mouse testis cDNA was purchased from Clontech, and a
Necl-2-binding protein(s) was screened using pGBD-C1-Necl-2-EC as bait
as described (24). Two-hybrid
screening using the yeast strain PJ69–4A (MATa trp1–901
leu2-3, 112 ura3-52 his3-200 gal4 gal80
GAL2-ADE2 LYS2::GAL1-HIS3 met2::GAL7-lacZ) was done
as described (24).
Other Procedures—Immunofluorescence microscopy of cultured cells and co-immunoprecipitation assay were done as described (28). The cell aggregation assay, chemical cross-linking, and affinity chromatography were done as described (29). Immunoelectron microscopy of mouse tissues was done using the silver enhancement technique as described (31). SDS-PAGE was done as described (32). Protein concentrations were determined with bovine serum albumin as a reference protein as described (33).
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RESULTS |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
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Ca2+-independent Heterophilic Cell-Cell Adhesion Activity of Necl-2—Nectins show both homophilic and heterophilic cell-cell adhesion activities (5). We next examined by the cell aggregation assay whether Necl-2 shows heterophilic cell-cell adhesion activity with other nectins and Necls. Necl-2-L cells formed heterophilic cell aggregates with L cells stably expressing Necl-1 or nectin-3 (Necl-1-L and nectin-3-L cells, respectively) but not with L cells stably expressing Necl-5, nectin-1, or nectin-2 (Necl-5-L, nectin-1-L, or -2-L cells, respectively) (Fig. 2, A–E). Necl-1-L cells formed homophilic cell aggregates (Fig. 2F). The sizes of the aggregates were not significantly affected by the presence of Ca2+ or EDTA (data not shown). The detailed properties of Necl-1 will be described elsewhere. Necl-5-L cells did not form homophilic cell aggregates as described (Fig. 2G) (6). Nectin-1-L, -2-L, and -3-L cells formed homophilic cell aggregates as described (Fig. 2, H–J) (28, 29). The size of the cell aggregates formed between nectin-1-L and nectin-3-L cells was the biggest among various combinations (5). The sizes of the cell aggregates formed between Necl-2-L and Necl-2-L cells, between Necl-2-L and Necl-1-L cells, and between Necl-2-L and nectin-3-L cells were about 5, 10, and 10% that of the aggregates formed between nectin-1-L and nectin-3-L cells, respectively. These results indicate that Necl-2 has both Ca2+-independent homophilic and heterophilic cell-cell adhesion activities.
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Tissue Distribution and Subcellular Localization of Necl-2— TSLC1 has been shown by Northern blotting to be expressed ubiquitously, except the skeletal muscle, in which the expression of TSLC1 was not detected (11, 19). We confirmed these earlier results by Western blotting using the anti-Necl-2 mAb. Western blotting showed that an immunoreactive band at a molecular mass of 92 kDa was detected in various tissues thus far examined, including the brain, the lung, and the kidney (Fig. 3). In the testis, a larger band at 105 kDa was detected and might be one of the alternative splicing variants as described (8). After long exposure, the immunoreactive band of Necl-2 was detected in other tissues including the heart, the spleen, and the liver but was not detected in the skeletal muscle (data not shown). Immunofluorescence microscopy revealed that the signal for Necl-2 was highly concentrated at the basolateral plasma membrane of the epithelial cells of the mouse gall bladder, liver, and pancreas (Fig. 4A, a1, b1, and c1). It may be noted that the signal for Necl-2 was not overlapped with the signal for afadin, which is known to be confined to AJs undercoated with the F-actin bundles (Fig. 4A, a1–a3), nor the signal for ZO-1, which is known to be confined to TJs (Fig. 4A, b1–b3 and c1–c3). Consistently, immunoelectron microscopy showed that the immunogold particles for Necl-2 were indeed concentrated at the basolateral plasma membrane of the epithelial cells of gall bladder, but was undetectable at the areas of TJs, AJs, and DSs (Fig. 4B, a–c). These findings about Necl-2 showed sharp contrast to the localization of nectins and afadin that are strictly confined to AJs, which are undercoated with F-actin bundles (5).
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Expression of Necl-2 in an Epithelial Cell Line, but Not in Fibroblast Cell Lines—We next examined whether Necl-2 is differentially expressed in cells in culture. Western blotting revealed that Necl-2 was detected in mouse MTD-1A epithelial cells but not in mouse fibroblastic L, NIH3T3, or Swiss3T3 cells (Fig. 5A). The larger protein of 105 kDa detected in MTD-1A cells appeared to be an alternative splicing variant of Necl-2 as detected in the testis. In MTD-1A cells the immunofluorescence signal for Necl-2 was concentrated at the basolateral plasma membrane of cell-cell contact sites (Fig. 5B, a1–a3 and b1–b3). In contrast, the signal for Necl-2 was not observed in L, NIH3T3, or Swiss3T3 cells (data not shown). These results suggest that Necl-2 is dominantly expressed in epithelial cells but not in fibroblasts.
Assembly of Necl-2 to Cell-Cell Junctions at the Initial Stage of Their
Formation—We next studied how Necl-2 localizes to the basolateral
plasma membrane. The nectin-afadin unit plays a key role in the formation of
the junctional complex of AJs and TJs in epithelial cells
(5). Wound healing assay using
MTD-1A cells have revealed that nectin, afadin, ZO-1, E-cadherin, and -
and 
-catenins are first assembled at the primordial, spot-like adhesion
sites including AJs (34,
35). These primordial adhesion
sites fuse with each other to form short line-like adhesion sites, which
develop into more matured AJs. During and/or after the formation of AJs,
junctional adhesion molecule (JAM) is first assembled at these adhesion sites
(36). Finally, occludin and
claudin are recruited at the apical side of AJs, resulting in the formation of
TJs (37,
38). We examined at which
stage Necl-2 is recruited to the adhesion sites. The immunofluorescence signal
for Necl-2 was detected at the spot-like adhesion sites
(Fig. 6, Aa–Ac).
The signal was also observed at the line-like adhesion sites
(Fig. 6, Ba–Bc),
but the sites of the signal for Necl-2 were different from those for ZO-1 and
afadin (Fig. 6, Ca-Cc and
Da-Dc). These results suggest that Necl-2 is assembled to
the cell-cell adhesion sites at the very early stage together with the
components of the nectinafadin and E-cadherin-catenin units, and thereafter,
is translocated to the other sites, presumably the extra-junctional region of
the basolateral plasma membrane.
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Direct Binding of Pals2 to Necl-2—Nectins except nectin-4
have a C-terminal conserved motif of four aa residues that interacts with the
PDZ domain of afadin (5).
Although Necl-2 has this motif, Necl-2 did not bind afadin, as estimated by
the yeast two-hybrid assay and the affinity chromatography assay
(Fig. 7, A and
D). Therefore, in the last set of experiments we
attempted to isolate a Necl-2-binding protein(s). By use of the transmembrane
and cytoplasmic region of Necl-2 (Necl-2-EC) as bait, we searched a
Necl-2-binding protein(s) by the yeast two-hybrid screening and isolated one
positive clone from a mouse testis library
(Fig. 7A). It encoded
Pals2 (lacking the N-terminal 1–31 aa). We then examined whether Necl-2
directly binds Pals2 in vitro and in vivo using the
constructs of full-length Pals2. FLAG-tagged Necl-2 and HA-tagged Pals2 were
coexpressed in HEK293 cells, and FLAG-tagged Necl-2 was immunoprecipitated
with the anti-FLAG mAb. HA-tagged Pals2 was co-immunoprecipitated with
FLAG-tagged Necl-2 (Fig.
7B). When HA-tagged Pals2 was overexpressed in Necl-2-L
cells, the signal for Pals2 was co-localized with that for Necl-2 at the
cell-cell contact sites (Fig. 7C,
a1–a3). However, when HA-tagged Pals2 was overexpressed
in Necl-2-C-L cells (L cells stably expressing the C-terminal four
aa-deleted Necl-2), the signal for Necl-2-C was concentrated at the
cell-cell contact sites, but the signal for Pals2 was not concentrated there
(Fig. 7C,
b1–b3). The pure recombinant protein of the cytoplasmic
region of Necl-2 (GST-Necl-2-CP) bound the pure recombinant protein of
full-length Pals2 (MBP-Pals2) (Fig.
7D) and the PDZ domain of Pals2 (MBP-Pals2-PDZ) (data not
shown). However, the pure recombinant protein of the cytoplasmic region of
Necl-2, of which the C-terminal four aa were deleted (GST-Necl-2-CPC),
did not bind MBP-Pals2 (Fig.
7D) or MBP-Pals2-PDZ (data not shown). These results
indicate that Necl-2 directly binds Pals2 and that this binding is mediated
through the C-terminal four aa of Necl-2 and the PDZ domain of Pals2.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
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TSLC1 and SgIGSF have been shown to be expressed ubiquitously as estimated by Northern blotting (11, 19), but SynCAM1 has been shown to be specifically expressed in the mouse brain, as analyzed by Western blotting (8). Our present result indicates that Necl-2 is expressed in a wide variety of mouse tissues thus far examined and is consistent with the results of TSLC1 and SgIGSF but not with that of SynCAM1 (8). The exact reason for this inconsistency between the result of SynCAM1 and those of TSLC1, SgIGSF, and Necl-2 is not known, but it could be attributed to the specificity of the Ab used for SynCAM1.
Immunofluorescence microscopic analysis indicates that Necl-2 localizes at the basolateral plasma membrane of many epithelial cell types, and this result is consistent with the earlier observation that TSLC1 localizes at the basolateral plasma membrane of MDCK cells expressing GFP-tagged TSLC1 (17). Detailed analysis by immunoelectron microscopy indicates that Necl-2 localizes at the basolateral plasma membrane except for specialized cell-cell junctions, such as AJs, TJs, and DSs. This unique localization pattern of Necl-2 is quite different from those of any other known cell-cell adhesion molecules: claudins, occludin, and JAM at TJs, nectins at AJs, E-cadherin at AJs and the lateral plasma membrane, and desmocollin and desmoglein at DSs (1, 4, 5, 39, 40).
Nectin-3 has been shown to be involved in the formation of AJs in epithelial cells (5). Therefore, the ability of Necl-2 to interact with nectin-3 suggests that Necl-2 may be recruited to the nectin-3-based cell-cell adhesion in the process of forming AJs. Consistently, wound healing assay analysis using MTD-1A cells indicates that Necl-2 is assembled to the cell-cell adhesion sites at the very early stage together with the components of the nectin-afadin and E-cadherin-catenin units. After Necl-2 is assembled to the primordial cell-cell adhesion sites, it may be translocated from there to the extra-junctional region of the basolateral plasma membrane. Nectins are confined to AJs undercoated with F-actin bundles and are absent from the areas where Necl-2 localizes (5). Therefore, Necl-2 is likely to form homodimers at these areas lacking nectins. The mechanism of segregation of Necl-2 from nectin-3 at the plasma membrane is currently unknown, but it is of crucial importance for our understanding of how the membrane domains of epithelial cells are organized.
It has been shown that TSLC1 binds DAL-1 through a band 4.1-binding motif at the juxtamembrane region (18). We have shown here that Necl-2 does not bind afadin but directly binds Pals2. This binding is mediated through the C-terminal consensus motif of four aa of Necl-2 and the PDZ domain of Pals2. Thus, Necl-2 appears to bind both DAL-1 and Pals2. DAL-1 belongs to the band 4.1 family, connects TSLC1/Necl-2 to the actin cytoskeleton (18), and is known as a tumor suppressor (41). In contrast, Pals2 is a membrane-associated guanylate kinase family member and binds to Lin-7, of which the C. elegans homologue is implicated in the proper localization of the Let-23 protein, the homologue of mammalian epidermal growth factor receptor (42). Taken together, Necl-2 directly binds to Necl-1 and nectin-3 extracellularly, mediating cell adhesions, and also binds Pals2 intracellularly, mediating localizations of transmembrane proteins. Further studies would be necessary for our understanding of the physiological role of Necl-2, which regulates cell-cell adhesion and localization of transmembrane proteins in mammals.
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FOOTNOTES |
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* The work at Osaka University was supported by grants-in-aid for Scientific
Research and that for Cancer Research was supported by grants from the
Ministry of Education, Culture, Sports, Science, and Technology, Japan (2001,
2002). The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section 1734
solely to indicate this fact. 
|| To whom correspondence should be addressed. Tel.: 81-6-6879-3410; Fax: 81-6-6879-3419; E-mail: ytakai{at}molbio.med.osaka-u.ac.jp.
1 The abbreviations used are: TJs, tight junctions; AJs, adherens junctions;
DSs, desmosomes; F-actin, actin filament; aa, amino acid(s); Necl, nectin-like
molecule; GST, glutathione S-transferase; MBP, maltose-binding
protein; nectin-1-L cells, L cells stably expressing human nectin-1;
nectin-2-L cells, L cells stably expressing mouse nectin-2; nectin-3-L
cells, L cells stably expressing mouse nectin-3; Necl-5-L cells, L
cells stably expressing Necl-5; Necl-1-L cells, L cells stably expressing
FLAG-Necl-1; non-tagged Necl-2-L cells, L cells stably expressing full-length
Necl-2; Necl-2-L cells, L cells stably expressing FLAG-Necl-2;
Necl-2-C-L cells, L cells stably expressing the C-terminal four
aa-deleted Necl-2; GST-Necl-2-CP, the cytoplasmic region of Necl-2 fused to
GST; Ab, antibody; mAb, monoclonal Ab; pAb, polyclonal Ab; MDCK, Madin-Darby
canine kidney; GFP, green fluorescent protein; JAM, junctional adhesion
molecule; Necl-2-EC, the transmembrane and cytoplasmic region of
Necl-2; MBP-Pals2, full-length Pals2 fused to MBP; MBP-Pals2-PDZ, the PDZ
domain of Pals2 fused to MBP; GST-Necl-2-CPC, the C-terminal
four-aa-deleted cytoplasmic region of Necl-2 fused to GST; HA,
hemagglutinin.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
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