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Licensed Unlicensed Requires Authentication Published by De Gruyter June 1, 2005

Roles of nectins in cell adhesion, migration and polarization

  • Hiroyuki Nakanishi and Yoshimi Takai
From the journal Biological Chemistry


Nectins are Ca2+-independent immunoglobulin (Ig)-like cell-cell adhesion molecules, which comprise a family consisting of four members. Nectins have five activities: (1) they show Ca2+-independent cell-cell adhesion activity by homo- and hetero-trans-interactions through their extracellular regions; (2) they bind afadin, an actin filament (F-actin)-binding protein, through their cytoplasmic tails and are connected to the actin cytoskeleton; (3) they induce activation of Cdc42 and Rac small G proteins through their cytoplasmic tails; (4) they bind Par-3, a cell polarity protein, through their cytoplasmic tails; and (5) they heterophilically trans-interact with Necls, nectin-like molecules, through their extracellular regions. Through these activities, nectins regulate a variety of cellular functions, including adhesion, migration, and polarization. Here we describe these activities and functions of nectins.



Adams, C.L., Chen, Y.T., Smith, S.J., and Nelson, W.J. (1998). Mechanisms of epithelial cell-cell adhesion and cell compaction revealed by high-resolution tracking of E-cadherin-green fluorescent protein. J. Cell Biol.142, 1105–1119.10.1083/jcb.142.4.1105Search in Google Scholar

Amaral, D.G., and Dent, J.A. (1981). Development of the mossy fibers of the dentate gyrus: I. A light and electron microscopic study of the mossy fibers and their expansions. J. Comp. Neurol.195, 51–86.Search in Google Scholar

Asada, M., Irie, K., Morimoto, K., Yamada, A., Ikeda, W., Takeuchi, M., and Takai, Y. (2003). ADIP, a novel Afadin- and α-actinin-binding protein localized at cell-cell adherens junctions. J. Biol. Chem.278, 4103–4111.10.1074/jbc.M209832200Search in Google Scholar

Biederer, T., Sara, Y., Mozhayeva, M., Atasoy, D., Liu, X., Kavalali, E.T., and Sudhof, T.C. (2002). SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science297, 1525–1531.10.1126/science.1072356Search in Google Scholar

Bouchard, M.J., Dong, Y., McDermott, B.M. Jr., Lam, D.H., Brown, K.R., Shelanski, M., Bellve, A.R., and Racaniello, V.R. (2000). Defects in nuclear and cytoskeletal morphology and mitochondrial localization in spermatozoa of mice lacking nectin-2, a component of cell-cell adherens junctions. Mol. Cell. Biol.20, 2865–2873.10.1128/MCB.20.8.2865-2873.2000Search in Google Scholar

Brummendorf, T., and Lemmon, V. (2001). Immunoglobulin superfamily receptors: cis-interactions, intracellular adaptors and alternative splicing regulate adhesion. Curr. Opin. Cell Biol.13, 611–618.10.1016/S0955-0674(00)00259-3Search in Google Scholar

Chadeneau, C., LeMoullac, B., and Denis, M.G. (1994). A novel member of the immunoglobulin gene superfamily in rat carcinoma cell lines. J. Biol. Chem.269, 15601–15605.10.1016/S0021-9258(17)40723-XSearch in Google Scholar

Chadeneau, C., LeCabellec, M., LeMoullac, B., Meflah, K., and Denis, M.G. (1996). Over-expression of a novel member of the immunoglobulin superfamily in Min mouse intestinal adenomas. Int. J. Cancer68, 817–821.10.1002/(SICI)1097-0215(19961211)68:6<817::AID-IJC21>3.0.CO;2-WSearch in Google Scholar

Ehrlich, J.S., Hansen, M.D., and Nelson, W.J. (2002). Spatiotemporal regulation of Rac1 localization and lamellipodia dynamics during epithelial cell-cell adhesion. Dev. Cell3, 259–270.10.1016/S1534-5807(02)00216-2Search in Google Scholar

Fukami, T., Satoh, H., Fujita, E., Maruyama, T., Fukuhara, H., Kuramochi, M., Takamoto, S., Momoi, T., and Murakami, Y. (2002). Identification of the Tslc1 gene, a mouse orthologue of the human tumor suppressor TSLC1 gene. Gene295, 7–12.10.1016/S0378-1119(02)00835-1Search in Google Scholar

Fukuhara, A., Shimizu, K., Kawakatsu, T., Fukuhara, T., and Takai, Y. (2003). Involvement of nectin-activated Cdc42 small G protein in organization of adherens and tight junctions in Madin-Darby canine kidney cells. J. Biol. Chem.278, 51885–51893.10.1074/jbc.M308015200Search in Google Scholar

Fukuhara, T., Shimizu, K., Kawakatsu, T., Fukuyama T., Minami, Y., Honda, T., Hoshino, T., Yamada, T., Ogita, H., Okada, M., and Takai, Y. (2004). Activation of Cdc42 by trans-interactions of cell adhesion molecules nectins through c-Src and Cdc42–GEF FRG. J. Cell Biol.166, 393–405.10.1083/jcb.200401093Search in Google Scholar

Gumbiner, B.M. (1996). Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell84, 345–357.10.1016/S0092-8674(00)81279-9Search in Google Scholar

Honda, T., Shimizu, K., Kawakatsu, T., Fukuhara, A., Irie, K., Nakamura, T., Matsuda, M., and Takai, Y. (2003). Cdc42 and Rac small G proteins activated by trans-interactions of nectins are involved in activation of c-Jun N-terminal kinase, but not in association of nectins and cadherin to form adherens junctions, in fibroblasts. Genes Cells8, 481–491.10.1046/j.1365-2443.2003.00649.xSearch in Google Scholar PubMed

Hoshino, T., Shimizu, K., Honda, T., Kawakatsu, T., Fukuyama, T., Nakamura, T., Matsuda, M., and Takai, Y. (2004) A novel role of nectins in inhibition of the E-cadherin-induced activation of Rac and formation of cell-cell adherens junctions. Mol. Biol. Cell15, 1077–1088.10.1091/mbc.e03-05-0321Search in Google Scholar PubMed PubMed Central

Ikeda, W., Nakanishi, H., Miyoshi, J., Mandai, K., Ishizaki, H., Tanaka, M., Togawa, A., Takahashi, K., Nishioka, H., Yoshida, H. et al. (1999). Afadin: a key molecule essential for structural organization of cell-cell junctions of polarized epithelia during embryogenesis. J. Cell Biol.146, 1117–1132.10.1083/jcb.146.5.1117Search in Google Scholar PubMed PubMed Central

Ikeda, W., Kakunaga, S., Itoh, S., Shingai, T., Takekuni, K., Satoh, K., Inoue, Y., Hamaguchi, A., Morimoto, K., Takeuchi, M., Imai, T., and Takai, Y. (2003). Tage4/nectin-like molecule-5 heterophilically trans-interacts with cell adhesion molecule nectin-3 and enhances cell migration. J. Biol. Chem.278, 28167–28172.10.1074/jbc.M303586200Search in Google Scholar PubMed

Ikeda, W., Kakunaga, S., Takekuni, K., Shingai, T., Satoh, K., Morimoto, K., Takeuchi, M., Imai, T., and Takai, Y. (2004). Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, nectin-3–independent manner. J. Biol. Chem.279, 18015–18025.10.1074/jbc.M312969200Search in Google Scholar PubMed

Kakunaga, S., Ikeda, W., Shingai, T., Fujito, T., Yamada, A., Minami, Y., Imai, T., and Takai, Y. (2004). Enhancement of serumand platelet-derived growth factor-induced cell proliferation by Necl-5/Tage4/PVR/CD155 through the Ras-Raf-MEK-ERK signaling. J. Biol. Chem., in press.Search in Google Scholar

Koike, S., Horie, H., Ise, I., Okitsu, A., Yoshida, M., Iizuka, N., Takeuchi, K., Takegami, T., and Nomoto, A. (1990). The poliovirus receptor protein is produced both as membrane-bound and secreted forms. EMBO J.9, 3217–3224.10.1002/j.1460-2075.1990.tb07520.xSearch in Google Scholar PubMed PubMed Central

Kuramochi, M., Fukuhara, H., Nobukuni, T., Kanbe, T., Maruyama, T., Ghosh, H.P., Pletcher, M., Isomura, M., Onizuka, M., Kitamura, T. et al. (2001). TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat. Genet.27, 427–430.10.1038/86934Search in Google Scholar PubMed

Mandai, K., Nakanishi, H., Satoh, A., Takahashi, K., Satoh, K., Nishioka, H., Mizoguchi, A., Takai, Y. (1999). Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions. J. Cell Biol.144, 1001–1017.10.1083/jcb.144.5.1001Search in Google Scholar PubMed PubMed Central

Masson, D., Jarry, A., Baury, B., Blanchardie, P., Laboisse, C., Lustenberger, P., and Denis, M.G. (2001). Overexpression of the CD155 gene in human colorectal carcinoma. Gut46, 236–240.10.1136/gut.49.2.236Search in Google Scholar

Masuda, M., Yageta, M., Fukuhara, H., Kuramochi, M., Maruyama, T., Nomoto, A., and Murakami, Y. (2002). The tumor suppressor protein TSLC1 is involved in cell-cell adhesion. J. Biol. Chem.277, 31014–31019.10.1074/jbc.M203620200Search in Google Scholar

Mendelsohn, C.L., Wimmer, E., and Racaniello, V.R. (1989). Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell56, 855–865.10.1016/0092-8674(89)90690-9Search in Google Scholar

Mizoguchi, A., Nakanishi, H., Kimura, K., Matsubara, K., Ozaki-Kuroda, K., Katata, T,. Honda, T., Kiyohara, Y., Heo, K., Higashi, M. et al. (2002). Nectin: an adhesion molecule involved in formation of synapses. J. Cell Biol.156, 555–565.10.1083/jcb.200103113Search in Google Scholar

Mueller, S., and Wimmer, E. (2003). Recruitment of nectin-3 to cell-cell junctions through trans-heterophilic interaction with CD155, a vitronectin and poliovirus receptor that localizes to αvβ3 integrin-containing membrane microdomains. J. Biol. Chem.278, 31251–31260.10.1074/jbc.M304166200Search in Google Scholar

Ohno, S. (2001). Intercellular junctions and cellular polarity: the PAR-aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr. Opin. Cell Biol.13, 641–648.10.1016/S0955-0674(00)00264-7Search in Google Scholar

Okabe, N., Shimizu, K., Ozaki-Kuroda, K., Nakanishi, H., Morimoto, K., Takeuchi, M., Katsumaru, H., Murakami, F., and Takai, Y. (2004). Contacts between the commissural axons and the floor plate cells are mediated by nectins. Dev. Biol.230, 174–186.10.1016/j.ydbio.2004.05.034Search in Google Scholar

Ooshio, T., Irie, K., Morimoto, K., Fukuhara, A., Imai, T., and Takai, Y. (2004). Involvement of LMO7 in the association of two cell-cell adhesion molecules, nectin and E-cadherin, through Afadin and α-actinin in epithelial cells. J. Biol. Chem.279, 31365–31373.10.1074/jbc.M401957200Search in Google Scholar

Ozaki-Kuroda, K., Nakanishi, H., Ohta, H., Tanaka, H., Kurihara, H., Mueller, S., Irie, K., Ikeda, W., Sasaki, T., Wimmer, E., Nishimune, Y., and Takai, Y. (2002). Nectin couples cell-cell adhesion and the actin scaffold at heterotypic testicular junctions. Curr. Biol.12, 1145–1150.10.1016/S0960-9822(02)00922-3Search in Google Scholar

Sato, T., Irie, K., Ooshio, T., Ikeda, W., and Takai, Y. (2004). Involvement of heterophilic trans-interaction of Necl-5/Tage4/PVR/CD155 with nectin-3 in formation of nectin- and cadherin-based adherens junctions. Genes Cells, in press.10.1111/j.1365-2443.2004.00763.xSearch in Google Scholar PubMed

Shimizu, K., and Takai, Y. (2003). Roles of the intercellular adhesion molecule nectin in intracellular signaling. J. Biochem. (Tokyo) 134, 631–636.10.1093/jb/mvg198Search in Google Scholar PubMed

Shingai, T., Ikeda, W., Kakunaga, S., Morimoto, K., Takekuni, K., Itoh, S., Satoh, K., Takeuchi, M., Imai, T., Monden, M., and Takai, Y. (2003). Implications of nectin-like molecule-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 in cell-cell adhesion and transmembrane protein localization in epithelial cells. J. Biol. Chem.278, 35421–35427.10.1074/jbc.M305387200Search in Google Scholar PubMed

Sozen, M.A., Suzuki, K., Tolarova, M.M., Bustos, T., Fernandez Iglesias, J.E., and Spritz, R.A. (2001). Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nat. Genet.29, 141–142.10.1038/ng740Search in Google Scholar PubMed

Suzuki, K., Hu, D., Bustos, T., Zlotogora, J., Richieri-Costa, A., Helms, J.A., and Spritz, R.A. (2000). Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat. Genet.25, 427–430.10.1038/78119Search in Google Scholar PubMed

Takai, Y., and Nakanishi, H. (2003). Nectin and afadin: novel organizers of intercellular junctions. J. Cell Sci.116, 17–27.10.1242/jcs.00167Search in Google Scholar PubMed

Takai, Y., Sasaki, T., and Matozaki, T. (2001). Small GTP-binding proteins. Physiol. Rev.81, 153–208.10.1152/physrev.2001.81.1.153Search in Google Scholar PubMed

Takai, Y., Irie, K., Shimizu, K., Sakisaka, T., and Ikeda,W. (2003a). Nectins and nectin-like molecules: roles in cell adhesion, migration, and polarization. Cancer Sci.94, 655–667.10.1111/j.1349-7006.2003.tb01499.xSearch in Google Scholar PubMed

Takai, Y., Shimizu, K., and Ohtsuka, T. (2003b). The roles of cadherins and nectins in interneuronal synapse formation. Curr. Opin. Neurobiol.13, 520–526.10.1016/j.conb.2003.09.003Search in Google Scholar PubMed

Takeichi, M. (1991). Cadherin cell adhesion receptors as a morphogenetic regulator. Science251, 1451–1455.10.1126/science.2006419Search in Google Scholar PubMed

Takekuni, K., Ikeda, W., Fujito, T., Morimoto, K., Takeuchi, M., Monden, M., and Takai, Y. (2003). Direct binding of cell polarity protein PAR-3 to cell-cell adhesion molecule nectin at neuroepithelial cells of developing mouse. J. Biol. Chem.278, 5497–5500.10.1074/jbc.C200707200Search in Google Scholar PubMed

Takenawa, T., and Miki, H. (2001). WASP and WAVE family proteins: key molecules for rapid rearrangement of cortical actin filaments and cell movement. J. Cell Sci.114, 1801–1809.10.1242/jcs.114.10.1801Search in Google Scholar

Tsukita, S., Furuse, M., and Itoh, M. (1999). Structural and signalling molecules come together at tight junctions. Curr. Opin. Cell Biol.11, 628–633.10.1016/S0955-0674(99)00016-2Search in Google Scholar

Tsukita, S., Furuse, M., and Itoh, M. (2001). Multifunctional strands in tight junctions. Nat. Rev. Mol. Cell Biol.4, 285–293.10.1038/35067088Search in Google Scholar

Vasioukhin, V., Bauer, C., Yin, M., and Fuchs, E. (2000). Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell100, 209–219.10.1016/S0092-8674(00)81559-7Search in Google Scholar

Yageta, M., Kuramochi, M., Masuda, M., Fukami, T., Fukuhara, H., Maruyama, T., Shibuya, M., and Murakami, Y. (2002). Direct association of TSLC1 and DAL-1, two distinct tumor suppressor proteins in lung cancer. Cancer Res.62, 5129–5133.Search in Google Scholar

Yagi, T., and Takeichi, M. (2000). Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev.14, 1169–1180.10.1101/gad.14.10.1169Search in Google Scholar

Yap, A.S., Brieher, W.M., and Gumbiner, B.M. (1997) Molecular and functional analysis of cadherin-based adherens junctions. Annu. Rev. Cell Dev. Biol.13, 119–146.10.1146/annurev.cellbio.13.1.119Search in Google Scholar PubMed

Yap, A.S., and Kovacs, E.M. (2003). Direct cadherin-activated cell signaling: a view from the plasma membrane. J. Cell Biol.160, 11–16.10.1083/jcb.200208156Search in Google Scholar PubMed PubMed Central

Yamada, A., Irie, K., Fukuhara, A., Ooshio, T., and Takai, Y. (2004). Requirement of the actin cytoskeleton for the association of nectins and other cell adhesion molecules at adherens and tight junctions in MDCK cells. Genes Cells, in press.10.1111/j.1365-2443.2004.00768.xSearch in Google Scholar PubMed

Yonemura, S., Itoh, M., Nagafuchi, A., and Tsukita, S. (1995). Cell-to-cell adherens junction formation and actin filament organization: similarities and differences between non-polarized fibroblasts and polarized epithelial cells. J. Cell Sci.108, 127–142.10.1242/jcs.108.1.127Search in Google Scholar PubMed

Published Online: 2005-06-01
Published in Print: 2004-10-01

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