Abstract
The functional units of cell adhesion are typically multiprotein complexes made up of three general classes of proteins; the adhesion receptors, the cell-extracellular matrix (ECM) proteins, and the cytoplasmic plaque/peripheral membrane proteins. The cell adhesion receptors are usually transmembrane glycoproteins (for example E-cadherin and integrin) that mediate binding at the extracellular surface and determine the specificity of cell-cell and cell-ECM recognition. E-cadherin-mediated cell-cell adhesion can be both temporally and spatially regulated during development, and represents a key step in the acquisition of the invasive phenotype for many tumors. On the other hand, integrin-mediated cell-ECM interactions play important roles in cytoskeleton organization and in the transduction of intracellular signals to regulate various processes such as proliferation, differentiation and cell migration. ECM proteins are typically large glycoproteins, including the collagens, fibronectins, laminins, and proteoglycans that assemble into fibrils or other complex macromolecular arrays. The most of these adhesive proteins are glycosylated. Here, we focus mainly on the modification of N-glycans of integrins and laminin-332, and a mutual regulation between cell adhesion and bisected N-glycan expression, to address the important roles of N-glycans in cell adhesion.
Similar content being viewed by others
References
Gumbiner, B.M.: Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84(3), 345–357 (1996)
Dennis, J.W., Laferte, S., Waghorne, C., Breitman, M.L., Kerbel, R.S.: Beta 1–6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 236(4801), 582–585 (1987)
Hakomori, S.: Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res. 56(23), 5309–5318 (1996)
Asada, M., Furukawa, K., Segawa, K., Endo, T., Kobata, A.: Increased expression of highly branched N-glycans at cell surface is correlated with the malignant phenotypes of mouse tumor cells. Cancer Res. 57(6), 1073–1080 (1997)
Thiery, J.P.: Epithelial-mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15(6), 740–746 (2003)
Gu, J., Nishikawa, A., Tsuruoka, N., Ohno, M., Yamaguchi, N., Kangawa, K., Taniguchi, N.: Purification and characterization of UDP-N-acetylglucosamine: alpha-6-D-mannoside beta 1-6 N-acetylglucosaminyltransferase (N-acetylglucosaminyltransferase V) from a human lung cancer cell line. J. Biochem. (Tokyo) 113(5), 614–619 (1993)
Schachter, H.: Biosynthetic controls that determine the branching and microheterogeneity of protein-bound oligosaccharides. Adv. Exp. Med. Biol. 205, 53–85 (1986)
Schachter, H., Narasimhan, S., Gleeson, P., Vella, G.: Control of branching during the biosynthesis of asparagine-linked oligosaccharides. Can. J. Biochem. Cell. Biol. 61(9), 1049–1066 (1983)
Kariya, Y., Gu, J.: N-glycosylation of ss4 integrin controls the adhesion and motility of keratinocytes. PLoS One 6(11), e27084.
Dennis, J.W., Lau, K.S., Demetriou, M., Nabi, I.R.: Adaptive regulation at the cell surface by N-glycosylation. Traffic 10(11), 1569–1578 (2009)
Pochec, E., Litynska, A., Amoresano, A., Casbarra, A.: Glycosylation profile of integrin alpha 3 beta 1 changes with melanoma progression. Biochim. Biophys. Acta 7, 1–3 (2003)
Granovsky, M., Fata, J., Pawling, J., Muller, W.J., Khokha, R., Dennis, J.W.: Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat. Med. 6(3), 306–312 (2000)
Priatel, J.J., Sarkar, M., Schachter, H., Marth, J.D.: Isolation, characterization and inactivation of the mouse Mgat3 gene: the bisecting N-acetylglucosamine in asparagine-linked oligosaccharides appears dispensable for viability and reproduction. Glycobiology 7(1), 45–56 (1997)
Bhattacharyya, R., Bhaumik, M., Raju, T.S., Stanley, P.: Truncated, inactive N-acetylglucosaminyltransferase III (GlcNAc-TIII) induces neurological and other traits absent in mice that lack GlcNAc-TIII. J. Biol. Chem. 277(29), 26300–26309 (2002)
Bhaumik, M., Harris, T., Sundaram, S., Johnson, L., Guttenplan, J., Rogler, C., Stanley, P.: Progression of hepatic neoplasms is severely retarded in mice lacking the bisecting N-acetylglucosamine on N-glycans: evidence for a glycoprotein factor that facilitates hepatic tumor progression. Cancer Res. 58(13), 2881–2887 (1998)
Yang, X., Bhaumik, M., Bhattacharyya, R., Gong, S., Rogler, C.E., Stanley, P.: New evidence for an extra-hepatic role of N-acetylglucosaminyltransferase III in the progression of diethylnitrosamine-induced liver tumors in mice. Cancer Res. 60(12), 3313–3319 (2000)
Gu, J., Taniguchi, N.: Potential of N-glycan in cell adhesion and migration as either a positive or negative regulator. Cell. Adh. Migr. 2(4), 243–245 (2008)
Guo, H.B., Lee, I., Kamar, M., Akiyama, S.K., Pierce, M.: Aberrant N-glycosylation of beta1 integrin causes reduced alpha5beta1 integrin clustering and stimulates cell migration. Cancer Res. 62(23), 6837–6845 (2002)
Sato, Y., Isaji, T., Tajiri, M., Yoshida-Yamamoto, S., Yoshinaka, T., Somehara, T., Fukuda, T., Wada, Y., Gu, J.: An N-glycosylation site on the beta-propeller domain of the integrin alpha5 subunit plays key roles in both its function and site-specific modification by beta1,4-N-acetylglucosaminyltransferase III. J. Biol. Chem. 284(18), 11873–11881 (2009)
Isaji, T., Gu, J., Nishiuchi, R., Zhao, Y., Takahashi, M., Miyoshi, E., Honke, K., Sekiguchi, K., Taniguchi, N.: Introduction of bisecting GlcNAc into integrin alpha5beta1 reduces ligand binding and down-regulates cell adhesion and cell migration. J. Biol. Chem. 279(19), 19747–19754 (2004)
Zhao, Y., Nakagawa, T., Itoh, S., Inamori, K., Isaji, T., Kariya, Y., Kondo, A., Miyoshi, E., Miyazaki, K., Kawasaki, N., Taniguchi, N., Gu, J.: N-acetylglucosaminyltransferase III antagonizes the effect of N-acetylglucosaminyltransferase V on alpha3beta1 integrin-mediated cell migration. J. Biol. Chem. 281(43), 32122–32130 (2006)
Shigeta, M., Shibukawa, Y., Ihara, H., Miyoshi, E., Taniguchi, N., Gu, J.: beta1,4-N-Acetylglucosaminyltransferase III potentiates beta1 integrin-mediated neuritogenesis induced by serum deprivation in Neuro2a cells. Glycobiology 16(6), 564–571 (2006)
Kariya, Y., Kawamura, C., Tabei, T., Gu, J.: Bisecting GlcNAc residues on laminin-332 down-regulate galectin-3-dependent keratinocyte motility. J Biol Chem 285(5), 3330–3340 (2010)
Hakomori, S.I.: Structure and function of glycosphingolipids and sphingolipids: recollections and future trends. Biochim. Biophys. Acta 1780(3), 325–346 (2008)
Si, H.: S.I.: Inaugural Article: The glycosynapse. Proc. Natl. Acad. Sci. U. S. A. 99(1), 225–232 (2002)
Taniguchi, N., Miyoshi, E., Gu, J., Honke, K., Matsumoto, A.: Decoding sugar functions by identifying target glycoproteins. Curr. Opin. Struct. Biol. 16(5), 561–566 (2006)
Partridge, E.A., Le Roy, C., Di Guglielmo, G.M., Pawling, J., Cheung, P., Granovsky, M., Nabi, I.R., Wrana, J.L., Dennis, J.W.: Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306(5693), 120–124 (2004)
Rebbaa, A., Yamamoto, H., Saito, T., Meuillet, E., Kim, P., Kersey, D.S., Bremer, E.G., Taniguchi, N., Moskal, J.R.: Gene transfection-mediated overexpression of beta1,4-N-acetylglucosamine bisecting oligosaccharides in glioma cell line U373 MG inhibits epidermal growth factor receptor function. J. Biol. Chem. 272(14), 9275–9279 (1997)
Gu, J., Zhao, Y., Isaji, T., Shibukawa, Y., Ihara, H., Takahashi, M., Ikeda, Y., Miyoshi, E., Honke, K., Taniguchi, N.: Beta1,4-N-Acetylglucosaminyltransferase III down-regulates neurite outgrowth induced by costimulation of epidermal growth factor and integrins through the Ras/ERK signaling pathway in PC12 cells. Glycobiology 14(2), 177–186 (2004)
Isaji, T., Sato, Y., Zhao, Y., Miyoshi, E., Wada, Y., Taniguchi, N., Gu, J.: N-glycosylation of the beta-propeller domain of the integrin alpha5 subunit is essential for alpha5beta1 heterodimerization, expression on the cell surface, and its biological function. J. Biol. Chem. 281(44), 33258–33267 (2006)
Seales, E.C., Shaikh, F.M., Woodard-Grice, A.V., Aggarwal, P., McBrayer, A.C., Hennessy, K.M., Bellis, S.L.: A protein kinase C/Ras/ERK signaling pathway activates myeloid fibronectin receptors by altering beta1 integrin sialylation. J. Biol. Chem. 280(45), 37610–37615 (2005)
Xiong, J.P., Stehle, T., Zhang, R., Joachimiak, A., Frech, M., Goodman, S.L., Arnaout, M.A.: Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 296(5565), 151–155 (2002)
Xiong, J.P., Stehle, T., Diefenbach, B., Zhang, R., Dunker, R., Scott, D.L., Joachimiak, A., Goodman, S.L., Arnaout, M.A.: Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science 294(5541), 339–345 (2001)
Mould, A.P., Symonds, E.J., Buckley, P.A., Grossmann, J.G., McEwan, P.A., Barton, S.J., Askari, J.A., Craig, S.E., Bella, J., Humphries, M.J.: Structure of an integrin-ligand complex deduced from solution x-ray scattering and site-directed mutagenesis. J. Biol. Chem. 278(41), 39993–39999 (2003)
Manya, H., Chiba, A., Yoshida, A., Wang, X., Chiba, Y., Jigami, Y., Margolis, R.U., Endo, T.: Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc. Natl. Acad. Sci. U. S. A. 101(2), 500–505 (2004)
Ju, T., Cummings, R.D.: A unique molecular chaperone Cosmc required for activity of the mammalian core 1 beta 3-galactosyltransferase. Proc. Natl. Acad. Sci. U. S. A. 99(26), 16613–16618 (2002)
Sasai, K., Ikeda, Y., Ihara, H., Honke, K., Taniguchi, N.: Caveolin-1 regulates the functional localization of N-acetylglucosaminyltransferase III within the golgi apparatus. J. Biol. Chem. 278(28), 25295–25301 (2003)
Isaji, T., Sato, Y., Fukuda, T., Gu, J.: N-glycosylation of the I-like domain of beta1 integrin is essential for beta1 integrin expression and biological function: identification of the minimal N-glycosylation requirement for alpha5beta1. J. Biol. Chem. 284(18), 12207–12216 (2009)
Hoffmeister, K.M., Josefsson, E.C., Isaac, N.A., Clausen, H., Hartwig, J.H., Stossel, T.P.: Glycosylation restores survival of chilled blood platelets. Science 301(5639), 1531–1534 (2003)
Josefsson, E.C., Gebhard, H.H., Stossel, T.P., Hartwig, J.H., Hoffmeister, K.M.: The macrophage alphaMbeta2 integrin alphaM lectin domain mediates the phagocytosis of chilled platelets. J. Biol. Chem. 280(18), 18025–18032 (2005)
Colognato, H., Yurchenco, P.D.: Form and function: the laminin family of heterotrimers. Dev. Dyn. 218(2), 213–234 (2000)
Kariya, Y., Kariya, Y., Gu, J.: Roles of laminin-332 and alpha6beta4 integrin in tumor progression. Mini. Rev. Med. Chem. 9(11), 1284–1291 (2009)
Kariya, Y., Kato, R., Itoh, S., Fukuda, T., Shibukawa, Y., Sanzen, N., Sekiguchi, K., Wada, Y., Kawasaki, N., Gu, J.: N-Glycosylation of laminin-332 regulates its biological functions. A novel function of the bisecting GlcNAc. J. Biol. Chem. 283(48), 33036–33045 (2008)
Crocker, P.R., Varki, A.: Siglecs in the immune system. Immunology 103(2), 137–145 (2001)
Ono, M., Handa, K., Withers, D.A., Hakomori, S.: Glycosylation effect on membrane domain (GEM) involved in cell adhesion and motility: a preliminary note on functional alpha3, alpha5-CD82 glycosylation complex in ldlD 14 cells. Biochem. Biophys. Res. Commun. 279(3), 744–750 (2000)
Gumbiner, B.M.: Regulation of cadherin-mediated adhesion in morphogenesis. Nat. Rev. Mol. Cell Biol. 6(8), 622–634 (2005)
Takeichi, M.: Cadherins: a molecular family important in selective cell-cell adhesion. Annu. Rev. Biochem. 59, 237–252 (1990)
Vernon, A.E., LaBonne, C.: Tumor metastasis: a new twist on epithelial-mesenchymal transitions. Curr. Biol. 14(17), R719–R721 (2004)
Lickert, H., Bauer, A., Kemler, R., Stappert, J.: Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. J. Biol. Chem. 275(7), 5090–5095 (2000)
Zhu, W., Leber, B., Andrews, D.W.: Cytoplasmic O-glycosylation prevents cell surface transport of E-cadherin during apoptosis. EMBO J. 20(21), 5999–6007 (2001)
Liwosz, A., Lei, T., Kukuruzinska, M.A.: N-glycosylation affects the molecular organization and stability of E-cadherin junctions. J. Biol. Chem. 281(32), 23138–23149 (2006)
Zhou, F., Su, J., Fu, L., Yang, Y., Zhang, L., Wang, L., Zhao, H., Zhang, D., Li, Z., Zha, X.: Unglycosylation at Asn-633 made extracellular domain of E-cadherin folded incorrectly and arrested in endoplasmic reticulum, then sequentially degraded by ERAD. Glycoconj J (2008).
Yoshimura, M., Nishikawa, A., Ihara, Y., Taniguchi, S., Taniguchi, N.: Suppression of lung metastasis of B16 mouse melanoma by N-acetylglucosaminyltransferase III gene transfection. Proc. Natl. Acad. Sci. U. S. A. 92(19), 8754–8758 (1995)
Yoshimura, M., Ihara, Y., Matsuzawa, Y., Taniguchi, N.: Aberrant glycosylation of E-cadherin enhances cell-cell binding to suppress metastasis. J. Biol. Chem. 271(23), 13811–13815 (1996)
Gu, J., Sato, Y., Kariya, Y., Isaji, T., Taniguchi, N., Fukuda, T.: A mutual regulation between cell-cell adhesion and N-glycosylation: implication of the bisecting GlcNAc for biological functions. J. Proteome. Res. 8(2), 431–435 (2009)
Iijima, J., Zhao, Y., Isaji, T., Kameyama, A., Nakaya, S., Wang, X., Ihara, H., Cheng, X., Nakagawa, T., Miyoshi, E., Kondo, A., Narimatsu, H., Taniguchi, N., Gu, J.: Cell-cell interaction-dependent regulation of N-acetylglucosaminyltransferase III and the bisected N-glycans in GE11 epithelial cells. Involvement of E-cadherin-mediated cell adhesion. J. Biol. Chem. 281(19), 13038–13046 (2006)
Akama, R., Sato, Y., Kariya, Y., Isaji, T., Fukuda, T., Lu, L., Taniguchi, N., Ozawa, M., Gu, J.: N-acetylglucosaminyltransferase III expression is regulated by cell-cell adhesion via the E-cadherin-catenin-actin complex. Proteomics 8(16), 3221–3228 (2008)
Wieser, R.J., Baumann, C.E., Oesch, F.: Cell-contact mediated modulation of the sialylation of contactinhibin. Glycoconj. J. 12(5), 672–679 (1995)
Xu, Q., Akama, R., Isaji, T., Lu, Y., Hashimoto, H., Kariya, Y., Fukuda, T., Du, Y., Gu, J.: Wnt/beta-catenin signaling down-regulates N-acetylglucosaminyltransferase III expression: the implications of two mutually exclusive pathways for regulation. J Biol Chem 286(6), 4310–4318 (2011)
Moustakas, A., Heldin, C.H.: Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer. Sci. 98(10), 1512–1520 (2007)
Xu, Q., Isaji, T., Lu, Y., Gu, W., Kondo, M., Fukuda, T., Du, Y., Gu, J.: Roles of N-acetylglucosaminyltransferase III in epithelial-to-mesenchymal transition induced by TGF-β1 in epithelial cell lines. J Biol Chem. (2012) Mar 26. doi:10.1074/jbc.M111.262154
Kim, Y., Kugler, M.C., Wei, Y., Kim, K.K., Li, X., Brumwell, A.N., Chapman, H.A.: Integrin alpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signaling to cell contacts. J. Cell. Biol. 184(2), 309–322 (2009)
Kim, K.K., Wei, Y., Szekeres, C., Kugler, M.C., Wolters, P.J., Hill, M.L., Frank, J.A., Brumwell, A.N., Wheeler, S.E., Kreidberg, J.A., Chapman, H.A.: Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J. Clin. Invest. 119(1), 213–224 (2009)
Pinho, S.S., Osorio, H., Nita-Lazar, M., Gomes, J., Lopes, C., Gartner, F., Reis, C.A.: Role of E-cadherin N-glycosylation profile in a mammary tumor model. Biochem. Biophys. Res. Commun. 379(4), 1091–1096 (2009)
Terao, M., Ishikawa, A., Nakahara, S., Kimura, A., Kato, A., Moriwaki, K., Kamada, Y., Murota, H., Taniguchi, N., Katayama, I., Miyoshi, E.: Enhanced epithelial-mesenchymal transition-like phenotype in N-acetylglucosaminyltransferase V transgenic mouse skin promotes wound healing. J Biol Chem 286(32), 28303–28311 (2011)
Stanley, P.: Biological consequences of overexpressing or eliminating N-acetylglucosaminyltransferase-TIII in the mouse. Biochim. Biophys. Acta 1573(3), 363–368 (2002)
Acknowledgments
This work was partly supported by a Grant-in-Aid for Scientific Research NO. 21370059 (JG), for Challenging Exploratory Research No. 23651196 (JG) from the Japan Society for the Promotion of Science and by the Academic Frontier Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Mizutani Foundation for Glycoscience (JG).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gu, J., Isaji, T., Xu, Q. et al. Potential roles of N-glycosylation in cell adhesion. Glycoconj J 29, 599–607 (2012). https://doi.org/10.1007/s10719-012-9386-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10719-012-9386-1