Preventing E-cadherin Aberrant N-glycosylation at Asn-554 Improves Its Critical Function in Gastric Cancer

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2015 Jul 21

PMID 26189796

Citations 59

Authors

S Carvalho

T A Catarino

A M Dias

M Kato

A Almeida

B Hessling

J Figueiredo

F Gartner

J M Sanches

T Ruppert

E Miyoshi

M Pierce

F Carneiro

D Kolarich

R Seruca

Y Yamaguchi

N Taniguchi

C A Reis

S S Pinho

Affiliations

Soon will be listed here.

Abstract

E-cadherin is a central molecule in the process of gastric carcinogenesis and its posttranslational modifications by N-glycosylation have been described to induce a deleterious effect on cell adhesion associated with tumor cell invasion. However, the role that site-specific glycosylation of E-cadherin has in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples, we demonstrated that N-acetylglucosaminyltransferase V (GnT-V)-mediated glycosylation causes an abnormal pattern of E-cadherin expression in the gastric mucosa. In vitro models further indicated that, among the four potential N-glycosylation sites of E-cadherin, Asn-554 is the key site that is selectively modified with β1,6 GlcNAc-branched N-glycans catalyzed by GnT-V. This aberrant glycan modification on this specific asparagine site of E-cadherin was demonstrated to affect its critical functions in gastric cancer cells by affecting E-cadherin cellular localization, cis-dimer formation, molecular assembly and stability of the adherens junctions and cell-cell aggregation, which was further observed in human gastric carcinomas. Interestingly, manipulating this site-specific glycosylation, by preventing Asn-554 from receiving the deleterious branched structures, either by a mutation or by silencing GnT-V, resulted in a protective effect on E-cadherin, precluding its functional dysregulation and contributing to tumor suppression.

Citing Articles

Implication of protein post translational modifications in gastric cancer.

Song H, Zhang M, Guo C, Guo X, Ma Y, Ma Y Front Cell Dev Biol. 2025; 13:1523958.

PMID: 39968176 PMC: 11833226. DOI: 10.3389/fcell.2025.1523958.

The branched N-glycan of PD-L1 predicts immunotherapy responses in patients with recurrent/metastatic HNSCC.

Huang H, Huang Y, Chen Y, Wu H, Hsu C, Kao H Oncogenesis. 2024; 13(1):36.

PMID: 39353912 PMC: 11445275. DOI: 10.1038/s41389-024-00532-3.

Regulation of intracellular activity of N-glycan branching enzymes in mammals.

Kizuka Y J Biol Chem. 2024; 300(7):107471.

PMID: 38879010 PMC: 11328876. DOI: 10.1016/j.jbc.2024.107471.

Decoding the glycoproteome: a new frontier for biomarker discovery in cancer.

He K, Baniasad M, Kwon H, Caval T, Xu G, Lebrilla C J Hematol Oncol. 2024; 17(1):12.

PMID: 38515194 PMC: 10958865. DOI: 10.1186/s13045-024-01532-x.

Dynamics and functions of E-cadherin complexes in epithelial cell and tissue morphogenesis.

Zhang N, Haring M, Wolf F, Grosshans J, Kong D Mar Life Sci Technol. 2023; 5(4):585-601.

PMID: 38045551 PMC: 10689684. DOI: 10.1007/s42995-023-00206-w.

References

Deshpande N, Jensen P, Packer N, Kolarich D . GlycoSpectrumScan: fishing glycopeptides from MS spectra of protease digests of human colostrum sIgA. J Proteome Res. 2009; 9(2):1063-75. DOI: 10.1021/pr900956x. View

Soderberg O, Gullberg M, Jarvius M, Ridderstrale K, Leuchowius K, Jarvius J . Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 2006; 3(12):995-1000. DOI: 10.1038/nmeth947. View

Langer M, Guo H, Shashikanth N, Pierce J, Leckband D . N-glycosylation alters cadherin-mediated intercellular binding kinetics. J Cell Sci. 2012; 125(Pt 10):2478-85. DOI: 10.1242/jcs.101147. View

Pinho S, Figueiredo J, Cabral J, Carvalho S, Dourado J, Magalhaes A . E-cadherin and adherens-junctions stability in gastric carcinoma: functional implications of glycosyltransferases involving N-glycan branching biosynthesis, N-acetylglucosaminyltransferases III and V. Biochim Biophys Acta. 2013; 1830(3):2690-700. DOI: 10.1016/j.bbagen.2012.10.021. View

Pinho S, Seruca R, Gartner F, Yamaguchi Y, Gu J, Taniguchi N . Modulation of E-cadherin function and dysfunction by N-glycosylation. Cell Mol Life Sci. 2010; 68(6):1011-20. PMC: 11114786. DOI: 10.1007/s00018-010-0595-0. View

Thaysen-Andersen M, Packer N . Site-specific glycoproteomics confirms that protein structure dictates formation of N-glycan type, core fucosylation and branching. Glycobiology. 2012; 22(11):1440-52. DOI: 10.1093/glycob/cws110. View

Pinho S, Osorio H, Nita-Lazar M, Gomes J, Lopes C, Gartner F . Role of E-cadherin N-glycosylation profile in a mammary tumor model. Biochem Biophys Res Commun. 2009; 379(4):1091-6. DOI: 10.1016/j.bbrc.2009.01.024. View

Sato Y, Isaji T, Tajiri M, Yoshida-Yamamoto S, Yoshinaka T, Somehara T . 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. 2009; 284(18):11873-81. PMC: 2673256. DOI: 10.1074/jbc.M807660200. View

Takeichi M . Functional correlation between cell adhesive properties and some cell surface proteins. J Cell Biol. 1977; 75(2 Pt 1):464-74. PMC: 2109947. DOI: 10.1083/jcb.75.2.464. View

10.

York W, Agravat S, Aoki-Kinoshita K, McBride R, Campbell M, Costello C . MIRAGE: the minimum information required for a glycomics experiment. Glycobiology. 2014; 24(5):402-6. PMC: 3976285. DOI: 10.1093/glycob/cwu018. View

11.

Nelson W . Regulation of cell-cell adhesion by the cadherin-catenin complex. Biochem Soc Trans. 2008; 36(Pt 2):149-55. PMC: 3368607. DOI: 10.1042/BST0360149. View

12.

de-Freitas-Junior J, Carvalho S, M Dias A, Oliveira P, Cabral J, Seruca R . Insulin/IGF-I signaling pathways enhances tumor cell invasion through bisecting GlcNAc N-glycans modulation. an interplay with E-cadherin. PLoS One. 2013; 8(11):e81579. PMC: 3839884. DOI: 10.1371/journal.pone.0081579. View

13.

Kabsch W, Sander C . Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983; 22(12):2577-637. DOI: 10.1002/bip.360221211. View

14.

Chou P, Fasman G . Prediction of beta-turns. Biophys J. 1979; 26(3):367-83. PMC: 1328558. DOI: 10.1016/S0006-3495(79)85259-5. View

15.

Ceroni A, Maass K, Geyer H, Geyer R, Dell A, Haslam S . GlycoWorkbench: a tool for the computer-assisted annotation of mass spectra of glycans. J Proteome Res. 2008; 7(4):1650-9. DOI: 10.1021/pr7008252. View

16.

Jensen P, Karlsson N, Kolarich D, Packer N . Structural analysis of N- and O-glycans released from glycoproteins. Nat Protoc. 2012; 7(7):1299-310. DOI: 10.1038/nprot.2012.063. View

17.

BAUSE E . Structural requirements of N-glycosylation of proteins. Studies with proline peptides as conformational probes. Biochem J. 1983; 209(2):331-6. PMC: 1154098. DOI: 10.1042/bj2090331. View

18.

Paredes J, Figueiredo J, Albergaria A, Oliveira P, Carvalho J, Ribeiro A . Epithelial E- and P-cadherins: role and clinical significance in cancer. Biochim Biophys Acta. 2012; 1826(2):297-311. DOI: 10.1016/j.bbcan.2012.05.002. View

19.

Pinho S, Reis C, Paredes J, Magalhaes A, Ferreira A, Figueiredo J . The role of N-acetylglucosaminyltransferase III and V in the post-transcriptional modifications of E-cadherin. Hum Mol Genet. 2009; 18(14):2599-608. DOI: 10.1093/hmg/ddp194. View

20.

Guo H, Johnson H, Randolph M, Pierce M . Regulation of homotypic cell-cell adhesion by branched N-glycosylation of N-cadherin extracellular EC2 and EC3 domains. J Biol Chem. 2009; 284(50):34986-97. PMC: 2787361. DOI: 10.1074/jbc.M109.060806. View