Top

Molecular Cancer

Published in:

Open Access 01-12-2010 | Research

Helicobacter pylori-induced activation of β-catenin involves low density lipoprotein receptor-related protein 6 and Dishevelled

Authors: Thorsten Gnad, Maria Feoktistova, Martin Leverkus, Uwe Lendeckel, Michael Naumann

Published in: Molecular Cancer | Issue 1/2010

Abstract

Background

The human microbial pathogen Helicobacter pylori resides in the stomach of about fifty percent of the world's population and represents a risk factor for chronic gastritis, peptic ulcers and, in rare cases, gastric cancer. Alterations of the Wnt/β-catenin signaling pathway have been described in almost every human cancer disease, due to the regulation of target genes being involved in cell cycle control, differentiation, cell migration or stem cell control. Our study aimed to elucidate the role of proximal Wnt signaling components low density lipoprotein receptor-related protein 6 (LRP6) and Dishevelled (Dvl) in the activation of β-catenin early after infection of gastric epithelial cells with H. pylori.

Results

Infection of gastric epithelial NCI-N87 cells with H. pylori induces rapid phosphorylation of the Wnt/β-catenin pathway co-receptor LRP6 independent of the cytotoxin-associated gene A (CagA) or vacuolating cytotoxin A (VacA). However, bacteria lacking a functional type 4 secretion system (T4SS) failed to induce LRP6 phosphorylation. Further, we identified proteins of the Dvl family, namely Dvl2 and Dvl3, which are involved in LRP6 phosphorylation. H. pylori-induced nuclear accumulation of β-catenin and its transcriptional activation, and expression of Wnt target genes are strongly reduced in stable knockdown cell lines deficient for LRP6, Dvl2 or Dvl3.

Conclusion

We analysed the H. pylori-induced activation of Wnt-signaling factors and demonstrate for the first time that the canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of β-catenin.

Available only for authorised users

Naumann M, Crabtree JE: Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis. TRENDS in Microbiol. 2004, 12: 29-36. 10.1016/j.tim.2003.11.005.CrossRef

Park WS, Oh RR, Park JY, Lee SH, Shin MS, Kim YS, Kim SY, Lee HK, Kim PJ, Oh ST, Yoo NJ, Lee JY: Frequent somatic mutations of the β-catenin in intestinal-type gastric cancer. Cancer Res. 1999, 59: 4257-4260.PubMed

Clements WM, Wang J, Sarniak A, Kim OJ, MacDonald J, Fenoglio-Preiser C, Groden J, Lowy AM: β-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 2002, 62: 3503-3506.PubMed

Cheng XX, Wang ZC, Chen XY, Sun Y, Kong QY, Liu J, Gao X, Guan HW, Li H: Frequent loss of membranous E-cadherin in gastric cancers: A cross-talk with Wnt in determining the fate of β-catenin. Clin Exp Metastas. 2005, 22: 85-93. 10.1007/s10585-005-4578-8.CrossRef

Huiping C, Kristjansdottir S, Jonasson JG, Magnusson J, Egilsson V, Ingvarsson S: Alterations of E-cadherin and β-catenin in gastric cancer. BMC Cancer. 2001, 1: 16- 10.1186/1471-2407-1-16PubMedCentralCrossRefPubMed

Nelson WJ: Regulation of cell-cell adhesion by the cadherin-catenin complex. Biochem Soc Trans. 2008, 36: 149-155. 10.1042/BST0360149PubMedCentralCrossRefPubMed

Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW: Constitutive transcriptional activation by a β-catenin-Tcf complex in APC^-/- colon carcinoma. Science. 1997, 275: 1784-1787. 10.1126/science.275.5307.1784CrossRefPubMed

He TC, Sparks AB, Carlo R, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW: Identification of c-myc as a target of the APC pathway. Science. 1998, 281: 1509-1512. 10.1126/science.281.5382.1509CrossRefPubMed

Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, Wetering van de M, Clevers H, Schlag PM, Birchmeier W, Behrens J: Negative feedback loop of Wnt signaling through upregulation of Conductin/Axin2 in colorectal and liver tumors. Mol Cell Biol. 2002, 22: 1184-1193. 10.1128/MCB.22.4.1184-1193.2002PubMedCentralCrossRefPubMed

10.

Brabletz T, Jung A, Dag A, Hlubek F, Kirchnek T: β-catenin regulates the expression of matrix metalloproteinase-7 in colorectal cancer. Am J Pathol. 1999, 155: 1033-1038.PubMedCentralCrossRefPubMed

11.

Logan CY, Nusse R: The Wnt Signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004, 20: 781-810. 10.1146/annurev.cellbio.20.010403.113126CrossRefPubMed

12.

Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y: Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002, 108: 837-847. 10.1016/S0092-8674(02)00685-2CrossRefPubMed

13.

Kimelman D, Xu W: β-catenin destruction complex: insights and questions from a structural perspective. Oncogene. 2006, 25: 7482-7491. 10.1038/sj.onc.1210055CrossRefPubMed

14.

Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X: A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature. 2005, 438: 873-877. 10.1038/nature04185PubMedCentralCrossRefPubMed

15.

Davidson G, Wu W, Shen J, Bilic J, Fenger U, Stannek P, Glinka A, Niehrs C: Casein kinase 1γ couples Wnt receptor activation to cytoplasmic signal transduction. Nature. 2005, 438: 867-872. 10.1038/nature04170CrossRefPubMed

16.

Sokolova O, Bozko PM, Naumann M: Helicobacter pylori suppresses GSK3β activity to promote β-catenin activity. J Biol Chem. 2008, 283: 29367-29374. 10.1074/jbc.M801818200PubMedCentralCrossRefPubMed

17.

Bilic J, Huang YL, Davidson G, Zimmermann T, Cruciat CM, Bienz M, Niehrs C: Wnt induces LRP6 signalosomes and promotes Dishevelled-dependent LRP6 phosphorylation. Science. 2007, 316: 1619-1622. 10.1126/science.1137065CrossRefPubMed

18.

Polakis P: Wnt signaling and cancer. Genes Dev. 2000, 14: 1837-1851.PubMed

19.

Nabais S, Machado JC, Lopes C, Seruca R, Carneiro F, Sobrinho-Simoes M: Patterns of β-catenin expression in gastric carcinoma: clinicopathological relevance and mutation analysis. Int J Surg Pathol. 2003, 11: 1-9. 10.1177/106689690301100102CrossRefPubMed

20.

Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, Aburatani H, Akiyama T, Peek RM, Azuma T, Hatakeyama M: Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene. 2007, 26: 4617-4626. 10.1038/sj.onc.1210251CrossRefPubMed

21.

Tabassam FH, Graham DY, Yamaoka Y: Helicobater pylori activate epidermal growth factor receptor- and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3β phosphorylation. Cell Microbiol. 2009, 11: 70-82. 10.1111/j.1462-5822.2008.01237.xPubMedCentralCrossRefPubMed

22.

Nakayama M, Hisatsune J, Yamasaki E, Isomoto H, Kurazono H, Hatakeyama M, Azuma T, Yamaoka Y, Yahiro K, Moss J, Hirayama T: Helicobacter pylori VacA-induced inhibition of GSK3β through the PI3K/Akt signaling pathway. J Biol Chem. 2009, 284: 1612-1619. 10.1074/jbc.M806981200PubMedCentralCrossRefPubMed

23.

Suzuki M, Mimuro H, Kiga K, Fukumatsu M, Ishijima N, Morikawa H, Nagai S, Koyasu S, Giman RH, Kersulyte D, Berg DE, Sasakawa C: Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe. 2009, 5: 23-34. 10.1016/j.chom.2008.11.010CrossRefPubMed

24.

Brembeck FH, Schwarz-Romond T, Bakkers J, Wilhelm S, Hammerschmidt M, Birchmeier W: Essential role of Bcl9-2 in the switch between β-catenin's adhesive and transcriptional functions. Genes Dev. 2004, 18: 2225-2230. 10.1101/gad.317604PubMedCentralCrossRefPubMed

25.

Piedra J, Miravet S, Castano J, Palmer HG, Heisterkamp N, de Herreros AG, Dunach M: p120 catenin-associated Fer and Fyn tyrosine kinases regulate β-catenin tyr-142 phosphorylation and β-catenin-α-catenin interaction. Mol Cell Biol. 2003, 23: 2287-2297. 10.1128/MCB.23.7.2287-2297.2003PubMedCentralCrossRefPubMed

26.

Churin Y, Al-Ghoul L, Kepp O, Meyer TF, Birchmeier W, Naumann M: Helicobacter pylori CagA protein targets the c-met receptor and enhances the motogenic response. J Cell Biol. 2003, 161: 249-255. 10.1083/jcb.200208039PubMedCentralCrossRefPubMed

27.

Crabtree JE, Naumann M: Epithelial cell signaling in H. pylori infection. Curr Signal Transduc Ther. 2006, 1: 53-65. 10.2174/157436206775269253.CrossRef

28.

Basque JR, Chenard M, Chailler P, Menard D: Gastric cancer cell lines as models to study human digestive functions. J Cell Biochem. 2001, 81: 241-251. 10.1002/1097-4644(20010501)81:2<241::AID-JCB1039>3.0.CO;2-BCrossRefPubMed

29.

Yokozaki H: Molecular characteristics of eight gastric cancer cell lines established in Japan. Pathol Int. 2000, 50: 767-777. 10.1046/j.1440-1827.2000.01117.xCrossRefPubMed

30.

Ikenoue T, Ijichi H, Kato N, Kanai F, Masaki T, Rengifo W, Okamoto M, Matsumura M, Kawabe T, Shiratori Y, Omata M: Analysis of the beta-catenin/T cell factor signaling pathway in 36 gastrointestinal and liver cancer cells. Jpn J Cancer Res. 2002, 93: 1213-1220.CrossRefPubMed

31.

Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X: LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000, 407: 530-535. 10.1038/35035117CrossRefPubMed

32.

Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z, He X: A mechanism for Wnt coreceptor activation. Mol Cell. 2004, 13: 149-156. 10.1016/S1097-2765(03)00484-2CrossRefPubMed

33.

Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, He X: R-Spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and β-catenin signaling. J Biol Chem. 2007, 282: 15903-15911. 10.1074/jbc.M701927200CrossRefPubMed

34.

Wehrli M, Dougan ST, Caldwell K, O' Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S: Arrow encodes an LDL-receptor-related protein essential for wingless signalling. Nature. 2000, 407: 527-530. 10.1038/35035110CrossRefPubMed

35.

Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, Almeida K, Wang J, Doble B, Woodgett J, Wynshaw-Boris A, Hsieh JC, He X: Initiation of Wnt signaling: control of Wnt co-receptor LRP6 phosphorylation activation via frizzled dishevelled and axin functions. Development. 2008, 135: 367-375. 10.1242/dev.013540CrossRefPubMed

36.

Wang J, Hamblet NS, Mark S, Dickinson ME, Brinkman BC, Segil N, Fraser SE, Chen P, Wallingford JB, Wynshaw-Boris A: Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development. 2006, 133: 1767-1778. 10.1242/dev.02347PubMedCentralCrossRefPubMed

37.

Lee YN, Gao Y, Wang HY: Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1, -2, and -3. Cell Sign. 2008, 20: 443-452. 10.1016/j.cellsig.2007.11.005. 10.1016/j.cellsig.2007.11.005CrossRef

38.

Suzuki M, Mimuro H, Suzuki T, Park M, Yamamoto T, Sasakawa C: Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med. 2005, 202: 1235-1247. 10.1084/jem.20051027PubMedCentralCrossRefPubMed

39.

Kurashima Y, Murata-Kamiya M, Kikuchi K, Higashi H, Azuma T, Kondo S, Hatakeyama M: Deregulation of β-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence. Int J Cancer. 2008, 122: 823-831. 10.1002/ijc.23190CrossRefPubMed

40.

Weydig C, Starzinski-Powitz A, Carra G, Löwer J, Wessler S: CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res. 2007, 313: 3459-3471. 10.1016/j.yexcr.2007.07.015CrossRefPubMed

41.

Bebb JR, Leach L, Zaitoun A, Hand N, Letley DP, Thomas R, Atherton JC: Effects of Helicobacter pylori on the cadherin-catenin complex. J Clin Pathol. 2006, 59: 1261-1266. 10.1136/jcp.2006.036772PubMedCentralCrossRefPubMed

42.

Schirrmeister W, Gnad T, Wex T, Higashiyama S, Wolke C, Naumann M, Lendeckel U: Ectodomain shedding of E-cadherin and c-Met is induced by Helicobacter pylori infection. Exp Cell Res. 2009, 315: 3500-3508. 10.1016/j.yexcr.2009.07.029CrossRefPubMed

Title: Helicobacter pylori-induced activation of β-catenin involves low density lipoprotein receptor-related protein 6 and Dishevelled
Authors: Thorsten Gnad
Maria Feoktistova
Martin Leverkus
Uwe Lendeckel
Michael Naumann
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-9-31

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2010

Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of an NFκB and microRNA network

Selective unresponsiveness to the inhibition of p38 MAPK activation by cAMP helps L929 fibroblastoma cells escape TNF-α-induced cell death

Serum N-glycome biomarker for monitoring development of DENA-induced hepatocellular carcinoma in rat

Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells

ΔNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation

MiTF links Erk1/2 kinase and p21CIP1/WAF1 activation after UVC radiation in normal human melanocytes and melanoma cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer