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E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells

Abstract

E-cadherin (cadh), a member of a family of integral membrane glycoproteins that represent the major component of adherens junctions (AJs), mediates cell–cell adhesion through the calcium-dependent homophilic interaction of its extracellular domain. Metastatic human carcinomas frequently lose E-cadh expression, whereas epithelial ovarian cancer (EOCs) maintain properties characteristic of Müllerian epithelium during tumor progression, including E-cadh expression. Here, we examined the potential role of cell–cell contacts in EOCs through E-cadh homophilic interactions in PI3K/AKT activation whose altered signaling has been implicated in EOC pathogenesis. We show that E-cadh is predominantly expressed at cell–cell contacts and its functionality is necessary and sufficient for the activation of the PI3K/AKT pathway. E-cadh knockdown and phosphoinositide-3-kinase (PI3K) inhibition complement each other in impairing cell-cycle progression and proliferation of ovarian carcinoma cells. E-cadh is stably bound to the PI3K complex, and the de novo formation of E-cadh/β-catenin complexes following calcium deprivation and subsequent calcium restoration recruits the PI3K p85 subunit to the site of the cell–cell contacts. The finding that E-cadh-mediated AJ formation contributes to PI3K/AKT activation in EOC cells by a mechanism that appears to be restricted to these cells provides the underpinning for therapeutic strategies that exploit PI3K inhibition to halt EOCs.

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References

  • Ahmed N, Thompson EW, Quinn MA . (2007). Epithelial–mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm. J Cell Physiol 213: 581–588.

    Article  CAS  Google Scholar 

  • Amzel LM, Huang CH, Mandelker D, Lengauer C, Gabelli SB, Vogelstein B . (2008). Structural comparisons of class I phosphoinositide 3-kinases. Nat Rev Cancer 8: 665–669.

    Article  CAS  Google Scholar 

  • Anderson CB, Neufeld KL, White RL . (2002). Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proc Natl Acad Sci USA 99: 8683–8688.

    Article  CAS  Google Scholar 

  • Andl CD, Rustgi AK . (2005). No one-way street: cross-talk between e-cadherin and receptor tyrosine kinase (RTK) signaling: a mechanism to regulate RTK activity. Cancer Biol Ther 4: 28–31.

    Article  CAS  Google Scholar 

  • Aunoble B, Sanches R, Didier E, Bignon YJ . (2000). Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review). Int J Oncol 16: 567–576.

    CAS  PubMed  Google Scholar 

  • Brugge J, Hung MC, Mills GB . (2007). A new mutational AKTivation in the PI3K pathway. Cancer Cell 12: 104–107.

    Article  CAS  Google Scholar 

  • Calautti E, Li J, Saoncella S, Brissette J, Goetinck P . (2005). Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. J Biol Chem 280: 32856–32865.

    Article  CAS  Google Scholar 

  • Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS et al. (2004). Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64: 7678–7681.

    Article  CAS  Google Scholar 

  • Carneiro F, Oliveira C, Suriano G, Seruca R . (2008). Molecular pathology of familial gastric cancer, with an emphasis on hereditary diffuse gastric cancer. J Clin Pathol 61: 25–30.

    Article  CAS  Google Scholar 

  • Castellano G, Reid JF, Alberti P, Carcangiu ML, Tomassetti A, Canevari S . (2006). New potential ligand-receptor signaling loops in ovarian cancer identified in multiple gene expression studies. Cancer Res 66: 10709–10719.

    Article  CAS  Google Scholar 

  • Conacci-Sorrell M, Simcha I, Ben Yedidia T, Blechman J, Savagner P, Ben Ze’ev A . (2003). Autoregulation of E-cadherin expression by cadherin–cadherin interactions: the roles of β-catenin. J Cell Biol 163: 847–857.

    Article  CAS  Google Scholar 

  • Davies BR, Worsley SD, Ponder BA . (1998). Expression of E-cadherin, alpha-catenin and beta-catenin in normal ovarian surface epithelium and epithelial ovarian cancers. Histopathology 32: 69–80.

    Article  CAS  Google Scholar 

  • Herzig M, Savarese F, Novatchkova M, Semb H, Christofori G . (2006). Tumor progression induced by the loss of E-cadherin independent of beta-catenin/Tcf-mediated Wnt signaling. Oncogene 26: 2290–2298.

    Article  Google Scholar 

  • Himanen JP, Saha N, Nikolov DB . (2007). Cell–cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol 19: 534–542.

    Article  CAS  Google Scholar 

  • Kovacs EM, Ali RG, McCormack AJ, Yap AS . (2002). E-cadherin homophilic ligation directly signals through Rac and phosphatidylinositol 3-kinase to regulate adhesive contacts. J Biol Chem 277: 6708–6718.

    Article  CAS  Google Scholar 

  • Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI et al. (2005). Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11: 2875–2878.

    Article  CAS  Google Scholar 

  • Marques FR, Fonsechi-Carvasan GA, Angelo Andrade LA, Bottcher-Luiz F . (2004). Immunohistochemical patterns for alpha- and beta-catenin, E- and N-cadherin expression in ovarian epithelial tumors. Gynecol Oncol 94: 16–24.

    Article  CAS  Google Scholar 

  • McLachlan RW, Kraemer A, Helwani FM, Kovacs EM, Yap AS . (2007). E-cadherin adhesion activates c-Src signaling at cell–cell contacts. Mol Biol Cell 18: 3214–3223.

    Article  CAS  Google Scholar 

  • McLachlan RW, Yap AS . (2007). Not so simple: the complexity of phosphotyrosine signaling at cadherin adhesive contacts. J Mol Med 85: 545–554.

    Article  CAS  Google Scholar 

  • Miotti S, Tomassetti A, Facetti I, Sanna E, Berno V, Canevari S . (2005). Simultaneous expression of caveolin-1 and E-cadherin in ovarian carcinoma cells stabilizes adherens junctions through inhibition of src-related kinases. Am J Pathol 167: 1411–1427.

    Article  CAS  Google Scholar 

  • Niessen CM, Gottardi CJ . (2008). Molecular components of the adherens junction. Biochim Biophys Acta 1778: 562–571.

    Article  CAS  Google Scholar 

  • Pang JH, Kraemer A, Stehbens SJ, Frame MC, Yap AS . (2005). Recruitment of phosphoinositide 3-kinase defines a positive contribution of tyrosine kinase signaling to E-cadherin function. J Biol Chem 280: 3043–3050.

    Article  CAS  Google Scholar 

  • Pece S, Chiariello M, Murga C, Gutkind JS . (1999). Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell–cell junctions. Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex. J Biol Chem 274: 19347–19351.

    Article  CAS  Google Scholar 

  • Qian X, Karpova T, Sheppard AM, McNally J, Lowy DR . (2004). E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J 23: 1739–1748.

    Article  CAS  Google Scholar 

  • Reddy P, Liu L, Ren C, Lindgren P, Boman K, Shen Y et al. (2005). Formation of E-cadherin-mediated cell–cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells. Mol Endocrinol 19: 2564–2578.

    Article  CAS  Google Scholar 

  • Samuels Y, Diaz Jr LA, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I et al. (2005). Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7: 561–573.

    Article  CAS  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554.

    Article  CAS  Google Scholar 

  • Sanna E, Miotti S, Mazzi M, De Santis G, Canevari S, Tomassetti A . (2007). Binding of nuclear caveolin-1 to promoter elements of growth-associated genes in ovarian carcinoma cells. Exp Cell Res 313: 1307–1317.

    Article  CAS  Google Scholar 

  • Seidel B, Braeg S, Adler G, Wedlich D, Menke A . (2004). E- and N-cadherin differ with respect to their associated p120ctn isoforms and their ability to suppress invasive growth in pancreatic cancer cells. Oncogene 23: 5532–5542.

    Article  CAS  Google Scholar 

  • Sundfeldt K . (2003). Cell–cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule. Mol Cell Endocrinol 202: 89–96.

    Article  CAS  Google Scholar 

  • Tomassetti A, De Santis G, Castellano G, Miotti S, Mazzi M, Tomasoni D et al. (2008). Variant HNF1 modulates epithelial plasticity of normal and transformed ovary cells. Neoplasia 10: 1481–1492.

    Article  CAS  Google Scholar 

  • van Hengel J, Van Roy F . (2007). Diverse functions of p120ctn in tumors. Biochim Biophys Acta 1773: 78–88.

    Article  CAS  Google Scholar 

  • Van Roy F, Berx G . (2008). The cell–cell adhesion molecule E-cadherin. Cell Mol Life Sci 65: 3756–3788.

    Article  CAS  Google Scholar 

  • Virnekas B, Ge L, Pluckthun A, Schneider KC, Wellnhofer G, Moroney SE . (1994). Trinucleotide phosphoramidites: ideal reagents for the synthesis of mixed oligonucleotides for random mutagenesis. Nucleic Acids Res 22: 5600–5607.

    Article  CAS  Google Scholar 

  • Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489–501.

    Article  CAS  Google Scholar 

  • Vogt PK, Kang S, Elsliger MA, Gymnopoulos M . (2007). Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem Sci 32: 342–349.

    Article  CAS  Google Scholar 

  • Wang Y, Helland A, Holm R, Kristensen GB, Borresen-Dale AL . (2005). PIK3CA mutations in advanced ovarian carcinomas. Hum Mutat 25: 322.

    Article  CAS  Google Scholar 

  • Woenckhaus J, Steger K, Sturm K, Munstedt K, Franke FE, Fenic I . (2007). Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer. Virchows Arch 450: 387–395.

    Article  CAS  Google Scholar 

  • Wong AS, Gumbiner BM . (2003). Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol 161: 1191–1203.

    Article  CAS  Google Scholar 

  • Woodfield RJ, Hodgkin MN, Akhtar N, Morse MA, Fuller KJ, Saqib K et al. (2001). The p85 subunit of phosphoinositide 3-kinase is associated with beta-catenin in the cadherin-based adhesion complex. Biochem J 360: 335–344.

    Article  CAS  Google Scholar 

  • Xie Z, Bikle DD . (2007). The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and human keratinocyte differentiation. J Biol Chem 282: 8695–8703.

    Article  CAS  Google Scholar 

  • Yap AS, Crampton MS, Hardin J . (2007). Making and breaking contacts: the cellular biology of cadherin regulation. Curr Opin Cell Biol 19: 508–514.

    Article  CAS  Google Scholar 

  • Zhang L, Huang J, Yang N, Greshock J, Liang S, Hasegawa K et al. (2007). Integrative genomic analysis of phosphatidylinositol 3′-kinase family identifies PIK3R3 as a potential therapeutic target in epithelial ovarian cancer. Clin Cancer Res 13: 5314–5321.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Gloria Bosco for her secretarial assistance. This work was supported by grants to SC from Associazione Italiana Ricerca Cancro (AIRC) and the Cariplo Foundation (grant number 2003-1740).

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Correspondence to A Tomassetti.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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De Santis, G., Miotti, S., Mazzi, M. et al. E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells. Oncogene 28, 1206–1217 (2009). https://doi.org/10.1038/onc.2008.470

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