Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

Oncogene volume 30, pages 2264–2274 (2011)Cite this article

Subjects

Abstract

Translationally controlled tumor protein (TCTP) is implicated in cell growth and malignant transformation. TCTP has been found to interact directly with the third cytoplasmic domain of the α subunit of Na,K-ATPase, but whether this interaction has a role in tumorigenesis is unclear. In this study, we examined TCTP-induced tumor progression signaling networks in human breast epithelial cells, using adenoviral infection. We found that TCTP (a) induces Src release from Na,K-ATPase α subunit and Src activation; (b) phosphorylates tyrosine residues 845, 992, 1086, 1148 and 1173 on anti-epidermal growth factor receptor (EGFR); (c) activates PI3K (phosphatidylinositol 3-kinase )–AKT, Ras–Raf–MEK–ERK1/2, Rac–PAK1/2, MKK3/6–p38 and phospholipase C (PLC)-γ pathways; (d) enhances NADPH oxidase-dependent reactive oxygen species (ROS) generation; (e) stimulates cytoskeletal remodeling and cell motility and (f) upregulates matrix metalloproteinase (MMP) 3 and 13. These findings suggest that TCTP induces tumorigenesis through distinct multicellular signaling pathways involving Src-dependent EGFR transactivation, ROS generation and MMP expression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Bae YS, Kang SW, Seo MS, Baines IC, Tekle E, Chock PB et al. (1997). Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 272: 217–221.

    Article  CAS  Google Scholar 

  • Barwe SP, Anilkumar G, Moon SY, Zheng Y, Whitelegge JP, Rajasekaran SA et al. (2005). Novel role for Na,K-ATPase in phosphatidylinositol 3-kinase signaling and suppression of cell motility. Mol Biol Cell 16: 1082–1094.

    Article  CAS  Google Scholar 

  • Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ . (2000). Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res 2: 203–210.

    Article  CAS  Google Scholar 

  • Brummelkamp TR, Bernards R, Agami R . (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550–553.

    Article  CAS  Google Scholar 

  • Chen JQ, Contreras RG, Wang R, Fernandez SV, Shoshani L, Russo IH et al. (2006). Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs? Breast Cancer Res Treat 96: 1–15.

    Article  CAS  Google Scholar 

  • Cheon MS, Suh JK, Kim MJ, Kim SH, Lee K . (2008). Identification of differentially expressed proteins in the heart of translationally controlled tumor protein over-expressing transgenic mice. Biomed Chromatogr 22: 1091–1099.

    Article  CAS  Google Scholar 

  • Cooper JA, Howell B . (1993). The when and how of Src regulation. Cell 73: 1051–1054.

    Article  CAS  Google Scholar 

  • Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR . (2007). p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell 11: 191–205.

    Article  CAS  Google Scholar 

  • Emlet DR, Moscatello DK, Ludlow LB, Wong AJ . (1997). Subsets of epidermal growth factor receptors during activation and endocytosis. J Biol Chem 272: 4079–4086.

    Article  CAS  Google Scholar 

  • Espineda C, Seligson DB, James Ball Jr W, Rao J, Palotie A, Horvath S et al. (2003). Analysis of the Na,K-ATPase alpha- and beta-subunit expression profiles of bladder cancer using tissue microarrays. Cancer 97: 1859–1868.

    Article  CAS  Google Scholar 

  • Gnanasekar M, Ramaswamy K . (2007). Translationally controlled tumor protein of Brugia malayi functions as an antioxidant protein. Parasitol Res 101: 1533–1540.

    Article  Google Scholar 

  • Haas M, Wang H, Tian J, Xie Z . (2002). Src-mediated inter-receptor cross-talk between the Na+/K+-ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J Biol Chem 277: 18694–18702.

    Article  CAS  Google Scholar 

  • Haux J . (1999). Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses 53: 543–548.

    Article  CAS  Google Scholar 

  • Impola U, Jeskanen L, Ravanti L, Syrjänen S, Baldursson B, Kähäri VM et al. (2005). Expression of matrix metalloproteinase (MMP)-7 and MMP-13 and loss of MMP-19 and p16 are associated with malignant progression in chronic wounds. Br J Dermatol 152: 720–726.

    Article  CAS  Google Scholar 

  • Irby RB, Yeatman TJ . (2000). Role of Src expression and activation in human cancer. Oncogene 19: 5636–5642.

    Article  CAS  Google Scholar 

  • Ishizawar R, Parsons SJ . (2004). c-Src and cooperating partners in human cancer. Cancer Cell 6: 209–214.

    Article  CAS  Google Scholar 

  • Jung J, Kim M, Choi S, Kim MJ, Suh JK, Choi EC et al. (2006). Molecular mechanism of cofilin dephosphorylation by ouabain. Cell Signal 18: 2033–2040.

    Article  CAS  Google Scholar 

  • Jung J, Kim M, Kim MJ, Kim J, Moon J, Lim JS et al. (2004). Translationally controlled tumor protein interacts with the third cytoplasmic domain of Na,K-ATPase alpha subunit and inhibits the pump activity in HeLa cells. J Biol Chem 279: 49868–49875.

    Article  CAS  Google Scholar 

  • Kim M, Jung J, Lee K . (2009). Roles of ERK, PI3 kinase, and PLC-gamma pathways induced by overexpression of translationally controlled tumor protein in HeLa cells. Arch Biochem Biophys 485: 82–87.

    Article  CAS  Google Scholar 

  • Kometiani P, Liu L, Askari A . (2005). Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. Mol Pharmacol 67: 929–936.

    Article  CAS  Google Scholar 

  • Kumar R, Gururaj AE, Barnes CJ . (2006). p21-activated kinases in cancer. Nat Rev Cancer 6: 459–471.

    Article  CAS  Google Scholar 

  • Liu J, Tian J, Haas M, Shapiro JI, Askari A, Xie Z . (2000). Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem 275: 27838–27844.

    CAS  PubMed  Google Scholar 

  • Lo HW, Hsu SC, Hung MC . (2006). EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res Treat 95: 211–218.

    Article  CAS  Google Scholar 

  • Martindale JL, Holbrook NJ . (2002). Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192: 1–15.

    Article  CAS  Google Scholar 

  • Mori K, Shibanuma M, Nose K . (2004). Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res 64: 7464–7472.

    Article  CAS  Google Scholar 

  • Nagano-Ito M, Banba A, Ichikawa S . (2009). Functional cloning of genes that suppress oxidative stress-induced cell death: TCTP prevents hydrogen peroxide-induced cell death. FEBS Lett 583: 1363–1367.

    Article  CAS  Google Scholar 

  • Nielsen HV, Johnsen AH, Sanchez JC, Hochstrasser DF, Schiotz PO . (1998). Identification of a basophil leukocyte interleukin-3-regulated protein that is identical to IgE-dependent histamine-releasing factor. Allergy 53: 642–652.

    Article  CAS  Google Scholar 

  • Oikawa K, Ohbayashi T, Mimura J, Fujii-Kuriyama Y, Teshima S, Rokutan K et al. (2002). Dioxin stimulates synthesis and secretion of IgE-dependent histamine-releasing factor. Biochem Biophys Res Commun 290: 984–987.

    Article  CAS  Google Scholar 

  • Park HS, Lee SH, Park D, Lee JS, Ryu SH, Lee WJ et al. (2004). Sequential activation of phosphatidylinositol 3-kinase, beta Pix, Rac1, and Nox1 in growth factor-induced production of H2O2. Mol Cell Biol 24: 4384–4394.

    Article  CAS  Google Scholar 

  • Rajasekaran SA, Palmer LG, Moon SY, Peralta Soler A, Apodaca GL, Harper JF et al. (2001a). Na,K-ATPase activity is required for formation of tight junctions, desmosomes, and induction of polarity in epithelial cells. Mol Biol Cell 12: 3717–3732.

    Article  CAS  Google Scholar 

  • Rajasekaran SA, Palmer LG, Quan K, Harper JF, Ball Jr WJ, Bander NH et al. (2001b). Na,K-ATPase beta-subunit is required for epithelial polarization, suppression of invasion, and cell motility. Mol Biol Cell 12: 279–295.

    Article  CAS  Google Scholar 

  • Rowe RG, Weiss SJ . (2008). Breaching the basement membrane: who, when and how? Trends Cell Biol 18: 560–574.

    Article  CAS  Google Scholar 

  • Shin I, Kim S, Song H, Kim HR, Moon A . (2005). H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. J Biol Chem 280: 14675–14683.

    Article  CAS  Google Scholar 

  • Song H, Ki SH, Kim SG, Moon A . (2006). Activating transcription factor 2 mediates matrix metalloproteinase-2 transcriptional activation induced by p38 in breast epithelial cells. Cancer Res 66: 10487–10496.

    Article  CAS  Google Scholar 

  • Sternlicht MD, Bissell MJ, Werb Z . (2000). The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene 19: 1102–1113.

    Article  CAS  Google Scholar 

  • Szatrowski TP, Nathan CF . (1991). Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51: 794–798.

    CAS  Google Scholar 

  • Teshima S, Rokutan K, Nikawa T, Kishi K . (1998). Macrophage colony-stimulating factor stimulates synthesis and secretion of a mouse homolog of a human IgE-dependent histamine-releasing factor by macrophages in vitro and in vivo. J Immunol 161: 6356–6366.

    CAS  PubMed  Google Scholar 

  • Tian J, Cai T, Yuan Z, Wang H, Liu L, Haas M et al. (2006). Binding of Src to Na+/K+-ATPase forms a functional signaling complex. Mol Biol Cell 17: 317–326.

    Article  CAS  Google Scholar 

  • Tice DA, Biscardi JS, Nickles AL, Parsons SJ . (1999). Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Pro Natl Acad Sci USA 96: 1415–1420.

    Article  CAS  Google Scholar 

  • Tuynder M, Fiucci G, Prieur S, Lespagnol A, Géant A, Beaucourt S et al. (2004). Translationally controlled tumor protein is a target of tumor reversion. Proc Natl Acad Sci USA 101: 15364–15369.

    Article  CAS  Google Scholar 

  • Tuynder M, Susini L, Prieur S, Besse S, Fiucci G, Amson R et al. (2002). Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1. Proc Natl Acad Sci USA 99: 14976–14981.

    Article  CAS  Google Scholar 

  • Xie Z . (2003). Molecular mechanisms of Na/K-ATPase-mediated signal transduction. Ann N Y Acad Sci 986: 497–503.

    Article  CAS  Google Scholar 

  • Yeatman TJ . (2004). A renaissance for SRC. Nat Rev Cancer 4: 470–480.

    Article  CAS  Google Scholar 

  • Yudowski GA, Efendiev R, Pedemonte CH, Katz AI, Berggren PO, Bertorello AM . (2000). Phosphoinositide-3 kinase binds to a proline-rich motif in the Na+, K+-ATPase alpha subunit and regulates its trafficking. Proc Natl Acad Sci USA 97: 6556–6561.

    Article  CAS  Google Scholar 

  • Zwick E, Hackel PO, Prenzel N, Ullrich A . (1999). The EGF receptor as central transducer of heterologous signalling systems. Trends Pharmacol Sci 20: 408–412.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs (A090030), NRF of Korea Grant funded by the Korean Government (2009-0064401), Mid-career Research Program through NRF grant funded by the MEST (R01-2007-000-20263-0), Seoul R&BD Program (ST090801) and the NCRC program of MOST/KOSEF (R15-2006-020).

Author information

Authors and Affiliations

  1. College of Pharmacy, Center for Cell Signalling & Drug Discovery Research, Ewha Womans University, Seoul, Korea

    J Jung, H Y Kim, M Kim, K Sohn, M Kim & K Lee

Authors
  1. J Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Y Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Sohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Lee.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jung, J., Kim, H., Kim, M. et al. Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src. Oncogene 30, 2264–2274 (2011). https://doi.org/10.1038/onc.2010.604

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.604

Keywords

This article is cited by

Search

Advanced search

Quick links