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:

BAG3 controls angiogenesis through regulation of ERK phosphorylation

Oncogene volume 31, pages 5153–5161 (2012)Cite this article

Subjects

Abstract

BAG3 is a co-chaperone of the heat shock protein (Hsp) 70, is expressed in many cell types upon cell stress, however, its expression is constitutive in many tumours. We and others have previously shown that in neoplastic cells BAG3 exerts an anti-apoptotic function thus favoring tumour progression. As a consequence we have proposed BAG3 as a target of antineoplastic therapies. Here we identify a novel role for BAG3 in regulation of neo-angiogenesis and show that its downregulation results in reduced angiogenesis therefore expanding the role of BAG3 as a therapeutical target. In brief we show that BAG3 is expressed in endothelial cells and is essential for the interaction between ERK and its phosphatase DUSP6, as a consequence its removal results in reduced binding of DUSP6 to ERK and sustained ERK phosphorylation that in turn determines increased levels of p21 and p15 and cell-cycle arrest in the G1 phase.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  1. Takayama S, Xie Z, Reed JC . An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators. J Biol Chem 1999; 274: 781–786.

    Article  CAS  Google Scholar 

  2. Rosati A, Ammirante M, Gentilella A, Basile A, Festa M, Pascale M et al. Apoptosis inhibition in cancer cells: a novel molecular pathway that involves BAG3 protein. Int J Biochem Cell Biol 2007; 39: 1337–1342.

    Article  CAS  Google Scholar 

  3. Franceschelli S, Rosati A, Lerose R, De Nicola S, Turco MC, Pascale M . Bag3 gene expression is regulated by heat shock factor 1. J Cell Physiol 2008; 215: 575–577.

    Article  CAS  Google Scholar 

  4. Homma S, Iwasaki M, Shelton GD, Engvall E, Reed JC, Takayama S . BAG3 deficiency results in fulminant myopathy and early lethality. Am J Pathol 2006; 169: 761–773.

    Article  CAS  Google Scholar 

  5. Romano MF, Festa M, Pagliuca G, Lerose R, Bisogni R, Chiurazzi F et al. BAG3 protein controls B-chronic lymphocytic leukaemia cell apoptosis. Cell Death Differ 2003; 10: 383–385.

    Article  CAS  Google Scholar 

  6. Rosati A, Di Salle E, Luberto L, Quinto I, Scala G, Turco MC et al. Identification of a Btk-BAG3 complex induced by oxidative stress. Leukemia 2009; 23: 823–824.

    Article  CAS  Google Scholar 

  7. Romano MF, Festa M, Petrella A, Rosati A, Pascale M, Bisogni R et al. BAG3 protein regulates cell survival in childhood acute lymphoblastic leukemia cells. Cancer Biol Ther 2003; 2: 508–510.

    Article  CAS  Google Scholar 

  8. Valdez BC, Murray D, Ramdas L, de Lima M, Jones R, Kornblau S et al. Altered gene expression in busulfan-resistant human myeloid leukemia. Leuk Res 2008; 32: 1684–1697.

    Article  CAS  Google Scholar 

  9. Liu P, Xu B, Li J, Lu H . BAG3 gene silencing sensitizes leukemic cells to Bortezomib induced apoptosis. FEBS Lett 2009; 583: 401–406.

    Article  CAS  Google Scholar 

  10. Bonelli P, Petrella A, Rosati A, Romano MF, Lerose R, Pagliuca MG et al. BAG3 protein regulates stress-induced apoptosis in normal and neoplastic leukocytes. Leukemia 2004; 18: 358–360.

    Article  CAS  Google Scholar 

  11. Tabuchi Y, Ando H, Takasaki I, Feril Jr LB, Zhao QL, Ogawa R et al. Identification of genes responsive to low intensity pulsed ultrasound in a human leukemia cell line Molt-4. Cancer Lett 2007; 246: 149–156.

    Article  CAS  Google Scholar 

  12. Cesaro E, Montano G, Rosati A, Crescitelli R, Izzo P, Turco MC et al. WT1 protein is a transcriptional activator of the antiapoptotic bag3 gene. Leukemia 2010; 24: 1204–1206.

    Article  CAS  Google Scholar 

  13. Liao Q, Ozawa F, Friess H, Zimmermann A, Takayama S, Reed JC et al. The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. FEBS Lett 2001; 503: 151–157.

    Article  CAS  Google Scholar 

  14. Chiappetta G, Ammirante M, Basile A, Rosati A, Festa M, Monaco M et al. The antiapoptotic protein BAG3 is expressed in thyroid carcinomas and modulates apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Clin Endocrinol Metab 2007; 92: 1159–1163.

    Article  CAS  Google Scholar 

  15. Gentilella A, Passiatore G, Deshmane S, Turco MC, Khalili K . Activation of BAG3 by Egr-1 in response to FGF-2 in neuroblastoma cells. Oncogene 2008; 27: 5011–5018.

    Article  CAS  Google Scholar 

  16. Jacobs AT, Marnett LJ . HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins. J Biol Chem 2009; 284: 9176–9183.

    Article  CAS  Google Scholar 

  17. Wang HQ, Liu BQ, Gao YY, Meng X, Guan Y, Zhang HY et al. Inhibition of the JNK signalling pathway enhances proteasome inhibitor-induced apoptosis of kidney cancer cells by suppression of BAG3 expression. Br J Pharmacol 2009; 158: 1405–1412.

    Article  CAS  Google Scholar 

  18. Festa M, Del Valle L, Franco R, Scognamiglio G, Khalili K, De Laurenzi L et al. BAG3 protein is overexpressed in human glioblastoma and is a potential target for its therapy. Am J Pathol 2011; 178: 2504–2512.

    Article  CAS  Google Scholar 

  19. Ammirante M, Rosati A, Arra C, Basile A, Falco A, Festa M et al. IKKγ protein is a target of BAG3 regulatory activity in human tumor growth. Proc Natl Acad Sci USA 2010; 107: 7497–7502.

    Article  CAS  Google Scholar 

  20. Jung SE, Kim YK, Youn DY, Lim MH, Ko JH, Ahn YS et al. Down-modulation of Bis sensitizes cell death in C6 glioma cells induced by oxygen-glucose deprivation. Brain Res 2010; 1349: 1–10.

    Article  CAS  Google Scholar 

  21. Dai C, Whitesell L, Rogers AB, Lindquist S . Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 2007; 130: 1005–1018.

    Article  CAS  Google Scholar 

  22. Baud V, Karin M . NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 2009; 8: 33–40.

    Article  CAS  Google Scholar 

  23. Doong H, Rizzo K, Fang S, Kulpa V, Weissman AM, Kohn EC . CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins. J Biol Chem 2003; 278: 28490–28500.

    Article  CAS  Google Scholar 

  24. Doong H, Price J, Kim YS, Gasbarre C, Probst J, Liotta LA et al. CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70. Oncogene 2000; 19: 4385–4395.

    Article  CAS  Google Scholar 

  25. Rosati A, Graziano V, De Laurenzi V, Pascale M, Turco MC . BAG3: a multifaceted protein that regulates major cell pathways. Cell Death Dis 2011; 2: e141.

    Article  CAS  Google Scholar 

  26. Guedez L, Rivera AM, Salloum R, Miller ML, Diegmueller JJ, Bungay PM et al. Quantitative assessment of angiogenic response by the directed in vivo angiogenesis assay. Am J Pathol 2003; 162: 1431–1439.

    Article  CAS  Google Scholar 

  27. Basile A, Del Gatto A, Diana D, Di Stasi R, Falco A, Festa M et al. Characterization of a designed vascular endothelial growth factor receptor antagonist helical peptide with antiangiogenic activity in vivo. J Med Chem 2011; 54: 1391–1400.

    Article  CAS  Google Scholar 

  28. Norrby K . In vivo models of angiogenesis. J Cell Mol Med 2006; 10: 588–612.

    Article  CAS  Google Scholar 

  29. Bodart JF . Extracellular-regulated kinase-mitogen-activated protein kinase cascade: unsolved issues. J Cell Biochem 2010; 109: 850–857.

    CAS  PubMed  Google Scholar 

  30. Cagnol S, Chambard JC . ERK and cell death: mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. FEBS J 2010; 277: 2–21.

    Article  CAS  Google Scholar 

  31. Meloche S, Pouysségur J . The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 2007; 26: 3227–3239.

    Article  CAS  Google Scholar 

  32. Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF . Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb. Proc Natl Acad Sci USA 1997; 94: 10699–10704.

    Article  CAS  Google Scholar 

  33. Cánepa ET, Scassa ME, Ceruti JM, Marazita MC, Carcagno AL, Sirkin PF et al. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 2007; 59: 419–426.

    Article  Google Scholar 

  34. Gil J, Peters G . Regulation of the INK4b-ARF-INK4a tumor suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 2006; 7: 667–677.

    Article  CAS  Google Scholar 

  35. Wainwright LJ, Lasorella A, Iavarone A . Distinct mechanisms of cell cycle arrest control the decision between differentiation and senescence in human neuroblastoma cells. Proc Natl Acad Sci USA 2001; 98: 9396–9400.

    Article  CAS  Google Scholar 

  36. Patterson KI, Brummer T, O'Brien PM, Daly RJ . Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 2009; 418: 475–489.

    Article  CAS  Google Scholar 

  37. Jurek A, Amagasaki K, Gembarska A, Heldin CH, Lennartsson J . Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced ERK activation. J Biol Chem 2009; 284: 4626–4634.

    Article  CAS  Google Scholar 

  38. Owens DM, Keyse SM . Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 2007; 26: 3203–3213 Review.

    Article  CAS  Google Scholar 

  39. Ramos JW . The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int J Biochem Cell Bio 2008; 40: 2707–2719.

    Article  CAS  Google Scholar 

  40. Katz M, Amit I, Yarden Y . Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta 2007; 1773: 1161–1176.

    Article  CAS  Google Scholar 

  41. Song J, Takeda M, Morimoto R . Bag1-Hsp70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth. Nat Cell Biol 2001; 3: 276–282.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by AIRC and Ministero Sanita' grants to VDL.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Biomedical Sciences (FARMABIOMED), University of Salerno, Fisciano, Italy

    A Falco, M Festa, A Basile, A Rosati, M Pascale, S L Nori & M C Turco

  2. BIOUNIVERSA srl, University of Salerno, Fisciano, Italy

    A Falco, M Festa, A Basile, A Rosati, M Pascale, V De Laurenzi & M C Turco

  3. IRCSS Fondazione Santa Lucia and European Brain Research Institute Rita Levi-Montalcini, Rome, Italy

    F Florenzano

  4. Clinical Department of Biomedicine, University of Trieste, Italy

    V Nicolin

  5. Clinical and Experimental Medicine Department, Federico II University, Naples, Italy

    M Di Benedetto & M L Vecchione

  6. Animal Facility, Pascale Tumor Institute, Naples, Italy

    C Arra & A Barbieri

  7. Department of Biomedical Sciences, University of Chieti-Pescara, Fondazione ‘G.D'Annunzio’ and Centro Studi sull'Invecchiamento (Ce.S.I), Chieti, Italy

    V De Laurenzi

Authors
  1. A Falco
    View author publications

    Search author on:PubMed Google Scholar

  2. M Festa
    View author publications

    Search author on:PubMed Google Scholar

  3. A Basile
    View author publications

    Search author on:PubMed Google Scholar

  4. A Rosati
    View author publications

    Search author on:PubMed Google Scholar

  5. M Pascale
    View author publications

    Search author on:PubMed Google Scholar

  6. F Florenzano
    View author publications

    Search author on:PubMed Google Scholar

  7. S L Nori
    View author publications

    Search author on:PubMed Google Scholar

  8. V Nicolin
    View author publications

    Search author on:PubMed Google Scholar

  9. M Di Benedetto
    View author publications

    Search author on:PubMed Google Scholar

  10. M L Vecchione
    View author publications

    Search author on:PubMed Google Scholar

  11. C Arra
    View author publications

    Search author on:PubMed Google Scholar

  12. A Barbieri
    View author publications

    Search author on:PubMed Google Scholar

  13. V De Laurenzi
    View author publications

    Search author on:PubMed Google Scholar

  14. M C Turco
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to M C Turco.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Falco, A., Festa, M., Basile, A. et al. BAG3 controls angiogenesis through regulation of ERK phosphorylation. Oncogene 31, 5153–5161 (2012). https://doi.org/10.1038/onc.2012.17

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/onc.2012.17

Keywords

This article is cited by

Search

Advanced search

Quick links