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 Paper
  • Published:

Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein

Oncogene volume 22, pages 710–721 (2003)Cite this article

Abstract

While PDZ domain-containing proteins represent cellular targets for several different viral oncoproteins, including human papillomavirus E6, human T-cell leukemia virus type 1 Tax, and human adenovirus E4-ORF1, the functional consequences for such interactions have not been elucidated. Here we report that, at the plasma membrane of cells, the adenovirus E4-ORF1 oncoprotein selectively and potently stimulates phosphatidylinositol 3-kinase (PI3K), triggering a downstream cascade of events that includes activation of both protein kinase B and p70S6-kinase. This activity of E4-ORF1 could be abrogated by overexpression of its PDZ-protein targets or by disruption of its PDZ domain-binding motif, which was shown to mediate complex formation between E4-ORF1 and PDZ proteins at the plasma membrane of cells. Furthermore, E4-ORF1 mutants unable to activate the PI3K pathway failed to transform cells in culture or to promote tumors in animals, and drugs that block either PI3K or p70S6-kinase inhibited E4-ORF1-induced transformation of cells. From these results, we propose that the transforming and tumorigenic potentials of the adenovirus E4-ORF1 oncoprotein depend on its capacity to activate PI3K through a novel PDZ protein-dependent mechanism of action.

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
Figure 7

Similar content being viewed by others

References

  • Aoki M, Blazek E and Vogt PK . (2001). Proc. Natl. Acad. Sci. USA, 98, 136–141.

  • Blume-Jensen P and Hunter T . (2001). Nature, 411, 355–365.

  • Bowman T, Garcia R, Turkson J and Jove R . (2000). Oncogene, 19, 2474–2488.

  • Bradford MM . (1976). Anal. Biochem., 72, 248–254.

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME . (1999). Cell, 96, 857–868.

  • Cantrell DA . (2001). J. Cell Sci., 114, 1439–1445.

  • Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM and Vogt PK . (1997). Science, 276, 1848–1850.

  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T and Gutkind JS . (1995). Cell, 81, 1137–1146.

  • Dufner A and Thomas G . (1999). Exp. Cell Res., 253, 100–109.

  • Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR and Tsichlis PN . (1995). Cell, 81, 727–736.

  • Glaunsinger BA, Lee SS, Thomas M, Banks L and Javier R . (2000). Oncogene, 19, 5270–5280.

  • Glaunsinger BA, Weiss RS, Lee SS and Javier R . (2001). EMBO J., 20, 5578–5586.

  • Gottardi CJ, Arpin M, Fanning AS and Louvard D . (1996). Proc. Natl. Acad. Sci. USA, 93, 10779–10784.

  • Hsueh YP, Wang TF, Yang FC and Sheng M . (2000). Nature, 404, 298–302.

  • Islas S, Vega J, Ponce L and Gonzalez-Mariscal L . (2002). Exp. Cell Res., 274, 138–148.

  • Javier R, Raska Jr K, Macdonald GJ and Shenk T . (1991). J. Virol., 65, 3192–3202.

  • Javier RT . (1994). J. Virol., 68, 3917–3924.

  • Kimble J and Simpson P . (1997). Annu. Rev. Cell. Dev. Biol., 13, 333–361.

  • Kingston RE . (1989). Current Protocols in Molecular Biology. Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, and Struhl K. (eds). Greene Publishing Associates and Wiley-Interscience: New York, NY.

    Google Scholar 

  • Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T and Ishibashi M . (1997). Proc. Natl. Acad. Sci. USA, 94, 11612–11616.

  • Klippel A, Escobedo MA, Wachowicz MS, Apell G, Brown TW, Giedlin MA, Kavanaugh WM and Williams LT . (1998). Mol. Cell. Biol., 18, 5699–5711.

  • Lee SS, Glaunsinger B, Mantovani F, Banks L and Javier RT . (2000). J. Virol., 74, 9680–9693.

  • Lee SS, Weiss RS and Javier RT . (1997). Proc. Natl. Acad. Sci. USA, 94, 6670–6675.

  • Lou X, Yano H, Lee F, Chao MV and Farquhar MG . (2001). Mol. Biol. Cell., 12, Q2615–627.

  • Medema RH, Kops GJ, Bos JL and Burgering BM . (2000). Nature, 404, 782–787.

  • Mills GB, Lu Y, Fang X, Wang H, Eder A, Mao M, Swaby R, Cheng KW, Stokoe D, Siminovitch K, Jaffe R and Gray, J . (2001). Semin. Oncol., 28, 125–141.

  • Mirza AM, Kohn AD, Roth RA and McMahon M . (2000). Cell Growth Differ., 11, 279–292.

  • Morgenstern JP and Land H . (1990). Nucleic Acids Res., 18, 3587–3596.

  • Muller BM, Kistner U, Veh RW, Cases-Langhoff C, Becker B, Gundelfinger ED and Garner CC . (1995). J. Neurosci., 15, 2354–2366.

  • Nishimura W, Iizuka T, Hirabayashi S, Tanaka N and Hata Y . (2000). J. Cell Physiol., 185, 358–365.

  • Pelech SL and Krebs EG . (1987). J. Biol. Chem., 262, 11598–11606.

  • Rameh LE, Chen CS and Cantley LC . (1995). Cell, 83, 821–830.

  • Sheng M and Sala C . (2001). Annu. Rev. Neurosci., 24, 1–29.

  • Susa M, Keeler M and Varticovski L . (1992). J. Biol. Chem., 267, 22951–22956.

  • Suzuki T, Ohsugi Y, Uchida-Toita M, Akiyama T and Yoshida M . (1999). Oncogene, 18, 5967–5972.

  • Thomas DL, Schaack J, Vogel H and Javier R . (2001). J. Virol., 75, 557–568.

  • Thomas DL, Shin S, Jiang BH, Vogel H, Ross MA, Kaplitt M, Shenk TE and Javier RT . (1999). J. Virol., 73, 3071–3079.

  • Tsatsanis C and Spandidos DA . (2000). Int. J. Mol. Med., 5, 583–590.

  • Tsunoda S and Zuker CS . (1999). Cell Calcium, 26, 165–171.

  • Uthoff SM, Eichenberger MR, McAuliffe TL, Hamilton CJ and Galandiuk S . (2001). Mol. Carcinogen., 31, 56–62.

  • Vogt PK . (2001). Oncogene, 20, 2365–2377.

  • Watton SJ and Downward J . (1999). Curr. Biol., 9, 433–436.

  • Weiss RS and Javier RT . (1997). J. Virol., 71, 7873–7880.

  • Weiss RS, Gold MO, Vogel H and Javier RT . (1997a). J. Virol., 71, 4385–4394.

  • Weiss RS, Lee SS, Prasad BV and Javier RT . (1997b). J. Virol., 71, 1857–1870.

  • Weiss RS, McArthur MJ and Javier RT . (1996). J. Virol., 70, 862–872.

  • Woods DF and Bryant PJ . (1991). Cell, 66, 451–464.

  • Wu X, Hepner K, Castelino-Prabhu S, Do D, Kaye MB, Yuan XJ, Wood J, Ross C, Sawyers CL and Whang YE . (2000a). Proc. Natl. Acad. Sci. USA, 97, 4233–4238.

  • Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q and Lasky LA . (2000b). J. Biol. Chem., 275, 21477–21485.

  • Yamada KM and Araki M . (2001). J. Cell Sci., 114, 2375–2382.

  • Yu Y and Sato JD . (1999). J. Cell. Physiol., 178, 235–246.

Download references

Acknowledgements

We thank Lyuba Varticovski for suggestions on performing PI3K assays. Predoctoral fellowships from the Viral Oncology Training Grant (T32 CA09197) to KKF and DLT, the US Army Breast Cancer Training Grant (DAMD17-94-J4204) to SSL, RSW, and IJL, and the Molecular Virology Training Grant (T32 AI07471) to BG helped to support this study. This research was funded by grants to RTJ from the National Cancer Institute (RO1 CA58541) and from the US Army (DAMD17-97-1-7082).

Author information

Author notes

  1. Siu Sylvia Lee

    Present address: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, 02114

  2. Darby L Thomas

    Present address: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104

  3. Robert S Weiss

    Present address: Department of Biomedical Sciences, Cornell University, Ithaca, NY, 14853

  4. Britt A Glaunsinger

    Present address: Department of Microbiology & Immunology, University of California Medical Center, San Francisco, CA, 94143

Authors and Affiliations

  1. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, 77030, TX, USA

    Kristopher K Frese, Siu Sylvia Lee, Darby L Thomas, Isabel J Latorre, Robert S Weiss, Britt A Glaunsinger & Ronald T Javier

Authors
  1. Kristopher K Frese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Siu Sylvia Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Darby L Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isabel J Latorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert S Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Britt A Glaunsinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ronald T Javier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald T Javier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frese, K., Lee, S., Thomas, D. et al. Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Oncogene 22, 710–721 (2003). https://doi.org/10.1038/sj.onc.1206151

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206151

Keywords

This article is cited by

Search

Advanced search

Quick links