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:

Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

Oncogene volume 19, pages 1153–1163 (2000)Cite this article

Abstract

Here we identify the hematopoietic proto-oncogene Vav1 as a caspase substrate during apoptosis in lymphoid cells. Cleavage of Vav1 is prevented by the caspase inhibitors zDEVD and zVAD as well as by expression of CrmA. Vav1 is cleaved in vivo at the evolutionary conserved caspase consensus cleavage site DLYD161C, generating the carboxy-terminal cleavage product Vav1p76 of intermediate stability. In vitro caspase assays reveal cleavage of Vav1 at position 161 either by apoptotic cell lysates or by recombinant caspase-3. Mutation of Asp 161 to Ala leads to the usage of the adjacent alternative cleavage sequence DQID150D. Mutation of both cleavage sites at position 150 and 161 protects Vav1 from caspase-mediated proteolysis in vitro and in vivo. The cleavage product Vav1p76 is capable of activating JNK in T-cells, but fails to induce the phosphorylation of p38/HOG1. Vav1p76 displays a diminished capacity to activate the transcription factors NF-AT, AP-1 and NF-κB, and thus completely fails to activate IL-2 transcription. Since Vav1 is essential for IL-2 production and plays a central role for cytoskeletal reorganization, its proteolytic inactivation during apoptosis affects multiple downstream targets.

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

  • Baichwal VR and Baeuerle PA. . 1997 Curr. Biol. 7: R94–R96.

  • Cantrell D. . 1998 Curr. Biol. 8: R535–R538.

  • Caulín C, Salvesen GS and Oshima RG. . 1997 J. Cell. Biol. 138: 1379–1394.

  • Coppola J, Bryant S, Koda T, Conway D and Barbacid M. . 1991 Cell Growth Differ. 2: 95–105.

  • Costello PS, Walters AE, Mee PJ, Turner M, Reynolds LF, Prisco A, Sarner N, Zamoyska R and Tybulewicz VLJ. . 1999 Proc. Natl. Acad. Sci. USA 96: 3035–3040.

  • Cosulich SC, Horiuchi H, Zerial M, Clarke PR and Woodman PG. . 1997 EMBO J. 16: 6182–6191.

  • Crespo P, Schuebel KE, Ostrom AA, Gutkind JS and Bustelo XR. . 1997 Nature 385: 169–172.

  • Cryns V and Yuan J. . 1998 Genes Dev. 12: 1551–1570.

  • Debatin KM, Goldmann CK, Bamford R, Waldmann TA and Krammer PH. . 1990 Lancet 335: 497–500.

  • Dumont A, Hehner SP, Hofman TG, Ueffing M, Dröge W and Schmitz ML. . 1999 Oncogene 18: 747–757.

  • Fischer KD, Zmuldzinas A, Gardner S, Barbacid M, Bernstein A and Guidos C. . 1995 Nature 374: 474–477.

  • Fischer KD, Kong YY, Nishina H, Tedford K, Marengere LE, Kozieradzki I, Sasaki T, Starr M, Chan G, Gardener S, Nghiem MP, Bouchard D, Barbacid M, Bernstein A and Penninger JM. . 1998 Curr. Biol. 8: 554–562.

  • Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW and Thornberry NA. . 1998 J. Biol. Chem. 273: 32608–32613.

  • Germani A, Romero F, Houlard M, Camonis J, Gisselbrecht S, Fischer S and Varin-Blank N. . 1999 Mol. Cell. Biol. 19: 3798–3807.

  • Gomez J, Gonzalez A, Martinez A-C and Rebollo A. . 1998 Crit. Rev. Immunol. 18: 185–220.

  • Gulbins E, Coggeshall KM, Baier G, Katzav S, Burn P and Altman A. . 1993 Science 260: 822–825.

  • Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A de-la-Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM and Mak TW. . 1998 Cell 94: 339–352.

  • Han J, Luby Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA and Broek D. . 1998 Science 279: 558–560.

  • Hehner SP, Hofmann TG, Ratter F, Dumont A, Dröge W and Schmitz ML. . 1998 J. Biol. Chem. 273: 18117–18121.

  • Hettmann T, DiDonato J, Karin M and Leiden JM. . 1999 J. Exp. Med. 189: 145–158.

  • Holsinger LJ, Graef IA, Swat W, Chi T, Bautista DM, Davidson L, Lewis RS, Alt FW and Crabtree GR. . 1998 Curr. Biol. 8: 563–572.

  • Jain J, Loh C and Rao A. . 1995 Curr. Opin. Immunol. 7: 333–342.

  • Katzav S. . 1995 Crit. Rev. Oncog. 6: 87–97.

  • Katzav S, Martin-Zanca D and Barbacid M. . 1989 EMBO J. 8: 2283–2290.

  • Kong YY, Fischer KD, Bachmann MF, Mariathasan S, Kozieradzki I, Nghiem MP, Bouchard D, Bernstein A, Ohashi PS and Penninger JM. . 1998 J. Exp. Med. 188: 2099–2111.

  • Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG and Earnshaw WC. . 1994 Nature 371: 346–347.

  • Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH and Peter ME. . 1997 EMBO J. 16: 2794–2804.

  • Movilla N and Bustelo XR. . 1999 Mol. Cell. Biol. 19: 7870–7885.

  • Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM. . 1996 Cell 85: 817–827.

  • Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C. . 1991 J. Immunol. Method 139: 271–279.

  • Nuñez G, Benedict MA, Hu Y and Inohara N. . 1998 Oncogene 17: 3237–3245.

  • O'Rourke LM, Tooze R, Turner M, Sandoval DM, Carter RH, Tybulewicz VL and Fearon DT. . 1998 Immunity 8: 635–645.

  • Romero F and Fischer S. . 1996 Cell. Signal 8: 545–553.

  • Salojin KV, Zhang J and Delovitch TL. . 1999 J. Immunol. 163: 844–853.

  • Scaffidi C, Medema JP, Krammer PH and Peter ME. . 1997 J. Biol. Chem. 272: 26953–26958.

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH and Peter ME. . 1998 EMBO J. 17: 1675–1687.

  • Schuebel KE, Movilla N, Rosa JL and Bustelo XR. . 1998 EMBO J. 17: 6608–6621.

  • Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME. . 1998 Eur. J. Biochem. 254: 439–459.

  • Schwartz RH. . 1997 Curr. Opin. Immunol. 9: 351–357.

  • Shapiro VS, Truitt KE, Imboden JB and Weiss A. . 1997 Mol. Cell. Biol. 17: 4051–4058.

  • Song JS, Haleem-Smith H, Arudchandran R, Gomez J, Scott PM, Mill JF, Tan TH and Rivera J. . 1999 J. Immunol. 163: 802–810.

  • Strasser A, Harris AW, Huang DC, Krammer PH and Cory S. . 1995 EMBO J. 14: 6136–6147.

  • Tan X, Martin SJ, Green DR and Wang JYJ. . 1997 J. Biol. Chem. 272: 9613–9616.

  • Tarakhovsky A, Turner M, Schaal S, Mee PJ, Duddy LP, Rajewsky K and Tybulewicz VL. . 1995 Nature 374: 467–470.

  • Tewari M, Quan LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS and Dixit VM. . 1995 Cell 81: 801–809.

  • Turner M, Mee PJ, Walters AE, Quinn ME, Mellor AL, Zamoyska R and Tybulewicz VL. . 1997 Immunity 7: 451–460.

  • Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckman JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P and Wallach D. . 1998 Immunity 9: 267–276.

  • Vaux DL and Korsmeyer SJ. . 1999 Cell 96: 245–254.

  • Villa P, Kaufmann SH and Earnshaw WC. . 1997 Trends Biochem. Sci. 22: 388–393.

  • Wange RL and Samelson LE. . 1996 Immunity 5: 197–205.

  • Varadhachary AS, Perdow SN, Hu C, Ramanarayanan M and Salgame P. . 1997 Proc. Natl. Acad. Sci. USA 94: 5778–5783.

  • Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW and Mak TW. . 1998 Genes Dev. 12: 806–819.

  • Wu J, Katzav S and Weiss A. . 1995 Mol. Cell. Biol. 15: 4337–4346.

  • Zhang R, Alt FW, Davidson L, Orkin SH and Swat W. . 1995 Nature 374: 470–473.

Download references

Acknowledgements

We thank Sandra Grunau and Claudia Ehmann for excellent technical assistance. We thank Dr V Dixit (San Francisco, USA) for kindly providing the CrmA expressing BJAB cells and all the colleagues who generously provided cDNAs, reporter plasmids and antibodies. This work was supported by grants from the cooperation program in cancer research of the DKFZ and of Israel's Ministry of Science (W Dröge and SP Hehner).

Author information

Author notes

  1. Thomas G Hofmann and Steffen P Hehner: TG Hofmann and SP Hehner contributed equally to this work

Authors and Affiliations

  1. Department of Immunochemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    Thomas G Hofmann, Steffen P Hehner, Wulf Dröge & M Lienhard Schmitz

Authors
  1. Thomas G Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steffen P Hehner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wulf Dröge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Lienhard Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hofmann, T., Hehner, S., Dröge, W. et al. Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription. Oncogene 19, 1153–1163 (2000). https://doi.org/10.1038/sj.onc.1203406

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203406

Keywords

This article is cited by

Search

Advanced search

Quick links