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The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways

Oncogene volume 19, pages 1684–1690 (2000)Cite this article

Abstract

Inappropriate activation of Abl family kinases plays a crucial role in different human leukaemias. In addition to the well known oncoproteins p190Bcr-Abl and p210Bcr-Abl, Tel-Abl, a novel fusion protein resulting from a different chromosomal translocation, has recently been described. In this study, the kinase specificities of the Bcr-Abl and Tel-Abl proteins were compared to the physiological Abl family kinases c-Abl and Arg (abl related gene). Using short peptides which correspond to the target epitopes in known substrate proteins of Abl family kinases, we found a higher catalytic promiscuity of Bcr-Abl and Tel-Abl. Similar to Bcr-Abl, Tel-Abl was found in complexes with the adapter protein CRKL. In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells. GTPase analysis with a RasGTP-specific precipitation assay showed constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl proteins. The mitogenic MAPK/Erk kinases as well as Akt/PKB, a kinase implicated to negatively regulate apoptosis, were also constitutively activated by both Bcr-Abl and Tel-Abl. The results indicate that the leukaemic Abl-fusion proteins have catalytic specificities different from the normal kinases c-Abl and Arg and that Tel-Abl is capable to activate at least some pathways which are also upregulated by Bcr-Abl.

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References

  • Ahmed M, Dusanter-Fourt I, Bernard M, Mayeux P, Hawley RG, Bennardo T, Novault S, Bonnet ML, Gisselbrecht S, Varet B and Turhan AG . 1998 Oncogene 16: 489–496

  • Anafi M, Gazit A, Gilon C, Ben-Neriah Y and Levitzki A . 1992 J Biol Chem 267: 4518–4523

  • Baskaran R, Dahmus ME and Wang JY . 1993 Proc Natl Acad Sci USA 90: 11167–11171

  • Baskaran R, Wood LD, Whitaker LL, Canman CE, Morgan SE, Xu Y, Barlow C, Baltimore D, Wynshaw-Boris A, Kastan MB and Wang JY . 1997 Nature 387: 516–519

  • Daley GQ, Van Etten RA and Baltimore D . 1990 Science 247: 824–830

  • de Jong R, ten Hoeve J, Heisterkamp N and Groffen J . 1997 Oncogene 14: 507–513

  • Elefanty AG, Hariharan IK and Cory S . 1990 EMBO J 9: 1069–1078

  • Feller SM, Knudsen B and Hanafusa H . 1994 EMBO J 13: 2341–2351

  • Feller SM, Knudsen B and Hanafusa H . 1995 Oncogene 10: 1465–1473

  • Feller SM, Posern G, Voss J, Kardinal C, Sakkab D, Zheng J and Knudsen BS . 1998 J Cell Physiol 177: 535–552

  • Golub TR, Goga A, Barker GF, Afar DE, McLaughlin J, Bohlander SK, Rowley JD, Witte ON and Gilliland DG . 1996 Mol Cell Biol 16: 4107–4116

  • Hannemann JR, McManus DM, Kabarowski JH and Wiedemann LM . 1998 Br J Haematol 102: 475–485

  • Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK and Groffen J . 1990 Nature 344: 251–253

  • Heisterkamp N, Stam K, Groffen J, de Klein A and Grosveld G . 1985 Nature 315: 758–761

  • Ilaria RL Jr and Van Etten RA . 1996 J Biol Chem 271: 31704–31710

  • Knudsen BS, Feller SM and Hanafusa H . 1994 J Biol Chem 269: 32781–32787

  • Kolibaba KS and Druker BJ . 1997 Biochim Biophys Acta 1333: F217–F248

  • Kruh GD, King CR, Kraus MH, Popescu NC, Amsbaugh SC, McBride WO and Aaronson SA . 1986 Science 234: 1545–1548

  • Kruh GD, Perego R, Miki T and Aaronson SA . 1990 Proc Natl Acad Sci USA 87: 5802–5806

  • Mayer BJ, Hirai H and Sakai R . 1995 Curr Biol 5: 296–305

  • McLaughlin J, Chianese E and Witte ON . 1989 Mol Cell Biol 9: 1866–1874

  • McWhirter JR, Galasso DL and Wang JY . 1993 Mol Cell Biol 13: 7587–7595

  • Nichols GL, Raines MA, Vera JC, Lacomis L, Tempst P and Golde DW . 1994 Blood 84: 2912–2918

  • Nilsson T, Andreasson P, Hoglund M, Fioretos T, Billstrom R, Garwicz S, Mitelman F and Johansson B . 1998 Leukemia 12: 1167–1168

  • Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD and Druker BJ . 1994 J Biol Chem 269: 22925–22928

  • Oehrl W, Kardinal C, Ruf S, Adermann K, Groffen J, Feng GS, Blenis J, Tan TH and Feller SM . 1998 Oncogene 17: 1893–1901

  • Okuda K, Golub TR, Gilliland DG and Griffin JD . 1996 Oncogene 13: 1147–1152

  • Papadopoulos P, Ridge SA, Boucher CA, Stocking C and Wiedemann LM . 1995 Cancer Res 55: 34–38

  • Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J and Gishizky ML . 1993 Cell 75: 175–185

  • Poirel H, Oury C, Carron C, Duprez E, Laabi Y, Tsapis A, Romana SP, Mauchauffe M, Le Coniat M, Berger R, Ghysdael J and Bernard OA . 1997 Oncogene 14: 349–357

  • Posern G, Weber CK, Rapp UR and Feller SM . 1998 J Biol Chem 273: 24297–24300

  • Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R and Pawson T . 1994 EMBO J 13: 764–773

  • Raitano AB, Halpern JR, Hambuch TM and Sawyers CL . 1995 Proc Natl Acad Sci USA 92: 11746–11750

  • Raitano AB, Whang YE and Sawyers CL . 1997 Biochim Biophys Acta 1333: F201–F216

  • Ren R, Ye ZS and Baltimore D . 1994 Genes Dev 8: 783–795

  • Salgia R, Pisick E, Sattler M, Li JL, Uemura N, Wong WK, Burky SA, Hirai H, Chen LB and Griffin JD . 1996 J Biol Chem 271: 25198–25203

  • Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E, Xu G, Li JL, Prasad KV and Griffin JD . 1996 Oncogene 12: 839–846

  • Sawyers CL . 1999 N Engl J Med 340: 1330–1340

  • Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN and Calabretta B . 1997 EMBO J 16: 6151–6161

  • Songyang Z, Carraway III KL, Eck JM, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, Mayer B and Cantley LC . 1995 Nature 373: 536–539

  • Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG, Birge RB, Fajardo JE, Chou MM, Hanafusa H, Schaffhausen B and Chantley LC . 1993 Cell 72: 767–778

  • Tauchi T, Okabe S, Miyazawa K and Ohyashiki K . 1998 Int J Oncol 12: 1269–1276

  • Taylor SJ and Shalloway D . 1996 Curr Biol 6: 1621–1627

  • ten Hoeve J, Arlinghaus RB, Guo JQ, Heisterkamp N and Groffen J . 1994 Blood 84: 1731–1736

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Acknowledgements

We thank Rajasekaran Baskaran and Jean Wang for supplying the 8E9 antibody, the NIH3T3 Bcr-Abl cells and the Abl−/− fibroblasts, Tomoyuki Shishido and Saburo Hanafusa for the Arg antiserum and Ulf Rapp (MSZ, Würzburg) for encouragement and support. J Voss is indebted to the members of his thesis committee for helpful comments and support. The grant support of S Feller, G Posern and C Kardinal by the Deutsche Forschungsgemeinschaft and the Wilhelm-Sander-Stiftung is gratefully acknowledged.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Versbacher Straße 5, Würzburg, D-97078, Germany

    Jan Voss, Guido Posern, Christian Kardinal & Stephan M Feller

  2. CellTec GmbH, Strathmann AG, Hamburg, 22459, Germany

    Jürgen R Hannemann

  3. Leukemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, London, UK

    Leanne M Wiedemann

  4. Institut Gustav-Roussy, INSERM U362, Villejuif, 94805, France

    Ali G Turhan

  5. U434 INSERM, CEPH, Paris, 75010, France

    Hélène Poirel & Olivier A Bernard

  6. Niedersächsisches Institut für Peptidforschung (IPF), Hannover, 30625, Germany

    Knut Adermann

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  1. Jan Voss
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Voss, J., Posern, G., Hannemann, J. et al. The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways. Oncogene 19, 1684–1690 (2000). https://doi.org/10.1038/sj.onc.1203467

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