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 Manuscript
  • Published:

Signal Transduction

Signal transduction and cellular functions of the TEL/ARG oncoprotein

Leukemia volume 19, pages 603–610 (2005)Cite this article

Abstract

The TEL/ARG oncogene is formed by t(1;12)(q25;p13) reciprocal translocation and is associated with human leukemia. We have previously demonstrated that the expression of TEL/ARG in Ba/F3 cells results in prolonged viability and hyper-responsiveness to IL-3. To determine the molecular mechanisms, a series of mutants of TEL/ARG were generated, and each cDNA was expressed in Ba/F3 or CHO cells. The PNT domain in TEL and K317 in ARG were essential for both signaling and biological effects. The SH3 domain in ARG was required for hyper-responsiveness to IL-3, but not for prolonged viability. The opposite was true for the SH2 domain in ARG. Mutation of Y314 in TEL, a putative GRB2-binding site, led to reduced viability, and loss of hyper-responsiveness to IL-3. All biological functions were profoundly impaired with deletion of the C-terminus in ARG, despite maintaining high levels of its kinase activity. When expressed in CHO cells, wild-type TEL/ARG induced the formation of fillopodia, in a fashion dependent on the C-terminal portion and intact kinase activity. Thus, these results suggest several critical domains within TEL/ARG necessary for function, and indicate that the signaling pathways necessary for viability, growth factor hyper-responsiveness and cytoskeletal reorganization are likely to be separate.

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
Figure 8

Similar content being viewed by others

References

  1. Kruh GD, King CR, Kraus MH, Popescu NC, Amsbaugh SC, McBride WO et al. A novel human gene closely related to the abl proto-oncogene. Science 1986; 234: 1545–1548.

    Article  CAS  PubMed  Google Scholar 

  2. Kruh GD, Perego R, Miki T, Aaronson SA . The complete coding sequence of arg defines the Abelson subfamily of cytoplasmic tyrosine kinases. Proc Natl Acad Sci USA 1990; 87: 5802–5806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Perego R, Ron D, Kruh GD . Arg encodes a widely expressed 145-kDa protein-tyrosine kinase. Oncogene 1991; 6: 1899–1902.

    CAS  PubMed  Google Scholar 

  4. Koleske AJ, Gifford AM, Scott ML, Nee M, Bronson RT, Miczek KA et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 1998; 21: 1259–1272.

    Article  CAS  PubMed  Google Scholar 

  5. Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P et al. The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13):molecular cloning of both reciprocal transcripts. Blood 1999; 94: 4370–4373.

    CAS  PubMed  Google Scholar 

  6. Iijima Y, Ito T, Oikawa T, Eguchi M, Eguchi-Ishimae M, Kamada N et al. A new ETV6/TEL partner gene ARG(ABL-related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. Blood 2000; 95: 2126–2131.

    CAS  PubMed  Google Scholar 

  7. Griesinger F, Janke A, Podleschny M, Boglander SK . Identification of an ETV6-ABL2 fusion transcript in combination with an ETV6 point mutation in a T-cell acute lymphoblastic leukaemia cell line. Br J Haematol 2002; 119: 454–458.

    Article  CAS  PubMed  Google Scholar 

  8. Iijima Y, Okuda K, Tojo A, Tri NK, Setoyama M, Sakaki Y et al. Transformation of Ba/F3 cells and Rat-1 cells by ETV6/ARG. Oncogene 2002; 21: 4374–4383.

    Article  CAS  PubMed  Google Scholar 

  9. Okuda K, Weisberg E, Gilliland DG, Griffin JD . ARG tyrosine kinase activity is inhibited by STI571. Blood 2001; 15: 2440–2448.

    Article  Google Scholar 

  10. Van Etten RA, Jackson P, Baltimore D . The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization. Cell 1989; 58: 669–678.

    Article  CAS  PubMed  Google Scholar 

  11. Ren R, Ye Z-S, Baltimore D . Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes Dev 1994; 8: 783–795.

    Article  CAS  PubMed  Google Scholar 

  12. Kipreos ET, Wang JY . Cell cycle-regulated binding of c-Abl tyrosine kinase to DNA. Science 1992; 256: 382–385.

    Article  CAS  PubMed  Google Scholar 

  13. Van Eten R, Jackson P, Baltimore D, Sanders MC, Matsudaira PT, Janmey PA . The COOH terminus of the c-Abl tyrosine kinase conteins distinct F- and G-actin binding domains with bundling activity. J Cell Biol 1994; 124: 325–340.

    Article  Google Scholar 

  14. Wang Y, Miller AL, Mooseker MS, Koleske AJ . The Abl-related gene (Arg) nonreceptor tyrosine kinase uses two F-actin-binding domains to bundle F-actin. Proc Natl Acad Sci USA 2001; 98: 14865–14870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Miller AL, Wang Y, Mooseker MS, Koleske AJ . The Abl-related gene (Arg) requires its F-actin-microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion. J Cell Biol 2004; 165: 407–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Carroll M, Tomasson MH, Barker GF, Golub TR, Gilliland DG . The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways. Proc Natl Acad Sci USA 1996; 93: 14845–14850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Golub TR, Goga A, Barker GF, Afar DEH, McLaughlin J, Bohlander SK et al. Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol Cell Biol 1996; 16: 4107–4116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS et al. Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J 1998; 17: 5321–5333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu Q, Schwaller J, Kutok J, Cain D, Aster JC, Williams IR et al. Signal transduction and transforming properties of the TEL-TRKC fusions associated with t(12;15)(p13;q25) in congenital fibrosarcoma and acute myelogenous leukemia. EMBO J 2000; 19: 1827–1838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pendergast AM, Quillian LA, Cripe LD, Bassing CH, Dai Z, Li N et al. BCR-ABL induced oncogenesis is mediated by derect interaction with the AH2 domain of the GRB2 adaptor protien. Cell 1993; 75: 175–185.

    Article  CAS  PubMed  Google Scholar 

  21. Palacios R, Steinmetz M . IL-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell 1985; 41: 727–734.

    Article  CAS  PubMed  Google Scholar 

  22. Klucher KM, Lopez DV, Daley GQ . Secondary mutation maintains the transformed state in BaF3 cells with inducible BCR/ABL expression. Blood 1998; 91: 3927–3934.

    CAS  PubMed  Google Scholar 

  23. Okuda K, Sato Y, Sonoda Y, Griffin JD . The TEL/ARG leukemia oncogene promotes viability and hyper-responsiveness to hematopoietic growth factors. Int J Hematol 2004; 79: 138–146.

    Article  CAS  PubMed  Google Scholar 

  24. Okuda K, Golub TR, Gilliland DG, Griffin JD . P210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines. Oncogene 1996; 13: 1147–1152.

    CAS  PubMed  Google Scholar 

  25. Oda A, Wada I, Miura K, Okawa K, Kadoya T, Kato T et al. CrkL directs ASAP1 to peripheral focal adhesions. J Biol Chem 2003; 278: 6456–6460.

    Article  CAS  PubMed  Google Scholar 

  26. Bazzoni G, Carlesso N, Griffin JD, Hemler ME . Bcr/Abl expression stimulates integrin function in hematopoietic cell lines. J Clin Invest 1996; 98: 521–528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Salgia R, Li JL, Ewaniuk DS, Pear W, Pisick E, Burky SA et al. BCR/ABL induces multiple abnormalities of cytoskeletal function. J Clin Invest 1997; 100: 46–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Golub TR, Barker G, Lovett M, Gilliland DG . Fusion of platelet-derived growth factor beta to a novel ets-like gene in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77: 307–316.

    Article  CAS  PubMed  Google Scholar 

  29. Wang B, Kruh GD . Subcellular localization of the Arg protein tyrosine kinase. Oncogene 1996; 13: 193–197.

    CAS  PubMed  Google Scholar 

  30. Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D . The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 1986; 233: 212–214.

    Article  CAS  PubMed  Google Scholar 

  31. Papadopoulos P, Ridge SA, Boucher DA, Stocking C, Wiedemann LM . The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res 1995; 55: 34–38.

    CAS  PubMed  Google Scholar 

  32. Okuda K, D'Andrea A, Van Etten RA, Griffin JD . The c-terminus of c-Abl is required for proliferation and viability signaling in a c-Abl/erythropoietin receptor fusion protein. Blood 1998; 92: 3848–3856.

    CAS  PubMed  Google Scholar 

  33. Skolnik EY, Lee CH, Batzer A, Vicentini LM, Zhou M, Daly R et al. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J 1993; 12: 1929–1936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Million RP, Van Etten RA . The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase. Blood 2000; 96: 664–670.

    CAS  PubMed  Google Scholar 

  35. Sattler M, Mohi MG, Pride YB, Quinnan LR, Malouf NA, Podar K et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 2002; 1: 479–492.

    Article  CAS  PubMed  Google Scholar 

  36. Van Etten RA, Debnath J, Zhow H, Casasnovas JM . Introduction of a loss-of function point mutation from the SH3 region of the Caenorhabditis elegans sem-5 gene activates the transforming ability of c-abl in vivo and abolishes binding of proline-rich ligands in vitro. Oncogene 1995; 10: 1977–1988.

    CAS  PubMed  Google Scholar 

  37. McWhirter JR, Wang JY . An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. EMBO J 1993; 12: 1533–1546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Salgia R, Brunkhorst B, Pisick E, Li JL, Lo SH, Chen LB et al. Increased tyrosine phosphorylation of focal adhesion proteins in myeloid cell lines expressing p210BCR/ABL. Oncogene 1995; 11: 1149–1155.

    CAS  PubMed  Google Scholar 

  39. Heisterkamp N, Voncken JW, Senadheera D, Gonzalez-Gomez I, Reichert A, Haataja L et al. Reduced oncogenicity of p190Bcr/Abl F-actin-binding domain mutants. Blood 2000; 96: 2226–2232.

    CAS  PubMed  Google Scholar 

  40. Wertheim JA, Perera SA, Hammer DA, Ren R, Boettiger D, Pear WS . Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development. Blood 2003; 102: 2220–2228.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (AO, KO), the Research Fund of the Mitsubishi Pharma Research Foundation (KO), the Sagawa Foundation for Promotion of Cancer Research (KO), and the Smoking Research Foundation (AO).

Author information

Authors and Affiliations

  1. Department of Health Sciences and Preventive Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

    K Okuda & Y Sonoda

  2. Laboratory of Environmental Biology, Department of Preventive Medicine, Hokkaido University School of Medicine, Sapporo, Japan

    A Oda, A Nakayama & H Fujita

  3. Division of Molecular Cytogenetics, Department of Clinical Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan

    Y Sato

  4. Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J D Griffin

  5. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

    J D Griffin

Authors
  1. K Okuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J D Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Okuda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okuda, K., Oda, A., Sato, Y. et al. Signal transduction and cellular functions of the TEL/ARG oncoprotein. Leukemia 19, 603–610 (2005). https://doi.org/10.1038/sj.leu.2403668

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403668

Keywords

This article is cited by

Search

Advanced search

Quick links