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.

  • Spotlight
  • Published:

Spotlight on IMATINIB as a Model for Signal Transduction Inhibitors

The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains

Leukemia volume 17, pages 283–289 (2003)Cite this article

Abstract

Bcr-Abl is found in more than 95% of cases with CML. The mechanism of Bcr-Abl-induced transformation is not fully understood. Bcr-Abl is a constitutively active tyrosine kinase with transforming capacity for hematopoietic cells. We demonstrated recently that the Src kinase Hck interacts directly with Bcr-Abl by a kinase-independent mechanism. Moreover, the inhibition of the Hck kinase seems to block some of the transforming effects of Bcr-Abl. To identify the binding domains mediating this interaction of Hck with Bcr-Abl, we co-expressed different plasmid and baculovirus vectors containing mutants or single domains of Bcr-Abl and/or Hck in COS7 and Sf9 cells. At least four independent binding regions for Hck were identified in Bcr-Abl, one in Bcr, one in the region comprising the SH3 and SH2 domain of Abl, one in the SH1 domain of Abl, and one in the C-terminal domain of Abl. In the Hck kinase, deletion of the SH2 and/or the SH3 region abolished binding to Bcr-Abl. In contrast, deletion of the Hck SH1 domain enhanced binding of Hck to Abl and Bcr-Abl. In conclusion, the results indicate that the interaction of Bcr-Abl with Hck is mediated by a novel, complex mechanism that involves multiple domains of Bcr-Abl and the SH2 and SH3 domains of Hck.

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

References

  1. 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  Google Scholar 

  2. Daley GQ, Baltimore D . Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci USA 1988; 85: 9312–9316.

    Article  CAS  Google Scholar 

  3. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

    Article  CAS  Google Scholar 

  4. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ . Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 1994; 83: 2038–2044.

    CAS  Google Scholar 

  5. Cortez D, Reuther G, Pendergast AM . The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells. Oncogene 1997; 15: 2333–2342.

    Article  CAS  Google Scholar 

  6. Konopka JB, Watanabe SM, Witte ON . An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell 1984; 37: 1035–1042.

    Article  CAS  Google Scholar 

  7. Wetzler M, Talpaz M, Van Etten RA, Hirsh-Ginsberg C, Beran M, Kurzrock R . Subcellular localization of Bcr, Abl, and Bcr-Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation. J Clin Invest 1993; 92: 1925–1939.

    Article  CAS  Google Scholar 

  8. Salgia R, Li JL, Lo SH, Brunkhorst B, Kansas GS, Sobhany ES, Sun Y, Pisick E, Hallek M, Ernst T, Tantravahi R, Bo Chen L, Griffin JD . Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL. J Biol Chem 1995; 270: 5039–5047.

    Article  CAS  Google Scholar 

  9. 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  Google Scholar 

  10. Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T . Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J 1994; 13: 764–773.

    Article  CAS  Google Scholar 

  11. Raitano AB, Halpern JR, Hambuch TM, Sawyers CL . The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc Natl Acad Sci USA 1995; 92: 11746–11750.

    Article  CAS  Google Scholar 

  12. Ilaria RL Jr, Van Etten RA . P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 1996; 271: 31704–31710.

    Article  CAS  Google Scholar 

  13. Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL . Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene 1996; 13: 247–254.

    CAS  PubMed  Google Scholar 

  14. 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, Calabretta B . Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 1997; 16: 6151–6161.

    Article  CAS  Google Scholar 

  15. Warmuth M, Bergmann M, Priess A, Hauslmann K, Emmerich B . Hallek M. The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr. J Biol Chem 1997; 272: 33260–33270.

    Article  CAS  Google Scholar 

  16. Warmuth M, Danhauser-Riedl S, Hallek M . Molecular pathogenesis of chronic myeloid leukemia: implications for new therapeutic strategies. Ann Hematol 1999; 78: 49–64.

    Article  CAS  Google Scholar 

  17. Danhauser-Riedl S, Warmuth M, Druker BJ, Emmerich B, Hallek M . Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res 1996; 56: 3589–3596.

    CAS  PubMed  Google Scholar 

  18. Abram CL, Courtneidge SA . Src family tyrosine kinases and growth factor signaling. Exp Cell Res 2000; 254: 1–13.

    Article  CAS  Google Scholar 

  19. Corey SJ, Anderson SM . Src-related protein tyrosine kinases in hematopoiesis. Blood 1999; 93: 1–14.

    CAS  PubMed  Google Scholar 

  20. Stanglmaier M, Kleinlein I, Warmuth M, Häuslmann K, Hallek M . The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by at least three binding regions in Bcr-Abl and by the SH2/SH3 domain of Hck. Blood 1998; 92: 221a.

    Google Scholar 

  21. Lionberger JM, Wilson MB, Smithgall TE . Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck. J Biol Chem 2000; 275: 18581–18585.

    Article  CAS  Google Scholar 

  22. Stanglmaier M, Winnacker EL . Cloning, sequence determination and functional expression of the genes encoding adenovirus type-4 polymerase and the terminal protein precursor. Gene 1996; 168: 177–182.

    Article  CAS  Google Scholar 

  23. Afar DE, Han L, McLaughlin J, Wong S, Dhaka A, Parmar K, Rosenberg N, Witte ON, Colicelli J . Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1. Immunity 1997; 6: 773–782.

    Article  CAS  Google Scholar 

  24. Williams JC, Wierenga RK, Saraste M . Insights into Src kinase functions: structural comparisons. Trends Biochem Sci 1998; 23: 179–184.

    Article  CAS  Google Scholar 

  25. Moarefi I, LaFevre-Bernt M, Sicheri F, Huse M, Lee CH, Kuriyan J, Miller WT . Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature 1997; 385: 650–653.

    Article  CAS  Google Scholar 

  26. Warmuth M, Forster K, Stanglmaier M, Schuster C, Hallek M . PP1, a tyrosine kinase inhibitor specific for Src-kinase familiy kinases, selectively inhibits survival of Bcr-Abl expressing myeloid cells. Blood 1999; 94: 387a.

    Google Scholar 

Download references

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Ha 1680/2–3 and 2–4 (to MH).

Author information

Author notes

  1. M Stanglmaier

    Present address: Trion Research, Frankfurter Ring 193a, 80807, München, Germany

Authors and Affiliations

  1. GSF – National Institute of Health and Environment, Klinische Kooperationsgruppe für Gentherapie, Marchioninistrasse 25, München, 81377, Germany

    M Stanglmaier, M Warmuth, I Kleinlein, S Reis & M Hallek

  2. Klinikum der Universität München, Medizinische Klinik III, München, Germany

    M Hallek

  3. Genzentrum, Universität München, München, Germany

    M Hallek

Authors
  1. M Stanglmaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Warmuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I Kleinlein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Hallek
    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

Stanglmaier, M., Warmuth, M., Kleinlein, I. et al. The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains. Leukemia 17, 283–289 (2003). https://doi.org/10.1038/sj.leu.2402778

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402778

Keywords

This article is cited by

Search

Advanced search

Quick links