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.

  • Review
  • Published:

Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia

Oncogene volume 21, pages 8560–8567 (2002)Cite this article

Abstract

The fusion of 5′ parts of the BCR gene to the ABL gene at the second exon yields several forms of an oncogenic Bcr-Abl oncoprotein observed in several types of Philadelphia chromosome positive leukemia patients. The first exon of the BCR gene is a critical part of this fusion, as the coiled-coil domain at the amino terminal domain of the Bcr protein causes oligomerization of the Bcr-Abl oncoprotein forming tetramers, thereby activating the tyrosine kinase activity of the normally silent c-Abl protein. Another consequence of this Bcr-Abl fusion is the extensive autophosphorylation of the cis Bcr protein sequences on tyrosine residues. This review will summarize the effects of Bcr-Abl autophosphorylation on tyrosines as they relate to the oncogenic activity of Bcr-Abl, and as a means to inactivate the serine/threonine kinase activity of the Bcr protein. The review also discusses our findings that show that phosphoserine Bcr by means of a unique structure, binds to the Abl SH2 domain of the Bcr-Abl oncoprotein, and as a result this SH2 binding inhibits the oncogenic effects of the oncoprotein. Our results indicate that one effect of this binding is inhibition of the Bcr-Abl tyrosine kinase. Serine 354 of Bcr plays a major role in this inhibition. In the case of Bcr(64-413), serine 354 is required for the formation of the unique Bcr structure that binds to the Abl SH2 domain.

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

Similar content being viewed by others

References

  • Abe J-I, Che W, Yoshizumi M, Huang Q, Glassman M, Ohta S, Wu Y, Arlinghaus R, Berk BC . 2001 Circulation 104: 1399–1406

  • Annamalai AE, Colman Jr RF . 1981 J. Biol. Chem. 256: 10276–10283

  • Arlinghaus RB . 1998 J. Crit. Rev. Oncogen. 9: 1–18

  • Campbell M, Li W, Arlinghaus RB . 1990 Oncogene 5: 773–776

  • Cleghon V, Morrison Jr DK . 1994 J. Biol. Chem. 269: 17749–17755

  • Hawk N, Liu J, Sun T, Wang Y, Wu Y, Arlinghaus RB . 2002 Cancer Res. 62: 386–390

  • He Y, Wetheim JA, Xu L, Miller JP, Karnell FG, Choi JK, Ren R, Pear WS . 2002 Blood 99: 2957–2968

  • Kloetzer W, Kurzrock R, Smith L, Talpaz M, Spiller M, Gutterman J, Arlinghaus RB . 1985 Virology 140: 230–238

  • Konopka JB, Watanabe SM, Witte ON . 1984 Cell 37: 1035–1042

  • Kurzrock R, Shtalrid M, Romero P, Kloetzer WS, Talpaz M, Trujillo JM, Blick M, Beran M, Gutterman JU . 1987 Nature 325: 631–635

  • Li W, Draezen O, Kloetzer WS, Gale RP, Arlinghaus RB . 1989 Oncogene 4: 127–138

  • Lin F, Liu J, Monaco G, Sun T, Liu J, Lin H, Stephens C, Belmont J, Arlinghaus RB . 2001 Oncogene 20: 1873–1881

  • Liu J, Campbell M, Guo JQ, Lu D, Xian YM, Arlinghaus RB . 1993 Oncogene 8: 101–109

  • Liu J, Wu Y, Arlinghaus RB . 1996a Cancer Res. 56: 5120–5124

  • Liu J, Wu Y, Lu D, Haataja L, Heisterkamp N, Groffen J, Arlinghaus RB . 1996b Mol. Cell Biol. 16: 998–1005

  • Lu D, Liu J, Campbell M, Guo JQ, Heisterkamp N, Groffen J, Canaani E, Arlinghaus RB . 1993 Blood 82: 1257–1263

  • Maru Y, Witte ON . 1991 Cell 67: 459–468

  • Mayer BJ, Jackson PK, Van Etten RA, Baltimore D . 1992 Mol. Cell Biol. 12: 609–618

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

  • McWhirter JR, Wang JYJ . 1997 Oncogene 15: 1625–1634

  • Muller AJ, Pendergast M, Havlik H, Puil L, Pawson T, Witte ON . 1992 Mol. Cell Biol. 12: 5087–5093

  • Park I, Chung J, Walsh CT, Yun Y, Strominger JL, Shin J . 1995 Proc. Natl. Acad. Sci. USA, 92: 12338–12342

  • Pendergast AM, Muller AJ, Havlik MH, Maru Y, Witte ON . 1991 Cell 66: 161–171

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

  • Pluk H, Dorey K, Superti-Furga G . 2002 Cell 108: 247–259

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

  • Sun T, Campbell M, Gordon W, Arlinghaus RB . 2001 Biopolymers (Peptide Science) 60: 61–75

  • Tomich JM, Marti C, Colman RF . 1981 Biochemistry, 20: 6711–6720

  • Wang Y, Liu J, Wu Y, Luo W, Lin S-H, Lin H, Hawk N, Sun T, Guo JQ, Estrov Z, Talpaz M, Champlin R, Arlinghaus RB . 2001 Cancer Res. 61: 138–144

  • Wu Y, Ma G, Lu D, Lin F, Xu H-J, Liu J, Arlinghaus RB . 1999 Oncogene 18: 4416–4424

  • Wu Y, Liu J, Arlinghaus RB . 1998 Oncogene 16: 141–146

  • Zhang X, Subrahmanyan R, Wong R, Gross AW, Ren R . 2001 Mol. Cell Biol. 21: 840–853

Download references

Acknowledgements

This research was supported by grants CA49639 and CA16672 from NCI. I thank Tong Sun and Shanhai Xie. for helpful comments, and Alice Powell for assistance in manuscript preparation.

Author information

Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Ralph B Arlinghaus

Authors
  1. Ralph B Arlinghaus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ralph B Arlinghaus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arlinghaus, R. Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia. Oncogene 21, 8560–8567 (2002). https://doi.org/10.1038/sj.onc.1206083

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206083

Keywords

This article is cited by

Search

Advanced search

Quick links