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:

Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells

Oncogene volume 21, pages 1423–1433 (2002)Cite this article

Abstract

CBL and the related CBL-B protein are two members of a family of RING finger type ubiquitin E3 ligases that are believed to function as negative regulators of signal transduction in hematopoietic and immune cells. In mice, expression of v-Cbl causes lymphomas, and targeted disruption of either the CBL gene or the CBL-B gene can result in a lymphoproliferative disorder or hypersensitivity of lymphocytes. CBL is one of the most prominent targets of the BCR/ABL tyrosine kinase oncogene. We compared the role of CBL and CBL-B in signal transduction of BCR/ABL using pairs of cell lines before and after expression of BCR/ABL. In contrast to CBL, BCR/ABL was found to rapidly downregulate the expression of CBL-B protein. The decrease in CBL-B protein induced by BCR/ABL was associated with downregulation of CBL-B mRNA. Downregulation and tyrosine phosphorylation of CBL-B required BCR/ABL kinase activity. However, despite their known similarities in structure and function, we found CBL and CBL-B proteins to be involved in distinct signaling complexes. CBL was predominantly in a complex with phosphatidylinositol 3′-kinase and CRKL, while CBL-B was not associated with any significant phosphatidylinositol 3′-kinase activity. A major CBL-B associated protein was identified as mono-ubiquitinated Vav, a nucleotide exchange factor for Rac1. These results demonstrate that BCR/ABL signals differentially through CBL and CBL-B, with downregulation of the CBL-B protein potentially contributing to BCR/ABL-mediated transformation.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  • Afar DE, Goga A, McLaughlin J, Witte ON, Sawyers CL . 1994 Science 264: 424–426

  • Andoniou CE, Thien CB, Langdon WY . 1994 EMBO J 13: 4515–4523

  • Andoniou CE, Thien CB, Langdon WY . 1996 Oncogene 12: 1981–1989

  • Bartkiewicz M, Houghton A, Baron R . 1999 J. Biol. Chem. 274: 30887–30895

  • Bustelo XR, Crespo P, Lopezbarahona M, Gutkind JS, Barbacid M . 1997 Oncogene 15: 2511–2520

  • Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H . 2000 Nature 403: 216–220

  • Datta SR, Dudek H, Tao X, Masters S, Fu HA, Gotoh Y, Greenberg ME . 1997 Cell 91: 231–241

  • Delpeso L, Gonzalezgarcia M, Page C, Herrera R, Nunez G . 1997 Science 278: 687–689

  • Donovan JA, Wange RL, Langdon WY, Samelson LE . 1994 J. Biol. Chem. 269: 22921–22924

  • Ettenberg SA, Keane MM, Nau MM, Frankel M, Wang LM, Pierce JH, Lipkowitz S . 1999a Oncogene 18: 1855–1866

  • Ettenberg SA, Magnifico A, Cuello M, Nau MM, Rubinstein YR, Yarden Y, Weissman AM, Lipkowitz S . 2001 J. Biol. Chem. 276: 27677–27684

  • Ettenberg SA, Rubinstein YR, Banerjee P, Nau MM, Keane MM, Lipkowitz S . 1999b Mol. Cell. Biol. Res. Commun. 2: 111–118

  • Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC . 2001 J. Biol. Chem. 276: 4872–4878

  • Fredrickson TN, Langdon WY, Hoffman PM, Hartley JW, Morse HD . 1984 J. Natl. Cancer Inst. 72: 447–454

  • Fukazawa T, Reedquist KA, Trub T, Soltoff S, Panchamoorthy G, Druker B, Cantley L, Shoelson SE, Band H . 1995 J. Biol. Chem. 270: 19141–19150

  • Gordon MY, Dowding CR, Riley GP, Goldman JM, Greaves MF . 1987 Nature 328: 342–344

  • Hamilton E, Miller KM, Helm KM, Langdon WY, Anderson SM . 2001 J. Biol. Chem. 276: 9028–9037

  • Hicke L . 2001 Nat. Rev. Mol. Cell. Biol. 2: 195–201

  • Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W . 2000 Nature 407: 390–395

  • Hunter S, Burton EA, Wu SC, Anderson SM . 1999 J. Biol. Chem. 274: 2097–2106

  • Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC . 1999 Science 286: 309–312

  • Keane MM, Ettenberg SA, Nau MM, Banerjee P, Cuello M, Penninger J, Lipkowitz S . 1999 Oncogene 18: 3365–3375

  • Keane MM, Rivero-Lezcano OM, Mitchell JA, Robbins KC, Lipkowitz S . 1995 Oncogene 10: 2367–2377

  • Krawczyk C, Bachmaier K, Sasaki T, Jones GR, Snapper BS, Bouchard D, Kozieradzki I, Ohashi SP, Alt WF, Penninger MJ . 2000 Immunity 13: 463–473

  • Murphy MA, Schnall RG, Venter DJ, Barnett L, Bertoncello I, Thien CB, Langdon WY, Bowtell DD . 1998 Mol. Cell. Biol. 18: 4872–4882

  • Mushinski JF, Goodnight J, Rudikoff E, Morse HR, Langdon WY . 1994 Oncogene 9: 2489–2497

  • Naramura M, Kole HK, Hu RJ, Gu H . 1998 Proc. Natl. Acad. Sci. USA 95: 15547–15552

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

  • Prasad KV, Janssen O, Kapeller R, Raab M, Cantley LC, Rudd CE . 1993a Proc. Natl. Acad. Sci. USA 90: 7366–7370

  • Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE . 1993b Mol. Cell. Biol. 13: 7708–7717

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

  • Rickles RJ, Botfield MC, Weng Z, Taylor JA, Green OM, Brugge JS, Zoller MJ . 1994 EMBO J. 13: 5598–5604

  • Salgia R, Li JL, Ewaniuk DS, Pear W, Pisick E, Burky SA, Ernst T, Sattler M, Chen LB, Griffin JD . 1997 J. Clin. Invest. 100: 46–57

  • Sattler M, Griffin JD . 2001 Intl. J. Hematol. 73: 278–291

  • Sattler M, Salgia R . 1997 Cytokine Growth Factor Rev. 8: 63–79

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

  • Sattler M, Verma S, Byrne CH, Shrikhande G, Winkler T, Algate PA, Rohrschneider LR, Griffin JD . 1999a Mol. Cell. Biol. 19: 7473–7480

  • Sattler M, Verma S, Pride YB, Salgia R, Rohrschneider LR, Griffin JD . 2001 J. Biol. Chem. 276: 2451–2458

  • Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T, Greenfield EA, Salgia R, Griffin JD . 2000 J. Biol. Chem. 275: 24273–24278

  • Sattler M, Winkler T, Verma S, Byrne CH, Shrikhande G, Salgia R, Griffin JD . 1999b Blood 93: 2928–2935

  • Senechal K, Halpern J, Sawyers CL . 1996 J. Biol. Chem. 271: 23255–23261

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

  • Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B . 1995 Blood 86: 726–736

  • Skorski T, Wlodarski P, Daheron L, Salomoni P, Nieborowska-Skorska M, Majewski M, Wasik M, Calabretta B . 1998 Proc. Natl. Acad. Sci. USA 95: 11858–11862

  • Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD . 1999 Nature 401: 79–82

  • Tanaka S, Neff L, Baron R, Levy JB . 1995 J. Biol. Chem. 270: 14347–14351

  • Tezuka T, Umemori H, Fusaki N, Yagi T, Takata M, Kurosaki T, Yamamoto T . 1996 J. Exp. Med. 183: 675–680

  • Uemura N, Salgia R, Li JL, Pisick E, Sattler M, Griffin JD . 1997 Leukemia 11: 376–385

  • Verfaillie CM, McCarthy JB, McGlave PB . 1992 J. Clin. Invest. 90: 1232–1241

Download references

Acknowledgements

This work was supported by the Leukemia Research Foundation (M Sattler), and National Institute of Health grants CA78348 (R Salgia) and DK50654 (JD Griffin).

Author information

Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, MA, USA

    Martin Sattler, Yuri B Pride, Laura R Quinnan, Shalini Verma, Nicole A Malouf, Hervé Husson, Ravi Salgia & James D Griffin

  2. Genetics Department, Medicine Branch, National Cancer Institute, National Naval Medical Center, Bethesda, 20889, Maryland, MD, USA

    Stanley Lipkowitz

Authors
  1. Martin Sattler
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Yuri B Pride
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Laura R Quinnan
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Shalini Verma
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Nicole A Malouf
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Hervé Husson
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Ravi Salgia
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Stanley Lipkowitz
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. James D Griffin
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Martin Sattler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sattler, M., Pride, Y., Quinnan, L. et al. Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells. Oncogene 21, 1423–1433 (2002). https://doi.org/10.1038/sj.onc.1205202

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205202

Keywords

Search

Advanced search

Quick links