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:

Isolation and characterization of a novel, transforming allele of the c-Cbl proto-oncogene from a murine macrophage cell line

Oncogene volume 21, pages 3677–3687 (2002)Cite this article

Abstract

The c-Cbl proto-oncogene acts as an E3 ubiquitin ligase via its RING finger domain to negatively regulate activated cellular signal transduction pathways. We have identified an aberrant Cbl-protein of approximately 95 kDa, which we have called p95Cbl, from the murine reticulum sarcoma cell-line, J-774. Cloning of the p95Cbl cDNA revealed that it contains a deletion resulting in the loss of 111 amino acids, eliminating two critical tyrosine residues in the linker region as well as the entire RING finger domain. p95Cbl displays a propensity for its interaction with the Src-family kinase Hck over cellular Cbl expressed in the same cells. Like its wildtype counterpart, p95Cbl is inducibly tyrosine phosphorylated in response to Fcγ receptor engagement on hematopoietic cells, however this phosphorylation is sustained beyond that of cellular Cbl. NIH3T3 fibroblasts stably expressing p95Cbl acquire the typical refractile morphology associated with cellular transformation and form colonies in a focus-formation assay. The exogenously expressed mutant protein is constitutively phosphorylated in fibroblasts and partitions into the particulate fraction of cells, while cellular Cbl is exclusively cytoplasmic. p95Cbl is a novel, oncogenic mutant of the c-Cbl proto-oncogene, which might act in a dominant negative fashion to prolong normal cellular signaling responses by interfering with the down-regulation of activated signaling complexes through c-Cbl.

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

  • Anderson SM, Burton EA, Koch BL . 1997 J. Biol. Chem. 272: 739–745

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

  • Blake TJ, Langdon WY . 1992 Oncogene 7: 757–762

  • Blake TJ, Shapiro M, Morse III HC, Langdon WY . 1991 Oncogene 6: 653–657

  • Bonita DP, Miyake S, Lupher Jr ML, Langdon WY, Band H . 1997 Mol. Cell. Biol. 17: 4597–4610

  • Brizzi MF, Rosso A, Dentelli P, Ferrero D, Lanfrancone L, Pegoraro L . 1998 Exp. Hematol. 26: 1229–1239

  • Cohn M . 1967 Cold Spring Harbor Symp. Quant. Biol. 32: 211–221

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

  • Durden DL, Kim HM, Calore B, Liu Y . 1995 J. Immunol. 154: 4039–4047

  • Feshchenko EA, Langdon WY, Tsygankov AY . 1998 J. Biol. Chem. 273: 8323–8331

  • 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

  • Hirst J, Jones G, Cohn M . 1971 J. Immunol. 107: 926–

  • Horita DA, Baldisseri DM, Zhang W, Altieri AS, Smithgall TE, Gmeiner WH, Byrd RA . 1998 J. Mol. Biol. 278: 253–265

  • Howlett CJ, Robbins SM . 2002 Oncogene 21: 1707–1716

  • Howlett CJ, Bisson SA, Resek ME, Tigley AW, Robbins SM . 1999 Biochem. Biophys. Res. Commun. 257: 129–138

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

  • Jongeward GD, Clandinin TR, Sternberg PW . 1995 Genetics 139: 1553–1566

  • Kaplan G, Morland B . 1978 Exp. Cell. Res. 115: 53–61

  • 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

  • Kuwae A, Yoshida S, Tamano K, Mimuro H, Suzuki T, Sasakawa C . 2001 J. Biol. Chem. 276: 32230–32239

  • Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse III HC . 1989a Proc. Natl. Acad. Sci. USA 86: 1168–1172

  • Langdon WY, Hyland CD, Grumont RJ, Morse III HC . 1989b J. Virol. 63: 5420–5424

  • Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M, Yarden Y . 1996 Oncogene 12: 1117–1125

  • Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechanover A, Lipkowitz S, Yarden Y . 1999 Mol. Cell. 4: 1029–1040

  • Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon WY, Beguinot L, Geiger B, Yarden Y . 1998 Genes Dev. 12: 3663–3674

  • Lill NL, Douillard P, Awwad RA, Ota S, Lupher Jr ML, Miyake S, Meissner-Lula N, Hsu VW, Band H . 2000 J. Biol. Chem. 275: 367–377

  • Liu YC, Altman A . 1998 Cell Signal 10: 377–385

  • Lupher Jr ML, Rao N, Lill NL, Andoniou CE, Miyake S, Clark EA, Druker B, Band H . 1998 J. Biol. Chem. 273: 35273–35281

  • Lupher Jr ML, Reedquist KA, Miyake S, Langdon WY, Band H . 1996 J. Biol. Chem. 271: 24063–24068

  • Marcilla A, Rivero-Lezcano OM, Agarwal A, Robbins KC . 1995 J. Biol. Chem. 270: 9115–9120

  • Meisner H, Daga A, Buxton J, Fernandez B, Chawla A, Banerjee U, Czech MP . 1997 Mol. Cell. Biol. 17: 2217–2225

  • Meng F, Lowell CA . 1998 EMBO J. 17: 4391–4403

  • Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ . 1999 Nature 398: 84–90

  • Miyake S, Mullane-Robinson KP, Lill NL, Douillard P, Band H . 1999 J. Biol. Chem. 274: 16619–16628

  • Morgenstern JP, Land H . 1990 Nucleic Acids Res. 18: 3587–3596

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

  • Odai H, Sasaki K, Iwamatsu A, Hanazono Y, Tanaka T, Mitani K, Yazaki Y, Hirai H . 1995 J. Biol. Chem. 270: 10800–10805

  • Ojaniemi M, Langdon WY, Vuori K . 1998 Oncogene 16: 3159–3167

  • Paige CJ, Kincade PW, Ralph P . 1978 J. Immunol. 121: 641–647

  • Panchamoorthy G, Fukazawa T, Miyake S, Soltoff S, Reedquist K, Druker B, Shoelson S, Cantley L, Band H . 1996 J. Biol. Chem. 271: 3187–3194

  • Ralph P, Nakoinz I . 1975 Nature 257: 393–394

  • Ralph P, Prichard J, Cohn M . 1975 J. Immunol. 114: 898–905

  • Rivero-Lezcano OM, Sameshima JH, Marcilla A, Robbins KC . 1994 J. Biol. Chem. 269: 17363–17366

  • Robbins SM, Quintrell NA, Bishop JM . 1995 Mol. Cell. Biol. 15: 3507–3515

  • Sanjay A, Houghton A, Neff L, DiDomenico E, Bardelay C, Antoine E, Levy J, Gailit J, Bowtell D, Horne WC, Baron R . 2001 J. Cell. Biol. 152: 181–195

  • Sato N, Kim MK, Schreiber AD . 1999 J. Immunol. 163: 6123–6131

  • Savage PD, Shapiro M, Langdon WY, Geurts van Kessel AD, Seuanez HN, Akao Y, Croce C, Morse III HC, Kersey JH . 1991 Cytogenet. Cell Genet. 56: 112–115

  • Scaife RM, Langdon WY . 2000 J. Cell. Sci. 113: 215–226

  • Scholt G, Cartledge K, Dunn AR . 2000 J. Biol. Chem. 273: 14615–14623

  • Sicheri F, Moarefi I, Kuriyan J . 1997 Nature 385: 602–609

  • Suzuki T, Kono H, Hirose N, Okada M, Yamamoto T, Yamamoto K, Honda Z . 2000 J. Immunol. 165: 473–482

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

  • Thien CB, Langdon WY . 2001 Nat. Rev. Mol. Cell. Biol. 2: 294–307

  • Thien CB, Walker F, Langdon WY . 2001 Mol. Cell. 7: 355–365

  • Wang AV, Scholl PR, Geha RS . 1994 J. Exp. Med. 180: 1165–1170

  • Yokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne WC, Zhang H, Yoshimura A, Baron R . 1999 J. Biol. Chem. 274: 31707–31712

  • Yoon CH, Lee J, Jongeward GD, Sternberg PW . 1995 Science 269: 1102–1105

  • Zell T, Warden CS, Chan AS, Cook ME, Dell CL, Hunt III SW, Shimizu Y . 1998 Curr. Biol. 8: 814–822

Download references

Acknowledgements

We would like to thank the members of the laboratory for their constructive comments and discussions during the course of this work. This work was supported by grants from the Canadian Institutes of Health Research and the Cancer Research Society of Canada. SA Bisson is supported by an Alberta Heritage Foundation for Medical Research (AHFMR) Studentship and an Honorary Izaak Walton Killam Scholarship (University of Calgary). SM Robbins is a Senior Scholar of the AHFMR and holds a Canada Research Chair in Cancer Biology.

Author information

Authors and Affiliations

  1. Department of Oncology, The University of Calgary, 3330 Hospital Drive NW, Calgary, T2N-4N1, Alberta, Canada

    Sabine A Bisson, Eva E Ujack & Stephen M Robbins

  2. Department of Biochemistry and Molecular Biology, The University of Calgary, 3330 Hospital Drive NW, Calgary, T2N-4N1, Alberta, Canada

    Sabine A Bisson & Stephen M Robbins

Authors
  1. Sabine A Bisson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva E Ujack
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen M Robbins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen M Robbins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bisson, S., Ujack, E. & Robbins, S. Isolation and characterization of a novel, transforming allele of the c-Cbl proto-oncogene from a murine macrophage cell line. Oncogene 21, 3677–3687 (2002). https://doi.org/10.1038/sj.onc.1205510

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205510

Keywords

This article is cited by

Search

Advanced search

Quick links