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Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation

Oncogene volume 21, pages 1707–1716 (2002)Cite this article

Abstract

The mammalian proto-oncogene Cbl and its cellular homologues in Caenorhabditis elegans (Sli-1) and Drosophila (D-Cbl) are negative regulators of some growth factor receptor signaling pathways. Herein we show that Cbl can negatively regulate another signaling molecule, namely theSrc-family kinase Hck by targeting it for degradation. Hck-mediated cellular transformation of murine fibroblasts is reverted by ectopic expression of a membrane-anchored allele of Cbl as assessed by the cellular morphology, suppression of anchorage independent growth, and an overall reduction in the total tyrosine phosphorylation levels within the cells. The expression of Cbl at the plasma membrane targets both Hck and itself for ubiquitination and degradation, requiring an intact RING finger. Pharmacological inhibition of the proteasome prevents the degradation of Hck correlating with an increase in the phosphotyrosine levels within the cells. Activated Hck and membrane-anchored Cbl are present in similar subcellular localizations and co-immunoprecipitate, suggesting that their interaction is required for subsequent ubiquitination and degradation. Interestingly, both constitutively active and kinase-inactive Hck interact with and are targeted for degradation by Cbl. This work illustrates alternate means to regulate Src-family kinases, and suggests that Cbl may be able to suppress many signaling pathways that are activated in various proliferative syndromes including cancer.

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References

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

  • Andoniou CE, Lill NL, Thien CB, Lupher ML, Ota S, Bowtell DDL, Scaife RM, Langdon WY, Band H . 2000 Mol. Cell. Biol. 20: 851–867

  • Brown MT, Cooper JA . 1996 Biochem. Biophys. Acta 1287: 121–149

  • Feshchenko EA, Shore SK, Tsygankov AY . 1999 Oncogene 18: 3703–3715

  • Hakak Y, Martin GS . 1999 Curr. Biol. 9: 1039–1042

  • Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA, Connelly PA . 1996 J. Biol. Chem. 271: 695–701

  • Harris KF, Shoji I, Cooper EM, Kumar S, Oda H, Howley PM . 1999 Proc. Natl. Acad. Sci. USA 96: 13738–13743

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

  • Joazeiro CA, Hunter T . 2000 Science 289: 2061–2062

  • Joazeiro CA, Weissman AM . 2000 Cell 102: 549–552

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

  • Johnson TM, Williamson NA, Scholz G, Jaworowski A, Wettenhall RE, Dunn AR, Cheng HC . 2000 J. Biol. Chem. 275: 33353–33364

  • Law DA, Gold MR, DeFranco AL . 1992 Mol. Immunol. 29: 917–926

  • Lee DH, Goldberg AL . 1998 Trends Cell Biol. 8: 397–403

  • Lee PSW, Wang Y, Dominquez MG, Yeung YG, Murphy MA, Bowtell DDL, Stanley ER . 1999 EMBO J. 18: 3616–3628

  • Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Chiechanover 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

  • Lichtenberg U, Quintrell N, Bishop JM . 1992 Oncogene. 7: 849–858

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

  • Lock P, Ralph S, Stanley E, Boulet I, Ramsay R, Dunn AR . 1991 Mol. Cell. Biol. 11: 4363–4370

  • McCabe JB, Berthiaume LG . 1999 Mol. Biol. Cell 10: 3771–3786

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

  • Miyake S, Lupher MLJ, Druker B, Band H . 1998 Proc. Natl. Acad. Sci. USA 95: 7927–7932

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

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

  • Oda H, Kumar S, Howley PM . 1999 Proc. Natl. Acad. Sci. USA 96: 9557–9562

  • Okamura-Oho Y, Zhang S, Callahan JW, Murata M, Oshima A, Suzuki Y . 1997 FEBS Lett. 419: 231–234

  • Ota Y, Samelson LE . 1997 Science 276: 418–420

  • Pawson T . 1997 Nature 385: 582–585

  • Quintrell N, Lebo R, Varmus H, Bishop JM, Pettenati MJ, LeBeau MM, Diaz MO, Rowley JD . 1987 Mol. Cell. Biol. 7: 2267–2275

  • Rivett AJ . 1998 Curr. Opinion Immunol. 10: 110–114

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

  • Scholz G, Cartledge K, Dunn AR . 2000 J. Biol. Chem. 275: 14615–14623

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

  • Wang Y, Yeung Y, Langdon WY, Stanley ER . 1996 J. Biol. Chem. 271: 17–20

  • Wang Y, Yeung Y, Stanley ER . 1999 J. Cell. Biochem. 72: 119–134

  • Wedegaertner PB, Wilson PT, Bourne HR . 1995 J. Biol. Chem. 270: 503–506

  • Xu W, Harrison SC, Eck MJ . 1997 Nature 385: 595–602

  • 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

  • Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y . 1991 J. Biol. Chem. 266: 17707–17712

  • Ziegler SF, Marth JD, Lewis DB, Perlmutter RM . 1987 Mol. Cell Biol. 7: 2276–2285

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Acknowledgements

We would like to thank the members of the lab for their constructive comments and discussions during the course of this work. We would also like to thank W Langdon, T Hunter and HC Cheng for valuable reagents used in this study. This work was supported by grants from the Canadian Institutes of Health Research and the Cancer Research Society (CRS) of Canada to SM Robbins. CJ Howlett is supported by an Alberta Heritage for Medical Research (AHFMR) Studentship and SM Robbins is a senior scholar of the AHFMR and holds a Canada Research Chair in Cancer Biology.

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

    Christopher J Howlett & Stephen M Robbins

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

    Christopher J Howlett & Stephen M Robbins

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Correspondence to Stephen M Robbins.

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Howlett, C., Robbins, S. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Oncogene 21, 1707–1716 (2002). https://doi.org/10.1038/sj.onc.1205228

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