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 Article
  • Published:

Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma

Oncogene volume 34, pages 5718–5728 (2015)Cite this article

Subjects

Abstract

Suppressor of cytokine signaling 1 (SOCS1) is considered as a tumor suppressor protein in hepatocellular carcinoma (HCC), but the underlying mechanisms remain unclear. Previously, we have shown that SOCS1-deficient hepatocytes displayed increased responsiveness to hepatocyte growth factor (HGF) due to enhanced signaling via the MET receptor tyrosine kinase. As aberrant MET activation occurs in many tumors including HCC, here we elucidated the mechanisms of SOCS1-mediated regulation. SOCS1 attenuated HGF-induced proliferation of human and mouse HCC cell lines and their growth as tumors in NOD.scid.gamma mice. Tumors formed by SOCS1 expressing HCC cells showed significantly reduced MET expression, indicating that SOCS1 not only attenuates MET signaling but also regulates MET expression. Mechanistically, SOCS1 interacted with MET via the Src homology 2 domain and this interaction was promoted by MET tyrosine kinase activity. The SOCS1-mediated reduction in MET expression does not require the juxtamembrane Y1003 residue implicated in Cbl-mediated downmodulation. Moreover, the proteasome inhibitor MG-132, but not the inhibitors of lysosomal degradation bafilomycin and chloroquine, reversed the SOCS1-mediated reduction in MET expression, indicating that this process is distinct from Cbl-mediated downmodulation. Accordingly, SOCS1 promoted polyubiquitination of MET via K48-dependent but not K63-mediated ubiquitin chain elongation. Furthermore, siRNA-mediated downmodulation of Cbl did not abolish SOCS1-mediated reduction in MET expression in HCC cells. SOCS1-dependent ubiquitination of endogenous MET receptor occurred rapidly following HGF stimulation in HCC cells, leading to proteasomal degradation of phosphorylated MET receptor. These findings indicate that SOCS1 mediates its tumor suppressor functions, at least partly, by binding to MET and interfering with downstream signaling pathways as well as by promoting the turnover of the activated MET receptor. We propose that loss of this control mechanism due to epigenetic repression of SOCS1 could contribute to oncogenic MET signaling in HCC and other cancers, and that MET inhibitors might be useful in treating these patients.

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
Figure 7

Similar content being viewed by others

References

  1. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth- suppression activity. Nat Genet 2001; 28: 29–35.

    CAS  Google Scholar 

  2. Yoshida T, Ogata H, Kamio M, Joo A, Shiraishi H, Tokunaga Y et al. SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. J Exp Med 2004; 199: 1701–1707.

    Article  CAS  Google Scholar 

  3. Inagaki-Ohara K, Kondo T, Ito M, Yoshimura A . SOCS, inflammation, and cancer. JAKSTAT 2013; 2: e24053.

    PubMed  PubMed Central  Google Scholar 

  4. Kazi JU, Kabir NN, Flores-Morales A, Ronnstrand L . SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol Life Sci 2014; 71: 3297–3310.

    Article  CAS  Google Scholar 

  5. Gui Y, Yeganeh M, Ramanathan S, Leblanc C, Pomerleau V, Ferbeyre G et al. SOCS1 controls liver regeneration by regulating HGF signaling in hepatocytes. J Hepatol 2011; 55: 1300–1308.

    Article  CAS  Google Scholar 

  6. Comoglio PM, Giordano S, Trusolino L . Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008; 7: 504–516.

    Article  CAS  Google Scholar 

  7. Trusolino L, Bertotti A, Comoglio PM . MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 2010; 11: 834–848.

    Article  CAS  Google Scholar 

  8. Mak HH, Peschard P, Lin T, Naujokas MA, Zuo D, Park M . Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr-Met, involves exclusion from the endocytic degradative pathway. Oncogene 2007; 26: 7213–7221.

    Article  CAS  Google Scholar 

  9. Kermorgant S, Parker PJ . Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation. J Cell Biol 2008; 182: 855–863.

    Article  CAS  Google Scholar 

  10. Abella JV, Parachoniak CA, Sangwan V, Park M . Dorsal ruffle microdomains potentiate Met receptor tyrosine kinase signaling and down-regulation. J Biol Chem 2010; 285: 24956–24967.

    Article  CAS  Google Scholar 

  11. Jeffers M, Taylor GA, Weidner KM, Omura S, Vande Woude GF . Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway. Mol Cell Biol 1997; 17: 799–808.

    Article  CAS  Google Scholar 

  12. Hammond DE, Urbe S, Vande Woude GF, Clague MJ . Down-regulation of MET, the receptor for hepatocyte growth factor. Oncogene 2001; 20: 2761–2770.

    Article  CAS  Google Scholar 

  13. Alexander WS . Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol 2002; 2: 1–7.

    Article  Google Scholar 

  14. Johnston JA . Are SOCS suppressors, regulators, and degraders? J Leukoc Biol 2004; 75: 743–748.

    Article  CAS  Google Scholar 

  15. Okumura F, Matsuzaki M, Nakatsukasa K, Kamura T . The role of elongin BC-containing ubiquitin ligases. Front Oncol 2012; 2: 10.

    Article  Google Scholar 

  16. Seki E, Kondo Y, Iimuro Y, Naka T, Son G, Kishimoto T et al. Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings. J Hepatol 2008; 48: 237–245.

    Article  CAS  Google Scholar 

  17. Ilangumaran S, Ramanathan S, Rottapel R . Regulation of the immune system by SOCS family adaptor proteins. Semin Immunol 2004; 16: 351–365.

    Article  CAS  Google Scholar 

  18. Zhu H, Naujokas MA, Park M . Receptor chimeras indicate that the met tyrosine kinase mediates the motility and morphogenic responses of hepatocyte growth/scatter factor. Cell Growth Differ 1994; 5: 359–366.

    CAS  PubMed  Google Scholar 

  19. De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R . Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation. EMBO J 1999; 18: 904–915.

    Article  CAS  Google Scholar 

  20. Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY et al. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol Cell 2001; 8: 995–1004.

    Article  CAS  Google Scholar 

  21. Grassian AR, Schafer ZT, Brugge JS . ErbB2 stabilizes epidermal growth factor receptor (EGFR) expression via Erk and Sprouty2 in extracellular matrix-detached cells. J Biol Chem 2011; 286: 79–90.

    Article  CAS  Google Scholar 

  22. Woelk T, Sigismund S, Penengo L, Polo S . The ubiquitination code: a signalling problem. Cell Div 2007; 2: 11.

    Article  Google Scholar 

  23. Thien CB, Langdon WY . c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses. Biochem J 2005; 391: 153–166.

    Article  CAS  Google Scholar 

  24. Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore PP, Dikic I . Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 2003; 5: 461–466.

    Article  CAS  Google Scholar 

  25. Zardo G, Tiirikainen MI, Hong C, Misra A, Feuerstein BG, Volik S et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat Genet 2002; 32: 453–458.

    Article  CAS  Google Scholar 

  26. Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res 2010; 70: 3119–3127.

    Article  CAS  Google Scholar 

  27. Babar IA, Cheng CJ, Booth CJ, Liang X, Weidhaas JB, Saltzman WM et al. Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci USA 2012; 109: E1695–E1704.

    Article  CAS  Google Scholar 

  28. Kobayashi N, Uemura H, Nagahama K, Okudela K, Furuya M, Ino Y et al. Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget 2012; 3: 1455–1471.

    Article  Google Scholar 

  29. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487: 500–504.

    Article  CAS  Google Scholar 

  30. Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487: 505–509.

    Article  CAS  Google Scholar 

  31. Casaletto JB, McClatchey AI . Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer 2012; 12: 387–400.

    Article  CAS  Google Scholar 

  32. Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG . Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors. Lancet Oncol 2009; 10: 709–717.

    Article  CAS  Google Scholar 

  33. Xu AM, Huang PH . Receptor tyrosine kinase coactivation networks in cancer. Cancer Res 2010; 70: 3857–3860.

    Article  CAS  Google Scholar 

  34. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G . Targeting MET in cancer: rationale and progress. Nat Rev Cancer 2012; 12: 89–103.

    Article  CAS  Google Scholar 

  35. Peschard P, Park M . From Tpr-Met to Met, tumorigenesis and tubes. Oncogene 2007; 26: 1276–1285.

    Article  CAS  Google Scholar 

  36. Longva KE, Blystad FD, Stang E, Larsen AM, Johannessen LE, Madshus IH . Ubiquitination and proteasomal activity is required for transport of the EGF receptor to inner membranes of multivesicular bodies. J Cell Biol 2002; 156: 843–854.

    Article  CAS  Google Scholar 

  37. Zhou L, Yang H . The von Hippel-Lindau tumor suppressor protein promotes c-Cbl-independent poly-ubiquitylation and degradation of the activated EGFR. PLoS One 2011; 6: e23936.

    Article  CAS  Google Scholar 

  38. Lin WW, Karin M . A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 2007; 117: 1175–1183.

    Article  CAS  Google Scholar 

  39. Fausto N, Campbell JS, Riehle KJ . Liver regeneration. Hepatology 2006; 43: S45–S53.

    Article  CAS  Google Scholar 

  40. Goyal L, Muzumdar MD, Zhu AX . Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res 2013; 19: 2310–2318.

    Article  CAS  Google Scholar 

  41. Esteller M . Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol 2005; 45: 629–656.

    Article  CAS  Google Scholar 

  42. Fukushima N, Sato N, Sahin F, Su GH, Hruban RH, Goggins M . Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms. Br J Cancer 2003; 89: 338–343.

    Article  CAS  Google Scholar 

  43. Shakya R, Gonda T, Quante M, Salas M, Kim S, Brooks J et al. Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma. Cancer Res 2013; 73: 885–896.

    Article  CAS  Google Scholar 

  44. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 1999; 18: 1309–1320.

    Article  CAS  Google Scholar 

  45. Ilangumaran S, Finan D, La Rose J, Raine J, Silverstein A, De Sepulveda P et al. A positive regulatory role for SOCS1 in interferon gamma-induced MHC class II expression in fibroblasts. J Immunol 2002; 169: 5010–5020.

    Article  Google Scholar 

  46. Lim KL, Chew KC, Tan JM, Wang C, Chung KK, Zhang Y et al. Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci 2005; 25: 2002–2009.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Morag Park for generously providing CSF-MET and Tpr-MET expression plasmids. Centre de Recherche Clinique du CHUS is an FRSQ-funded research center. This work was supported by the Cancer Research Society, Montreal, Canada (SI and CS).

Author information

Author notes

  1. C Saucier and S Ilangumaran: These authors share senior authorship.

Authors and Affiliations

  1. Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Centre de Recherche Clinique Etienne-Le Bel, Centre Hospitalier de l’Université de Sherbrooke, Sherbrooke, Quebec, Canada

    Y Gui, M Yeganeh, Y-C Donates, M Mayhue, S Ramanathan & S Ilangumaran

  2. Department of Anatomy and Cell biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Centre de Recherche Clinique Etienne-Le Bel, Centre Hospitalier de l’Université de Sherbrooke, Sherbrooke, Quebec, Canada

    W-S Tobelaim, W Chababi & C Saucier

  3. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

    A Yoshimura

Authors
  1. Y Gui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Yeganeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y-C Donates
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W-S Tobelaim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W Chababi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Mayhue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Ramanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Saucier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Ilangumaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Ilangumaran.

Ethics declarations

Competing interests

YG is a recipient of a graduate student fellowship from the Canadian Liver Foundation. MY was a recipient of FRQNT doctoral fellowship. All other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gui, Y., Yeganeh, M., Donates, YC. et al. Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma. Oncogene 34, 5718–5728 (2015). https://doi.org/10.1038/onc.2015.20

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.20

This article is cited by

Search

Advanced search

Quick links