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:

TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling

Oncogene volume 26, pages 7684–7691 (2007)Cite this article

Abstract

Growing evidence suggests that overexpression of TrkC, a member of the Trk family of neurotrophin receptors, could drive tumorigenesis, invasion and metastatic capability in cancer cells. However, relatively little is known about the mechanism of TrkC-mediated oncogenesis. The TrkC gene is a partner of the Tel-TrkC (ETV6-NTRK3) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages. Recently, we have shown that ETV6-NTRK3 suppresses transforming growth factor-β (TGF-β) signaling by directly binding to the type II TGF-β receptor (TβRII). Here, we report that expression of TrkC also suppresses TGF-β-induced Smad2/3 phosphorylation and transcriptional activation. Silencing TrkC expression by small interfering RNA in the highly metastatic 4T1 mammary tumor cell line expressing endogenous TrkC significantly enhanced TGF-β-induced Smad2/3 phosphorylation and restored TGF-β growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-β transcriptional activation. Moreover, we show that TrkC directly binds to the TβRII, thereby preventing it from interacting with the type I TGF-β receptor (TβRI). These results indicate that TrkC is an inhibitor of TGF-β tumor suppressor activity.

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

  • Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S et al. (2003). Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 300: 949.

    Article  CAS  Google Scholar 

  • Brodeur GM, Nakagawara A, Yamashiro DJ, Ikegaki N, Liu XG, Azar CG et al. (1997). Expression of TrkA, TrkB and TrkC in human neuroblastomas. J Neurooncol 31: 49–55.

    Article  CAS  Google Scholar 

  • Chang J, Park K, Bang Y-J, Kim WS, Kim D, Kim S-J . (1997). Expression of transforming growth factor β type II receptor reduces tumorigenicity in human gastric cancer cells. Cancer Res 57: 2856–2859.

    CAS  PubMed  Google Scholar 

  • Chao MV, Bothwell M . (2002). Neurotrophins: to cleave or not to cleave. Neuron 33: 9–12.

    Article  CAS  Google Scholar 

  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM . (1998). Direct binding of Smad3 and Smad4 to critical TGF β-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17: 3091–3100.

    Article  CAS  Google Scholar 

  • Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS . (2004). Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430: 1034–1039.

    Article  CAS  Google Scholar 

  • Eguchi M, Eguchi-Ishimae M, Tojo A, Morishita K, Suzuki K, Sato Y et al. (1999). Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood 93: 1355–1363.

    CAS  Google Scholar 

  • Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN et al. (2000). TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18: 1027–1035.

    Article  CAS  Google Scholar 

  • Guate JL, Fernandez N, Lanzas JM, Escaf S, Vega JA . (1999). Expression of p75(LNGFR) and Trk neurotrophin receptors in normal and neoplastic human prostate. BJU Int 84: 495–502.

    Article  CAS  Google Scholar 

  • Hahm K-B, Cho K, Lee C, Im Y-H, Chang J, Choi S-G et al. (1999). Repression of the gene encoding the TGF-β type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet 23: 222–227.

    Article  CAS  Google Scholar 

  • Hisaoka M, Sheng WQ, Tanaka A, Hashimoto H . (2002). Gene expression of TrkC (NTRK3) in human soft tissue tumours. J Pathol 197: 661–667.

    Article  CAS  Google Scholar 

  • Horton CD, Qi Y, Chikaraishi D, Wang JK . (2001). Neurotrophin-3 mediates the autocrine survival of the catecholaminergic CAD CNS neuronal cell line. J Neurochem 76: 201–209.

    Article  CAS  Google Scholar 

  • Jin W, Kim BC, Tognon C, Lee HJ, Patel S, Lannon CL et al. (2005). The ETV6-NTRK3 chimeric tyrosine kinase suppresses TGF-β signaling by inactivating the TGF-β type II receptor. Proc Natl Acad Sci USA 102: 16239–16244.

    Article  CAS  Google Scholar 

  • Kim S-J, Im Y-H, Markowitz SD, Bang Y-J . (2000). Molecular mechanisms of inactivation of TGF-β receptors during carcinogenesis. Cytokine Growth Factor Rev 11: 159–168.

    Article  CAS  Google Scholar 

  • Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH . (1998). A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18: 184–187.

    Article  CAS  Google Scholar 

  • Lee BI, Park SH, Kim JW, Sausville EA, Kim HT, Nakanishi O et al. (2001). MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor β type II receptor expression in human breast cancer cells. Cancer Res 61: 931–934.

    CAS  PubMed  Google Scholar 

  • Markowitz SD, Roberts AB . (1996). Tumor suppressor activity of the TGF-β pathway in human cancers. Cytokine Growth Factor Rev 7: 93–102.

    Article  CAS  Google Scholar 

  • Massagué J . (1998). TGF-β signal transduction. Annu Rev Biochem 67: 753–791.

    Article  Google Scholar 

  • Nakagawara A . (2001). Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169: 107–114.

    Article  CAS  Google Scholar 

  • Park K, Kim S-J, Bang Y-J, Park J-G, Kim NK, Roberts AB et al. (1994). Genetic changes in the transforming growth factor beta (TGF-β) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-β. Proc Natl Acad Sci USA 91: 8772–8776.

    Article  CAS  Google Scholar 

  • Rickert CH . (2004). Prognosis-related molecular markers in pediatric central nervous system tumors. J Neuropathol Exp Neurol 63: 1211–1224.

    Article  CAS  Google Scholar 

  • Roberts AB, Sporn MB . (1993). Physiological actions and clinical applications of transforming growth factor-β (TGF-β). Growth Factors 8: 1–9.

    Article  CAS  Google Scholar 

  • Ruggeri BA, Miknyoczki SJ, Singh J, Hudkins RL . (1999). Role of neurotrophin–trk interactions in oncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors in pre-clinical tumor models. Curr Med Chem 6: 845–857.

    CAS  PubMed  Google Scholar 

  • Ryden M, Sehgal R, Dominici C, Schilling FH, Ibanez CF, Kogner P . (1996). Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis. Br J Cancer 74: 773–779.

    Article  CAS  Google Scholar 

  • Satoh F, Mimata H, Nomura T, Fujita Y, Shin T, Sakamoto S et al. (2001). Autocrine expression of neurotrophins and their receptors in prostate cancer. Int J Urol 8: S28–S34.

    Article  CAS  Google Scholar 

  • Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL . (1994). Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci USA 91: 12867–12871.

    Article  CAS  Google Scholar 

  • Sun L, Wu G, Willson JK, Zborowska E, Yang J, Rajkarunanayake I et al. (1994). Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells. J Biol Chem 269: 26449–26455.

    CAS  PubMed  Google Scholar 

  • Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA et al. (2002). Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2: 367–376.

    Article  CAS  Google Scholar 

  • Wieser R, Wrana JL, Massague J . (1995). GS domain mutations that constitutively activate TβR-I, the downstream signaling component in the TGF-β receptor complex. EMBO J 14: 2199–2208.

    Article  CAS  Google Scholar 

  • Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M et al. (1992). TGF β signals through a heteromeric protein kinase receptor complex. Cell 71: 1003–1014.

    Article  CAS  Google Scholar 

  • Yamashiro DJ, Liu XG, Lee CP, Nakagawara A, Ikegaki N, McGregor LM et al. (1997). Expression and function of Trk-C in favourable human neuroblastomas. Eur J Cancer 33: 2054–2057.

    Article  CAS  Google Scholar 

  • Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B et al. (1998). Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1: 611–617.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. We thank E Kohn and A Hobbie for the critical reading of the manuscript.

Author information

Author notes

  1. M-K Kwak

    Present address: 3Current address: Cancer Research Institute, Seoul National University College of Medicine, Chongno-gu, Seoul 110-744, Republic of Korea,

Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA

    W Jin, C Yun, M-K Kwak, T-A Kim & S-J Kim

  2. Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Republic of Korea

    S-J Kim

Authors
  1. W Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M-K Kwak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T-A Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S-J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S-J Kim.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jin, W., Yun, C., Kwak, MK. et al. TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling. Oncogene 26, 7684–7691 (2007). https://doi.org/10.1038/sj.onc.1210571

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210571

Keywords

This article is cited by

Search

Advanced search

Quick links