Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Oncogene Submit manuscript

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, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

  • Springer Nature Limited

Keywords

This article is cited by

Search

Navigation