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.

  • Short Communication
  • Published:

The mouse soluble GFRα4 receptor activates RET independently of its ligand persephin

Oncogene volume 26, pages 3892–3898 (2007)Cite this article

Abstract

Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) all signal through the transmembrane receptor tyrosine kinase RET. The signalling complex consists of GFLs, GPI-anchored ligand binding GDNF family receptor alphas (GFRαs) and RET. Signalling via RET is required for the development of the nervous system and the kidney, as well as for spermatogenesis. However, constitutive activation of RET is implicated as a cause in several diseases. Mutations of the RET proto-oncogene cause the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). Recently, it has been suggested that mutations in the persephin binding GFRα4 receptor may have a potentially modifying role in MEN 2. Several naturally occurring, different splice variants of the mammalian GFRα4 have been reported. A 7 bp insertion–mutation in the human GFRα4 gene causes a shift of reading frame and thereby changes the balance between the transcripts encoding GPI-anchored and soluble GFRα4 receptors. We report here that the mammalian soluble GFRα4 can activate RET independently of its preferential ligand, persephin. Our data show that soluble GFRα4 can associate with, and induce, phosphorylation of RET. In addition, our data show that this isoform of GFRα4 can induce downstream signalling, as well as neuronal survival and differentiation, in the absence of persephin. These results suggest that, in line with the previous report, GFRα4 may be a candidate gene for, or modifier of, the MEN 2 diseases.

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

Similar content being viewed by others

References

  • Airaksinen MS, Saarma M . (2002). The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3: 383–394.

    Article  CAS  Google Scholar 

  • Asai N, Iwashita T, Matsuyama M, Takahashi M . (1995). Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 15: 1613–1619.

    Article  CAS  Google Scholar 

  • Eketjäll S, Fainzilber M, Murray-Rust J, Ibáñez CF . (1999). Distinct structural elements in GDNF mediate binding to GFRalpha1 and activation of the GFRalpha1-c-Ret receptor complex. EMBO J 18: 5901–5910.

    Article  Google Scholar 

  • Kato M, Iwashita T, Takeda K, Akhand AA, Liu W, Yoshihara M et al. (2000). Ultraviolet light induces redox reaction-mediated dimerization and superactivation of oncogenic Ret tyrosine kinases. Mol Biol Cell 11: 93–101.

    Article  CAS  Google Scholar 

  • Kodama Y, Asai N, Kawai K, Jijiwa M, Murakumo Y, Ichihara M et al. (2005). The RET proto-oncogene: a molecular therapeutic target in thyroid cancer. Cancer Sci 96: 143–148.

    Article  CAS  Google Scholar 

  • Kraulis PJ . (1991). MolScript: a program to produce both detailed and schematic plots of protein structures. J Appl Crystallogr 24: 946–950.

    Article  Google Scholar 

  • Leppänen VM, Bespalov MM, Runeberg-Roos P, Puurand U, Merits A, Saarma M et al. (2004). The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation. EMBO J 23: 1452–1462.

    Article  Google Scholar 

  • Lindahl M, Poteryaev D, Yu L, Arumäe U, Timmusk T, Bongarzone I et al. (2001). Human glial cell line-derived neurotrophic factor receptor alpha 4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells. J Biol Chem 276: 9344–9351.

    Article  CAS  Google Scholar 

  • Lindahl M, Timmusk T, Rossi J, Saarma M, Airaksinen MS . (2000). Expression and alternative splicing of mouse Gfra4 suggest roles in endocrine cell development. Mol Cell Neurosci 15: 522–533.

    Article  CAS  Google Scholar 

  • Lindfors PH, Lindahl M, Rossi J, Saarma M, Airaksinen MS . (2006). Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor alpha4 impairs thyroid calcitonin production in young mice. Endocrinology 147: 2237–2244.

    Article  CAS  Google Scholar 

  • Merritt EA, Bacon D . (1997). Raster3D: photorealistic molecular graphics. Method Enzymol 277: 505–524.

    Article  CAS  Google Scholar 

  • Milbrandt J, de Sauvage FJ, Fahrner TJ, Baloh RH, Leitner ML, Tansey MG et al. (1998). Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 20: 245–253.

    Article  CAS  Google Scholar 

  • Paratcha G, Ledda F, Baars L, Coulpier M, Besset V, Anders J et al. (2001). Released GFRalpha1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29: 171–184.

    Article  CAS  Google Scholar 

  • Schwede TJ, Kopp J, Guex N, Peitsch MC . (2003). SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res 31: 3381–3385.

    Article  CAS  Google Scholar 

  • Scott RP, Ibáñez CF . (2001). Determinants of ligand binding specificity in the glial cell line-derived neurotrophic factor family receptor alpha S. J Biol Chem 276: 1450–1458.

    Article  CAS  Google Scholar 

  • Tansey MG, Baloh RH, Milbrandt J, Johnson EM . (2000). GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neuron 25: 611–623.

    Article  CAS  Google Scholar 

  • Thompson JD, Higgins DG, Gibson TJ . (1994). CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22: 4673–4680.

    Article  CAS  Google Scholar 

  • Vanhorne JB, Andrew SD, Harrison KJ, Taylor SA, Thomas B, McDonald TJ et al. (2005). A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2. Oncogene 24: 1091–1097.

    Article  CAS  Google Scholar 

  • Virtanen H, Yang J, Bespalov MM, Hiltunen JO, Leppänen VM, Kalkkinen N et al (2005). The first cysteine-rich domain of the receptor GFRalpha1 stabilizes the binding of GDNF. Biochem J 387: 817–824.

    Article  CAS  Google Scholar 

  • Wang X, Baloh RH, Milbrandt J, Garcia KC . (2006). Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors. Structure 14: 1083–1092.

    Article  Google Scholar 

  • Yang J, Lindahl M, Lindholm P, Virtanen H, Coffey E, Runeberg-Roos P et al. (2004). PSPN/GFRalpha4 has a significantly weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. FEBS Lett 569: 267–271.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Maria Lindahl for providing us with the cDNA from the adrenal gland and the primers for the RT–PCR reaction. We also thank Päivi Linholm for providing us with the cDNA from Neuro 2a cells, Matthew Phillips for correcting the language, and Kerstin Krieglstein for commenting on the manuscript. This work was supported by grants from the Academy of Finland and Sigrid Jusélius Foundation (to MS).

Author information

Authors and Affiliations

  1. Institute of Biotechnology, Viikki Biocenter, University of Helsinki, Helsinki, Finland

    J Yang, P Runeberg-Roos, V-M Leppänen & M Saarma

Authors
  1. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Runeberg-Roos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V-M Leppänen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Saarma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Saarma.

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

Yang, J., Runeberg-Roos, P., Leppänen, VM. et al. The mouse soluble GFRα4 receptor activates RET independently of its ligand persephin. Oncogene 26, 3892–3898 (2007). https://doi.org/10.1038/sj.onc.1210161

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210161

Keywords

This article is cited by

Search

Advanced search

Quick links