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Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations

Oncogene volume 25, pages 7086–7095 (2006)Cite this article

Abstract

In patients with medullary thyroid carcinoma (MTC) and type 2A multiple endocrine neoplasia (MEN2A), mutations of cysteine residues in the extracellular juxtamembrane region of the RET receptor tyrosine kinase cause the formation of covalent receptor dimers linked by intermolecular disulfide bonds between unpaired cysteines, followed by oncogenic activation of the RET kinase. The close proximity to the plasma membrane of the affected cysteine residues prompted us to investigate the possible role of the transmembrane (TM) domain of RET (RET-TM) in receptor–receptor interactions underlying dimer formation. Strong self-association of the RET-TM was observed in a biological membrane. Mutagenesis studies indicated the involvement of the evolutionary conserved residues Ser-649 and Ser-653 in RET-TM oligomerization. Unexpectedly, RET-TM interactions were also abrogated in the A639G/A641R double mutant, first identified in a sporadic case of MTC. In agreement with this, no transforming activity could be detected in full-length RET carrying the A639G and A641R mutations, which remained fully responsive to glial cell-line-derived neurotrophic factor (GDNF) stimulation. When introduced in the context of C634R – a cysteine replacement that is prevalent in MEN2A cases – the A639G/A641R mutations significantly reduced dimer formation and transforming activity in this otherwise highly oncogenic RET variant. These data suggest that a strong propensity to self-association in the RET-TM underlies – and may be required for – dimer formation and oncogenic activation of juxtamembrane cysteine mutants of RET, and explains the close proximity to the plasma membrane of cysteine residues implicated in MEN2A and MTC syndromes.

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Acknowledgements

We thank Marçal Vilar for suggesting the use of the ToxCAT system and for fruitful discussions, and Xiaoli Li for secretarial help. This work was supported by grants from the Swedish Foundation for Strategic Research, Swedish Medical Research Council (K99-33X-10908-06C), Swedish Cancer Society (3872-B02-09XAC), Vth Framework Program of the European Union (QLRT-1999-00099) and Swedish Fund for Research without Laboratory Animals.

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Author notes

  1. S Kjær

    Present address: Structural Biology Laboratory, Cancer Research UK, London, UK

  2. K Kurokawa

    Present address: Department of Pathology, Aichi Medical University, School of Medicine, Nagakute, Aichi, Japan

  3. C Abrescia

    Present address: Telethon Institute of Genetics and Medicine, Napoli, Italy

Authors and Affiliations

  1. Department of Neuroscience, Division of Molecular Neurobiology, Karolinska Institute, Stockholm, Sweden

    S Kjær, K Kurokawa, M Perrinjaquet, C Abrescia & C F Ibáñez

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Correspondence to S Kjær or C F Ibáñez.

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Kjær, S., Kurokawa, K., Perrinjaquet, M. et al. Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations. Oncogene 25, 7086–7095 (2006). https://doi.org/10.1038/sj.onc.1209698

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