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Mol Cell Biol, June 1998, p. 3321-3329, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Mutations in the Extracellular Domain Cause RET Loss of Function by a Dominant Negative Mechanism

Maria Pia Cosma,1 Monica Cardone,1 Francesca Carlomagno,2 and Vittorio Colantuoni1,3,*

Dipartimento di Biochimica e Biotecnologie Mediche and Centro di Ingegneria Genetica, CEINGE,1 and Centro di Endocrinologia e Oncologia Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università di Napoli "Federico II",2 Naples, and Facoltà di Farmacia, Università di Reggio Calabria, Catanzaro,3 Italy

Received 26 February 1998/Accepted 19 March 1998

The RET proto-oncogene encodes a tyrosine kinase receptor expressed in neuroectoderm-derived cells. Mutations in specific regions of the gene are responsible for the tumor syndromes multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B), while mutations along the entire gene are involved in a developmental disorder of the gastrointestinal tract, Hirschsprung's disease (HSCR disease). Two mutants in the extracellular domain of RET, one associated with HSCR disease and one carrying a flag epitope, were analyzed to investigate the impact of the mutations on RET function. Both mutants were impeded in their maturation, resulting in the lack of the 170-kDa mature form and the accumulation of the 150-kDa immature form in the endoplasmic reticulum. Although not exposed on the cell surface, the 150-kDa species formed dimers and aggregates; this was more pronounced in a double mutant bearing a MEN 2A mutation. Tyrosine phosphorylation and the transactivation potential were drastically reduced in single and double mutants. Finally, in cotransfection experiments both mutants exerted a dominant negative effect over protoRET and RET2A through the formation of a heteromeric complex that prevents their maturation and function. These results suggest that HSCR mutations in the extracellular region cause RET loss of function through a dominant negative mechanism.

* Corresponding author. Mailing address: Dipartimento di Biochimica e Biotecnologie Mediche, Facoltà di Medicina e Chirurgia, Università di Napoli, "Federico II," Via Sergio Pansini, 5, 80131 Naples I, Italy. Phone: 39 81 746 3735. Fax: 39 81 746 3074. E-mail: colantuoni{at}dbbm.unina.it.

Mol Cell Biol, June 1998, p. 3321-3329, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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