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Volume 271, Number 46, Issue of November 15, 1996 pp. 29497-29501
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Ligand Stimulation of a Ret Chimeric Receptor Carrying the Activating Mutation Responsible for the Multiple Endocrine Neoplasia Type 2B

(Received for publication, July 19, 1996, and in revised form, August 28, 1996)

Claudia Rizzo , Daniela Califano ^§ , G. Luca Colucci-D'Amato , Gabriella De Vita , Amelia D'Alessio ^§ , Nina A. Dathan , Alfredo Fusco , Carmen Monaco ^§ , Giovanni Santelli ^§ , Giancarlo Vecchio , Massimo Santoro and Vittorio de Franciscis

From the Centro di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II," via S. Pansini 5, 80131 Napoli, Italy, ^§ Oncologia Sperimentale "E," Istituto Nazionale Tumori, Fondazione "G. Pascale," via M. Semmola, 80131 Napoli, Italy, and  Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Reggio Calabria, via T. Campanella 5, 88100 Catanzaro, Italy

Inherited activating mutations of Ret, a receptor tyrosine kinase, predispose to multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma. To investigate the effects induced by acute stimulation of Ret, we transfected both PC12 and NIH 3T3 cells with a molecular construct in which the ligand-binding domain of the epidermal growth factor receptor was fused to the catalytic domain of Ret. Acute stimulation of the chimeric receptor induced PC12 cells to express a neuronal-like phenotype. Moreover, we introduced the dominant mutation, responsible for the multiple endocrine neoplasia type 2B, in the catalytic domain of the Ret chimera. Expression of the mutant chimera, in the absence of ligand stimulation, induces the PC12 cells to acquire a flat morphology with short neuritic processes and transforms the NIH 3T3 cells. Stimulation of the mutant chimera with epidermal growth factor causes a drastic overgrowth of long neuritic processes, with the induction of the suc1-associated protein tyrosine phosphorylation in PC12 cells and higher transforming efficiency in NIH 3T3 cells. These data indicate that the gain-of-function MEN2B mutation does not abrogate ligand responsiveness of Ret and suggest that the presence of Ret ligand could play a role in the pathogenesis of the MEN2B syndrome.

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