This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carlomagno, F. Articles by Santoro, M. Search for Related Content PubMed PubMed Citation Articles by Carlomagno, F. Articles by Santoro, M.

The Different RET-activating Capability of Mutations of Cysteine 620 or Cysteine 634 Correlates with the Multiple Endocrine Neoplasia Type 2 Disease Phenotype¹

Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, via S. Pansini 5, 80131 Naples, Italy [F. C., G. S., A. M. C., G. D. V., R. M. M., V. d. F., M. S.]; Laboratoire de Génétique, Centre National de la Recherche Scientifique UMR5641, Domaine Rockefeller, Université Claude Bernard Lyon 1, 8 avenue Rockefeller, 69372 Lyon Cedex 08, France [M. B.]; and Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia di Catanzaro, Università di Reggio Calabria, via T. Campanella 5, 88100 Catanzaro, Italy [A. F.]

Distinct point mutations of RET, a tyrosine-kinase receptor encoding gene, are responsible for the inheritance of multiple endocrine neoplasia type 2 syndromes (MEN2A and MEN2B) and familial medullary thyroid carcinoma (FMTC). In particular, MEN2A is a more complex and aggressive disease than FMTC, being characterized by pheochromocytomas and parathyroid alterations, in addition to medullary thyroid carcinomas. The mutations associated with MEN2A and FMTC affect one of five cysteine residues mapping in the extracellular domain of the Ret protein. However, recent studies have indicated that MEN2A and FMTC disease phenotypes correlate with the position of mutations in RET. Mutations of Cys-634 are more frequent in families with MEN2A, whereas Cys-620 mutations are very rarely found in MEN2A patients and, in contrast, are frequently found in FMTC patients. We have reported previously that mutations of Cys-634 constitutively activate the RET transforming potential by causing a disulfide bridge-mediated homodimerization. Here, we report that the mutation Cys-620Tyr is able to cause a constitutive dimerization of Ret, with consequent activation of its kinase and transforming activities, to a lower extent than mutation of Cys-634. We suggest that the difference in ability to activate RET shown by mutations associated with FMTC and MEN2A represents the molecular basis of the phenotypic diversity between the two syndromes.

¹ This study was supported by the Associazione Italiana per la Ricerca sul Cancro; by the Progetto Finalizzato, Consiglio Nazionale delle Ricerche, Applicazioni Cliniche della Ricerca Oncologica, Sottoprogetto 2, Biologia Molecolare; by the Association de Recherche sur le Cancer; and by the Ligue Nationale Contre le Cancer.

² To whom requests for reprints should be addressed. Phone: 39-81-7463056; Fax: 39-81-7463037.

Received 9/26/96. Accepted 12/17/96.

This article has been cited by other articles:

				C. Carniti, S. Belluco, E. Riccardi, A. N. Cranston, P. Mondellini, B. A.J. Ponder, E. Scanziani, M. A. Pierotti, and I. Bongarzone The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease Am. J. Pathol., April 1, 2006; 168(4): 1262 - 1275. [Abstract] [Full Text] [PDF]

				L. D'Aloiso, F. Carlomagno, M. Bisceglia, S. Anaganti, E. Ferretti, A. Verrienti, F. Arturi, D. Scarpelli, D. Russo, M. Santoro, et al. In Vivo and in Vitro Characterization of a Novel Germline RET Mutation Associated with Low-Penetrant Nonaggressive Familial Medullary Thyroid Carcinoma J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 754 - 759. [Abstract] [Full Text] [PDF]

				X. Wei, S. Ni, and P. H. Correll Uncoupling Ligand-dependent and -independent Mechanisms for Mitogen-activated Protein Kinase Activation by the Murine Ron Receptor Tyrosine Kinase J. Biol. Chem., October 21, 2005; 280(42): 35098 - 35107. [Abstract] [Full Text] [PDF]

				G. Orgiana, G. Pinna, A. Camedda, V. De Falco, M. Santoro, R. M. Melillo, R. Elisei, C. Romei, S. Lai, C. Carcassi, et al. A New Germline RET Mutation Apparently Devoid of Transforming Activity Serendipitously Discovered in a Patient with Atrophic Autoimmune Thyroiditis and Primary Ovarian Failure J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4810 - 4816. [Abstract] [Full Text] [PDF]

				C. Jimenez, M. A. Habra, S.-C. E. Huang, A. El-Naggar, S. E. Shapiro, D. B. Evans, G. Cote, and R. F. Gagel Pheochromocytoma and Medullary Thyroid Carcinoma: A New Genotype-Phenotype Correlation of the RET Protooncogene 891 Germline Mutation J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4142 - 4145. [Abstract] [Full Text] [PDF]

				E. Arighi, A. Popsueva, D. Degl'Innocenti, M. G. Borrello, C. Carniti, N. M. Perala, M. A. Pierotti, and H. Sariola Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung's Disease Mol. Endocrinol., April 1, 2004; 18(4): 1004 - 1017. [Abstract] [Full Text] [PDF]

				J. Wang, J. A. Knauf, S. Basu, E. Puxeddu, H. Kuroda, M. Santoro, A. Fusco, and J. A. Fagin Conditional Expression of RET/PTC Induces a Weak Oncogenic Drive in Thyroid PCCL3 Cells and Inhibits Thyrotropin Action at Multiple Levels Mol. Endocrinol., July 1, 2003; 17(7): 1425 - 1436. [Abstract] [Full Text] [PDF]

				F. Carlomagno, D. Vitagliano, T. Guida, F. Basolo, M. D. Castellone, R. M. Melillo, A. Fusco, and M. Santoro Efficient Inhibition of RET/Papillary Thyroid Carcinoma Oncogenic Kinases by 4-Amino-5-(4-Chloro-Phenyl)-7-(t-Butyl)Pyrazolo[3,4-d]Pyrimidine (PP2) J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1897 - 1902. [Abstract] [Full Text] [PDF]

				L. Yip, G. J. Cote, S. E. Shapiro, G. D. Ayers, C. E. Herzog, R. V. Sellin, S. I. Sherman, R. F. Gagel, J. E. Lee, and D. B. Evans Multiple Endocrine Neoplasia Type 2: Evaluation of the Genotype-Phenotype Relationship Arch Surg, April 1, 2003; 138(4): 409 - 416. [Abstract] [Full Text] [PDF]

				B. Mograbi, R. Bocciardi, I. Bourget, T. Juhel, D. Farahi-Far, G. Romeo, I. Ceccherini, and B. Rossi The Sensitivity of Activated Cys Ret Mutants to Glial Cell Line-Derived Neurotrophic Factor Is Mandatory To Rescue Neuroectodermic Cells from Apoptosis Mol. Cell. Biol., October 15, 2001; 21(20): 6719 - 6730. [Abstract] [Full Text] [PDF]

				D. Salvatore, R. M. Melillo, C. Monaco, R. Visconti, G. Fenzi, G. Vecchio, A. Fusco, and M. Santoro Increased in Vivo Phosphorylation of Ret Tyrosine 1062 Is a Potential Pathogenetic Mechanism of Multiple Endocrine Neoplasia Type 2B Cancer Res., February 1, 2001; 61(4): 1426 - 1431. [Abstract] [Full Text]

				J. R Hansford and L. M Mulligan Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis J. Med. Genet., November 1, 2000; 37(11): 817 - 827. [Abstract] [Full Text]

				S. M Myers, R. Salomon, A. Goessling, A. Pelet, C. Eng, A. von Deimling, S. Lyonnet, and L. M Mulligan Investigation of germline GFRalpha -1 mutations in Hirschsprung disease J. Med. Genet., March 1, 1999; 36(3): 217 - 220. [Abstract] [Full Text]

				C. Eng RET Proto-Oncogene in the Development of Human Cancer J. Clin. Oncol., January 1, 1999; 17(1): 380 - 380. [Abstract] [Full Text] [PDF]

				F. Carlomagno, R. M. Melillo, R. Visconti, G. Salvatore, G. De Vita, G. Lupoli, Y. Yu, S. Jing, G. Vecchio, A. Fusco, et al. Glial Cell Line-Derived Neurotrophic Factor Differentially Stimulates Ret Mutants Associated with the Multiple Endocrine Neoplasia Type 2 Syndromes and Hirschsprung's Disease Endocrinology, August 1, 1998; 139(8): 3613 - 3619. [Abstract] [Full Text] [PDF]