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Only the Substitution of Methionine 918 with a Threonine and Not with Other Residues Activates RET Transforming Potential¹

Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche (A.M.C., G.S., G.D., F.C., N.A.D., R.V., R.M., M.S.), c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II", via S. Pansini 5, 80131 Napoli-Italy and the Dipartimento di Medicina Sperimentale e Clinica (A.F.), Facoltà di Medicina e Chirurgia di Catanzaro, Università degli Studi di Reggio Calabria, via T. Campanella 5, 88100 Catanzaro-Italy

Address all correspondence and requests for reprints to: Massimo Santoro, Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R., Facoltà di Medicina e Chirurgia, via S. Pansini 5, 80131 Napoli-Italy.

Specific point-mutations of the RET receptor tyrosine kinase protooncogene are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). MEN2B is caused by the substitution of methionine 918 by a threonine in the tyrosine kinase (TK) domain of RET. This mutation converts RET into a dominant transforming oncogene. We have substituted Met918 with four different residues and found that RET acquired transforming activity only when Met918 was substituted with a threonine. However, also when serine and valine, but not leucine or phenylalanine, were inserted in position 918, the RET TK function was activated and induced, especially in the case of the RET(918Ser), immmediate-early response genes. We conclude that the preservation of Met918 is critical for the control of RET kinase. However, only when a threonine residue is present in position 918, does RET efficiently couple with a transforming pathway.