Only the substitution of methionine 918 with a threonine and not with other residues activates RET transforming potential

Anna Maria Cirafici, Giuliana Salvatore, Gabriella De Vita, Francesca Carlomagno, Nina A. Dathan, Roberta Visconti, Rosa Marina Melillo, Alfredo Fusco, Massimo Santoro

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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), immediate-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.

Original languageEnglish
Pages (from-to)1450-1455
Number of pages6
JournalEndocrinology
Volume138
Issue number4
DOIs
Publication statusPublished - 1997

Fingerprint

Threonine
Methionine
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-ret
Multiple Endocrine Neoplasia Type 2b
Multiple Endocrine Neoplasia Type 2a
Immediate-Early Genes
Valine
Phenylalanine
Oncogenes
Point Mutation
Leucine
Serine
Phosphotransferases
Mutation

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Only the substitution of methionine 918 with a threonine and not with other residues activates RET transforming potential. / Cirafici, Anna Maria; Salvatore, Giuliana; De Vita, Gabriella; Carlomagno, Francesca; Dathan, Nina A.; Visconti, Roberta; Melillo, Rosa Marina; Fusco, Alfredo; Santoro, Massimo.

In: Endocrinology, Vol. 138, No. 4, 1997, p. 1450-1455.

Research output: Contribution to journalArticle

Cirafici, AM, Salvatore, G, De Vita, G, Carlomagno, F, Dathan, NA, Visconti, R, Melillo, RM, Fusco, A & Santoro, M 1997, 'Only the substitution of methionine 918 with a threonine and not with other residues activates RET transforming potential', Endocrinology, vol. 138, no. 4, pp. 1450-1455. https://doi.org/10.1210/en.138.4.1450
Cirafici, Anna Maria ; Salvatore, Giuliana ; De Vita, Gabriella ; Carlomagno, Francesca ; Dathan, Nina A. ; Visconti, Roberta ; Melillo, Rosa Marina ; Fusco, Alfredo ; Santoro, Massimo. / Only the substitution of methionine 918 with a threonine and not with other residues activates RET transforming potential. In: Endocrinology. 1997 ; Vol. 138, No. 4. pp. 1450-1455.
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AU - Cirafici, Anna Maria

AU - Salvatore, Giuliana

AU - De Vita, Gabriella

AU - Carlomagno, Francesca

AU - Dathan, Nina A.

AU - Visconti, Roberta

AU - Melillo, Rosa Marina

AU - Fusco, Alfredo

AU - Santoro, Massimo

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AB - 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), immediate-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.

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