Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease

Francesca Carlomagno, Rosa Marina Melillo, Roberta Visconti, Giuliana Salvatore, Gabriella De Vita, Gelsy Lupoli, Yanbin Yu, Shuqian Jing, Giancarlo Vecchio, Alfredo Fusco, Massimo Santoro

Research output: Contribution to journalArticle

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Abstract

Ret is a receptor tyrosine kinase involved in several neoplastic and developmental diseases affecting the thyroid gland and tissues of neuroectodermal origin. Different ret mutations are associated with different disease phenotypes. Gain-of-function of ret is caused by gene rearrangements in thyroid papillary carcinomas and by point mutations in multiple endocrine neoplasia (MEN) type 2A syndrome (MEN2A), in familial medullary thyroid carcinoma (FMTC), and in the more severe MEN2B syndrome. Conversely, Hirschsprung's disease (HSCR) is associated with loss of function of ret. Recently, it has been shown that glial cell line-derived neurotrophic factor (GDNF), by binding to the accessory molecule GDNFR-α, acts as a functional ligand of Ret and stimulates its tyrosine kinase and biological activity. To ascertain whether the biological effects of ret mutations are modulated by GDNF, we have investigated the responsiveness to GDNF of ret mutants in cell lines coexpressing GDNFR-α and MEN2A-, MEN2B-, FMTC-, or HSCR-associated ret mutants. Here, we show that triggering of GDNF affected only ret/MEN2B, i.e. it stimulated ret/MEN2B mitogenic and kinase activities, as well as its ability to phosphorylate Shc, a bona fide Ret substrate. In contrast, ret mutants associated with MEN2A or FMTC (carrying Cys634 or Cys620 mutations) were unresponsive to GDNF. HSCR mutations, by affecting either the extracellular or the intracellular Ret domain, impaired responsiveness to GDNF. These data suggest that the phenotype of human diseases caused by ret mutations can be differentially influenced by GDNF.

Original languageEnglish
Pages (from-to)3613-3619
Number of pages7
JournalEndocrinology
Volume139
Issue number8
DOIs
Publication statusPublished - 1998

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Multiple Endocrine Neoplasia Type 2a
Multiple Endocrine Neoplasia
Glial Cell Line-Derived Neurotrophic Factor
Hirschsprung Disease
Mutation
Phenotype
Gene Rearrangement
Thyroid Diseases
Receptor Protein-Tyrosine Kinases
Point Mutation
Protein-Tyrosine Kinases
Thyroid Gland
Phosphotransferases
Ligands
Cell Line

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease. / Carlomagno, Francesca; Melillo, Rosa Marina; Visconti, Roberta; Salvatore, Giuliana; De Vita, Gabriella; Lupoli, Gelsy; Yu, Yanbin; Jing, Shuqian; Vecchio, Giancarlo; Fusco, Alfredo; Santoro, Massimo.

In: Endocrinology, Vol. 139, No. 8, 1998, p. 3613-3619.

Research output: Contribution to journalArticle

Carlomagno, Francesca ; Melillo, Rosa Marina ; Visconti, Roberta ; Salvatore, Giuliana ; De Vita, Gabriella ; Lupoli, Gelsy ; Yu, Yanbin ; Jing, Shuqian ; Vecchio, Giancarlo ; Fusco, Alfredo ; Santoro, Massimo. / Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease. In: Endocrinology. 1998 ; Vol. 139, No. 8. pp. 3613-3619.
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T1 - Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease

AU - Carlomagno, Francesca

AU - Melillo, Rosa Marina

AU - Visconti, Roberta

AU - Salvatore, Giuliana

AU - De Vita, Gabriella

AU - Lupoli, Gelsy

AU - Yu, Yanbin

AU - Jing, Shuqian

AU - Vecchio, Giancarlo

AU - Fusco, Alfredo

AU - Santoro, Massimo

PY - 1998

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AB - Ret is a receptor tyrosine kinase involved in several neoplastic and developmental diseases affecting the thyroid gland and tissues of neuroectodermal origin. Different ret mutations are associated with different disease phenotypes. Gain-of-function of ret is caused by gene rearrangements in thyroid papillary carcinomas and by point mutations in multiple endocrine neoplasia (MEN) type 2A syndrome (MEN2A), in familial medullary thyroid carcinoma (FMTC), and in the more severe MEN2B syndrome. Conversely, Hirschsprung's disease (HSCR) is associated with loss of function of ret. Recently, it has been shown that glial cell line-derived neurotrophic factor (GDNF), by binding to the accessory molecule GDNFR-α, acts as a functional ligand of Ret and stimulates its tyrosine kinase and biological activity. To ascertain whether the biological effects of ret mutations are modulated by GDNF, we have investigated the responsiveness to GDNF of ret mutants in cell lines coexpressing GDNFR-α and MEN2A-, MEN2B-, FMTC-, or HSCR-associated ret mutants. Here, we show that triggering of GDNF affected only ret/MEN2B, i.e. it stimulated ret/MEN2B mitogenic and kinase activities, as well as its ability to phosphorylate Shc, a bona fide Ret substrate. In contrast, ret mutants associated with MEN2A or FMTC (carrying Cys634 or Cys620 mutations) were unresponsive to GDNF. HSCR mutations, by affecting either the extracellular or the intracellular Ret domain, impaired responsiveness to GDNF. These data suggest that the phenotype of human diseases caused by ret mutations can be differentially influenced by GDNF.

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