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Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations

M Takahashi1, N Asai, T Iwashita

  • 1Department of Pathology, Nagoya University School of Medicine, Japan. mtakaha@tsuru.med.nagoya-u.ac.jp

Journal of Internal Medicine
|July 29, 1998
PubMed

Insights

Multiple Endocrine Neoplasia (MEN) and familial medullary thyroid carcinoma (FMTC) mutations activate Ret, a key protein in cancer development. Cysteine mutations cause Ret dimerization and activation, while the MEN-2B mutation activates Ret intramolecularly.

Area of Science:

  • Oncology
  • Genetics
  • Biochemistry

Background:

  • Multiple Endocrine Neoplasia (MEN) types 2A and 2B, and familial medullary thyroid carcinoma (FMTC) are inherited disorders associated with RET proto-oncogene mutations.
  • Understanding the precise molecular mechanisms by which these RET mutations lead to disease is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the biological and biochemical effects of MEN-2A, MEN-2B, and FMTC mutations on Ret protein function.
  • To elucidate the distinct activation mechanisms of Ret by different mutation types and identify key intracellular tyrosine residues involved in transforming activity.

Main Methods:

  • Transfection of NIH 3T3 cells with various RET constructs encoding wild-type and mutant Ret proteins.
  • Assessment of Ret transforming activity, dimerization, cell surface expression, maturation, and tyrosine kinase activity.
  • Analysis of the role of specific intracellular tyrosine residues in mediating the transforming potential of mutant Ret proteins.

Main Results:

  • All investigated RET mutations conferred transforming activity on Ret, with varying levels.
  • Cysteine mutations (MEN-2A, FMTC) induced Ret homodimerization and activation of its tyrosine kinase, with codon 634 exhibiting the highest activity.
  • The MEN-2B mutation activated Ret via an intramolecular mechanism without dimerization, and specific tyrosines (905, 864, 952, 1062) were identified as critical for the transforming activity of different mutants.

Conclusions:

  • RET mutations in MEN-2A, MEN-2B, and FMTC activate Ret through distinct mechanisms, involving dimerization or intramolecular activation.
  • Specific intracellular tyrosine residues play critical roles in mediating the transforming activity of these oncogenic RET variants.
  • Tyrosine 1062 is a key regulator for both MEN-2A and MEN-2B Ret mutants and serves as a binding site for Shc, suggesting its importance in downstream signaling pathways.

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