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Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B

Taranjit S Gujral1, Vinay K Singh, Zongchao Jia

  • 1Departments of Pathology and Biochemistry, Queen's University, Kingston, Ontario, Canada.

Cancer Research
|November 17, 2006
PubMed

Insights

The M918T mutation in the RET receptor causes increased ATP binding and instability, leading to uncontrolled kinase activity. These molecular changes explain the development of Multiple Endocrine Neoplasia 2B (MEN 2B) and suggest therapeutic targets.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Multiple Endocrine Neoplasia 2B (MEN 2B) is an inherited disorder characterized by early-onset endocrine tumors.
  • The primary cause is the M918T mutation in the RET receptor tyrosine kinase.
  • The precise molecular mechanisms driving MEN 2B pathogenesis remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which the M918T mutation in the RET receptor leads to MEN 2B.
  • To investigate the impact of the M918T mutation on RET receptor kinase activity, stability, and signaling.

Main Methods:

  • Biochemical assays to measure ATP binding affinity and receptor-ATP complex stability.
  • Analysis of protein conformation and kinase autoinhibition.
  • Investigation of RET receptor dimerization and autophosphorylation in the absence of ligand stimulation.

Main Results:

  • The M918T mutation significantly increases ATP binding affinity (10-fold) and stabilizes the RET-ATP complex.
  • This mutation alters local protein conformation, resulting in partial loss of RET kinase autoinhibition.
  • The mutated 2B-RET receptor exhibits ligand-independent dimerization and autophosphorylation.

Conclusions:

  • Multiple, complementary molecular mechanisms driven by the M918T mutation contribute to the MEN 2B phenotype.
  • These findings identify potential therapeutic targets for MEN 2B treatment.
  • Understanding RET receptor dysregulation offers insights into endocrine tumor development.

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