Characterization of ret oncogenic activation in MEN2 inherited cancer syndromes

Endocrinology. 1996 May;137(5):1512-9. doi: 10.1210/endo.137.5.8612479.


Germline mutations of c-ret, encoding a receptor-type tyrosine kinase, were found to be associated with variants of multiple endocrine neoplasia type 2 (MEN2A, MEN2B), and familial medullary thyroid carcinoma. NIH/3T3 stable transfectants expressing RET with a mutation of MEN2A (MEN2A/RET) or MEN2B (MEN2B/RET) gained a transformed morphology, formed colonies in soft agar, and formed tumors in nude mice. These results confirmed that both MEN2A/RET and MEN2B/RET exert dominant transforming activities in NIH/3T3 cells. However, in contrast to their clinical manifestation, transfectants expressing MEN2A/RET exhibited a higher tumorigenicity in nude mice than transfectants expressing MEN2B/RET may depend on the presence of its ligand and/or substrates that are absent in NIH/3T3 cells. No change in the cellular localization of the mutated RET proteins was observed compared to c-RET. Interestingly, ret activation in NIT/3T3 cells appeared to be associated with up-regulation of homologous gap-junctional intercellular communication and increased expression of a gap-junctional protein, connexin43.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Membrane / chemistry
  • Connexin 43 / genetics
  • Cytoplasm / chemistry
  • Drosophila Proteins*
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression
  • Humans
  • Mice
  • Mice, Nude
  • Multiple Endocrine Neoplasia Type 2a / genetics*
  • Multiple Endocrine Neoplasia Type 2b / genetics*
  • Proto-Oncogene Proteins / analysis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / analysis
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Transfection


  • Connexin 43
  • Drosophila Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, mouse