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

Abstract

Multiple endocrine neoplasia 2B (MEN 2B) is an inherited syndrome of early onset endocrine tumors and developmental anomalies. The disease is caused primarily by a methionine to threonine substitution of residue 918 in the kinase domain of the RET receptor (2B-RET); however, the molecular mechanisms that lead to the disease phenotype are unclear. In this study, we show that the M918T mutation causes a 10-fold increase in ATP binding affinity and leads to a more stable receptor-ATP complex, relative to the wild-type receptor. Further, the M918T mutation alters local protein conformation, correlating with a partial loss of RET kinase autoinhibition. Finally, we show that 2B-RET can dimerize and become autophosphorylated in the absence of ligand stimulation. Our data suggest that multiple distinct but complementary molecular mechanisms underlie the MEN 2B phenotype and provide potential targets for effective therapeutics for this disease.

• Authors: Taranjit S Gujral, Vinay K Singh, Zongchao Jia, Lois M Mulligan
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 22 Pg. 10741-9 (Nov 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 17108110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenosine Triphosphate
• Proto-Oncogene Proteins c-ret

Topics

• Adenosine Triphosphate (metabolism)
• Amino Acid Sequence
• Dimerization
• Humans
• Models, Molecular
• Molecular Sequence Data
• Multiple Endocrine Neoplasia Type 2b (enzymology, genetics, metabolism)
• Oncogenes
• Phosphorylation
• Protein Conformation
• Proto-Oncogene Proteins c-ret (antagonists & inhibitors, chemistry, genetics, metabolism)
• Sequence Homology, Amino Acid
• Structure-Activity Relationship