Document Detail


Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B.
MedLine Citation:
PMID:  17108110     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-19     Completed Date:  2006-12-14     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10741-9     Citation Subset:  IM    
Affiliation:
Departments of Pathology and Biochemistry, Queen's University, Kingston, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
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
Chemical
Reg. No./Substance:
56-65-5/Adenosine Triphosphate; EC 2.7.10.1/Proto-Oncogene Proteins c-ret

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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