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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Gujral TS,Singh VK,Jia Z,Mulligan LMdoi
10.1158/0008-5472.CAN-06-3329subject
Has Abstractpub_date
2006-11-15 00:00:00pages
10741-9issue
22eissn
0008-5472issn
1538-7445pii
66/22/10741journal_volume
66pub_type
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