Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities

Xin Liu, Quinn Vega, Ruth A. Decker, Akhilesh Pandey, Carolyn A. Worby, Jack E. Dixon

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

The c-ret proto-oncogene encodes a receptor tyrosine kinase which plays an important role in neural crest as well as kidney development. Genetic studies have demonstrated that germ line mutations in the ret oncogene are the direct cause of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease. However, despite the large body of genetic and biological evidence suggesting the importance of RET in development and neoplastic processes, the signal transduction mechanisms of RET remain unknown. To begin to understand the molecular mechanisms of the disease states caused by mutations in RET, the patterns of autophosphorylation of the wild-type RET and the MEN mutants were studied using site-directed mutagenesis and phosphopeptide mapping. Among the 6 autophosphorylation sites found in the wild-type RET receptor, the MEN2B mutant lacked phosphorylation at Tyr-1096, leading to decreased Grb2 binding, while simultaneously creating a new phosphorylation site. These changes in autophosphorylation suggest that the MEN2B mutation may result in the more aggressive MEN2B phenotype by altering the receptor's signaling capabilities.

Original languageEnglish
Pages (from-to)5309-5312
Number of pages4
JournalJournal of Biological Chemistry
Volume271
Issue number10
DOIs
StatePublished - 8 Mar 1996

Fingerprint

Multiple Endocrine Neoplasia
Phosphorylation
Substrate Specificity
Binding Sites
Neoplastic Processes
Phosphopeptides
Hirschsprung Disease
Signal transduction
Mutagenesis
Mutation
Proto-Oncogenes
Germ-Line Mutation
Neural Crest
Thyroid Diseases
Receptor Protein-Tyrosine Kinases
Substrates
Site-Directed Mutagenesis
Oncogenes
Signal Transduction
Phenotype

Cite this

Liu, Xin ; Vega, Quinn ; Decker, Ruth A. ; Pandey, Akhilesh ; Worby, Carolyn A. ; Dixon, Jack E. / Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. In: Journal of Biological Chemistry. 1996 ; Vol. 271, No. 10. pp. 5309-5312.
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abstract = "The c-ret proto-oncogene encodes a receptor tyrosine kinase which plays an important role in neural crest as well as kidney development. Genetic studies have demonstrated that germ line mutations in the ret oncogene are the direct cause of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease. However, despite the large body of genetic and biological evidence suggesting the importance of RET in development and neoplastic processes, the signal transduction mechanisms of RET remain unknown. To begin to understand the molecular mechanisms of the disease states caused by mutations in RET, the patterns of autophosphorylation of the wild-type RET and the MEN mutants were studied using site-directed mutagenesis and phosphopeptide mapping. Among the 6 autophosphorylation sites found in the wild-type RET receptor, the MEN2B mutant lacked phosphorylation at Tyr-1096, leading to decreased Grb2 binding, while simultaneously creating a new phosphorylation site. These changes in autophosphorylation suggest that the MEN2B mutation may result in the more aggressive MEN2B phenotype by altering the receptor's signaling capabilities.",
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Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. / Liu, Xin; Vega, Quinn; Decker, Ruth A.; Pandey, Akhilesh; Worby, Carolyn A.; Dixon, Jack E.

In: Journal of Biological Chemistry, Vol. 271, No. 10, 08.03.1996, p. 5309-5312.

Research output: Contribution to journalArticle

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