title: Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities.
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.
authors.affiliation: Department of Biological Chemistry, University of Michigan School of Medicine, Ann Arbor, 48109, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: Q C
authors.initials: QC
authors.lastname: Vega
authors.forename: R A
authors.initials: RA
authors.lastname: Decker
authors.forename: A
authors.initials: A
authors.lastname: Pandey
authors.forename: C A
authors.initials: CA
authors.lastname: Worby
authors.forename: J E
authors.initials: JE
authors.lastname: Dixon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D029721:Drosophila Proteins; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D010748:Phosphopeptides / Q000737:chemistry / Q000302:isolation & purification; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013964:Thyroid Neoplasms / Q000235:genetics; D014162:Transfection
chemical_list: D029721:Drosophila Proteins; D000939:Epitopes; C000715470:MAS1 protein, human; D010446:Peptide Fragments; D010748:Phosphopeptides; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila