Abstract
The MEN2A oncogene encodes for a constitutive active member of the RET receptor tyrosine kinase family. Here, we report that MEN2A-RET activates Signal Transducer and Activator of Transcription 3 (STAT3) via two YxxV/Q STAT3 docking sites, Tyr752 and Tyr928. MEN2A-RET induces both Tyr705 and Ser727 phosphorylation of STAT3, and STAT3 serine phosphorylation is required for its maximal transcriptional activity. Stable NIH3T3 cell lines expressing both MEN2A-RET and STAT3alpha but not STAT3beta, are characterized by enhanced proliferation and cyclin-D1 promoter activity, and enhanced growth in soft agar. These data indicate that malignant cell growth induced by MEN2A-RET involves its activation of STAT3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Binding Sites
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COS Cells
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Cell Division
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Cell Line
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Cell Transformation, Neoplastic*
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DNA-Binding Proteins / metabolism*
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Dose-Response Relationship, Drug
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Drosophila Proteins*
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Enzyme Activation
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Genes, Reporter
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Humans
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Mice
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Multiple Endocrine Neoplasia Type 2a / genetics*
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Multiple Endocrine Neoplasia Type 2a / metabolism*
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Oncogenes / genetics
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Phosphorylation
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Precipitin Tests
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases / metabolism*
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STAT3 Transcription Factor
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Serine / chemistry
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Time Factors
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Trans-Activators / metabolism*
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Transcriptional Activation
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Transfection
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Tyrosine / chemistry
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Up-Regulation
Substances
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DNA-Binding Proteins
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Drosophila Proteins
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Trans-Activators
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Tyrosine
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Serine
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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Ret protein, mouse