MEN2A-RET-induced cellular transformation by activation of STAT3.
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.
Schuringa
J J
JJ
Department of Developmental Genetics, University of Groningen, Kerklaan 30, 9751 NN, Haren, The Netherlands.
Wojtachnio
K
K
Hagens
W
W
Vellenga
E
E
Buys
C H
CH
Hofstra
R
R
Kruijer
W
W
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004789:Enzyme Activation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D012694:Serine / Q000737:chemistry; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine; D012694:Serine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse