Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation.
Thyroid papillary carcinomas are characterized by RET/PTC (rearranged in transformation/papillary thyroid carcinoma) rearrangements that result in fusion of the tyrosine kinase domain of the RET receptor to the N-terminal sequences encoded by heterologous genes. This thyroid-specific rearrangement causes aberrant expression of RET/PTC and results in constitutive ligand-independent activation of RET kinase. However, it is unclear how RET/PTC activates the specific signaling pathways for cellular transformation. In this study, we show that RET/PTC associates with signal transducer and activator of transcription 3 (STAT3) and activates it by the specific phosphorylation of the tyrosine 705 residue. Activation of STAT3 requires the intrinsic kinase activity of RET/PTC; Janus tyrosine kinase and c-Src kinase are not involved in the RET/PTC-mediated activation of STAT3. RET/PTC-induced activation of STAT3 induces the STAT3-responsive genes, vascular endothelial growth factor, cyclin D1, and intercellular adhesion molecule 1. In addition, RET/PTC-mediated cellular transformation and proliferation of transformed cells require tyrosine 705 phosphorylation of STAT3 in NIH3T3 cells. We conclude that STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes, such as cyclin D1, vascular endothelial growth factor, and intercellular adhesion molecule 1, and for cellular transformation.
Hwang
Jung Hwan
JH
Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University College of Medicine, 640 Daesadong Chungku, Daejeon 301-721, Korea.
Kim
Dong Wook
DW
Suh
Jae Mi
JM
Kim
Ho
H
Song
Jung Hun
JH
Hwang
Eun Suk
ES
Park
Ki Cheol
KC
Chung
Hyo Kyun
HK
Kim
Jin Man
JM
Lee
Tae-Hoon
TH
Yu
Dae-Yeul
DY
Shong
Minho
M
D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human