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

Abstract

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.

GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3

“…Third, the levels of whole blood GDNF in patients with mood disorders are significantly lower than those in healthy control subjects [22]. Fourth, STAT3 might mediate astrogliogenesis from neural precursor cell [23,24,25,26,27] and GDNF-dependent mechanisms might exist for activation of STAT3 [28,29]. Our data show that GDNF increases ADP differentiation into astrocytes, but has no effect on ADP proliferation or apoptosis and that STAT3 is required for the effect of GDNF on ADP differentiation into astrocytes.…”

RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation

“…[26][27][28] Phosphorylation of the tyrosine 705 of STAT3 and therefore its activation has also been associated with RET fusion genes found in thyroid carcinomas and was shown to be independent from JAK TKs. 29 Case 1 was allografted rapidly after its diagnosis. Case 2 was treated initially using Imatinib but the white blood cells count continued to increase suggesting an inefficacity of this TK inhibitor.…”

Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

“…Chicken embryo fibroblasts grown in nonadherent conditions display decreased levels of STAT3 phosphorylation on residue Y705 compared to cells grown in adherent conditions (Uttamsingh et al, 2003). STAT3 also induces the expression of the intercellular adhesion molecule ICAM-1 through direct activation of the promoter, a transcriptional response requiring a functional Y705 residue (Hwang et al, 2003).…”