Involvement of JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) in the Thyrotropin Signaling Pathway

Abstract

TSH is an important physiological regulator of growth and function in thyroid gland. The mechanism of action of TSH depends on interaction with its receptor coupled to heterotrimeric G proteins. We show here that TSH induces the phosphorylation of tyrosine in the intracellular kinases Janus kinase 1 (JAK1) and -2 (JAK2) in rat thyroid cells and in Chinese hamster ovary (CHO) cells transfected with human TSH receptor (TSHR). The JAK family substrates STAT3 (signal transducers and activators of transcription) are rapidly tyrosine phosphorylated in response to TSH. We also find that JAK1, JAK2, and STAT3 coprecipitate with the TSHR, indicating that the TSHR may be able to signal through the intracellular phosphorylation pathway used by the JAK-STAT cascade. TSH increases STAT3-mediated promoter activity and also induces endogenous SOCS-1 (suppressor of cytokine signaling-1) gene expression, a known target gene of STAT3. The expression of a dominant negative form of STAT3 completely inhibited TSH-mediated SOCS-1 expression. These findings suggest that the TSHR is able to signal through JAK/STAT3 pathways.

Expression of cAMP-responsive element binding protein and inducible cAMP early repressor in hyperfunctioning thyroid adenomas

“…Furthermore, besides PKA, both the PKC and the tyrosine-kinase cascade have been related to the control of thyroid cell growth (13). Recent evidence has also demonstrated the involvement of JAK/STAT in the TSH-signalling pathway (39). These data might, at least in part, explain the case-to-case variability that we observed and also the unexpected absence of CREB expression in a few cases.…”

Overexpression of Wnt-1 in thyrocytes enhances cellular growth but suppresses transcription of the thyroperoxidase gene via different signaling mechanisms

“…We found that the amount of STAT3 protein phosphorylated on serine 727 was increased in the Wnt-1 overexpressing stable transfectant W1 clone, when compared with nontransfected FRTL-5 cells or to a vector-transfected clone. The increase in Ser727 phosphorylation of STAT3 seems not to be through the TSH/cAMP-signaling pathway, as TSH induces phosphorylation at both sites, Tyr 705 and Ser 727 in FRTL-5 cells (Park et al 2000). As there is evidence for a role of PKC in serine phosphorylation of STAT3 (Jain et al 1999), it is plausible that the Wnt-1 activation of the Wnt/Ca CC pathway leading to PKC activation increased serine phosphorylation of STAT3 in the Wnt-1 overexpressing cell.…”

Characterization of Mutations, Including a Novel Regulatory Defect in the First Intron, in Bruton’s Tyrosine Kinase Gene from Seven Korean X-Linked Agammaglobulinemia Families

“…Gel-purified oligonucleotides were labeled with [␥-32 P]ATP using T4 polynucleotide kinase and purified on an 8% native polyacrylamide gel. EMSA was performed as previously described (26). Binding reactions in high salt with detergent were conducted in a solution of 1.5 fmol of 32 P-labeled DNA, 2 g of nuclear extract, and 0.5 g of poly(dI-dC) in 10 mM Tris-HCl (pH 7.9), 5 mM MgCl 2 , 50 mM KCl, 1 mM DTT, 1 mM EDTA, 0.1% Triton X-100, and 12.5% glycerol.…”