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Tshr  -  thyroid stimulating hormone receptor

Rattus norvegicus

Synonyms: TSH-R, Thyroid-stimulating hormone receptor, Thyrotropin receptor
 
 
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Disease relevance of Tshr

  • Thyrotropin (TSH) and IgG preparations from patients with Graves' disease increase inositol phosphate as well as cAMP formation in Cos-7 cells transfected with rat TSH receptor cDNA [1].
  • These data provide a molecular link between the occurrence of TSH receptor mutations and thyroid autonomously functioning adenomas [2].
  • When we measured the p66Shc levels induced by individual Igs from 130 patients with Graves' disease, TSH receptor stimulating activity and goiter size showed a weak correlation [3].
  • Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism [4].
  • Treatment of newborn rats with a single dose of monoclonal antibody to TSH receptor, caused permanent changes in the body weight, T4 level, and different sexual parameters [5].
 

High impact information on Tshr

  • The kinetics of ICER protein induction mirrors the down-regulation of TSH-R mRNA [6].
  • There were minimal amounts of the two mRNAs in rat ovary, and neither was detected in RNA preparations from rat testis, liver, lung, brain, spleen, and FRT thyroid cells, which do not have a functional TSH receptor [7].
  • Down-regulation was also duplicated by thyroid-stimulating autoantibodies, which increased cAMP levels, but not by thyrotropin binding-inhibiting auto-antibodies, which actually increased TSH receptor mRNA levels [7].
  • The results indicate that more complex gangliosides do not serve as a component of the TSH receptor nor are they involved in the transmission of the hormone signal across the cell membrane of these cultured rat thyroid cells [8].
  • These results indicate that the fat cell expresses high levels of a TSH-R whose function is indistinguishable from that in the thyroid and suggest that the TSH-R autoantibody plays an important role in the pathogenesis of the extrathyroidal manifestations of Graves' disease [9].
 

Biological context of Tshr

  • The mutations increase the affinity of the TSH receptor for [125I]TSH and decrease Bmax; however, cells with an equivalently decreased Bmax as a result of transfection with lower levels of wild type receptor do not lose either TSH-induced inositol phosphate formation or cAMP signaling activity [1].
  • A similar approach also generated a soluble TSH receptor fragment capable of blocking TSH-induced signal transduction [10].
  • To investigate the function of TSH-R from adipose tissue, we screened a rat fat cell lambda gt11 cDNA library for TSH-R sequences using a 32P-labeled rat thyroid TSH-R cDNA as a probe [9].
  • This supports the hypothesis that common transcription factors regulate TSHR and major histocompatibility gene expression [11].
  • TSH/cAMP induces negative autoregulation of the TSHR, in part, by decreasing maximal expression resultant from SSBP-1 binding to the SSBP elements [11].
 

Anatomical context of Tshr

 

Associations of Tshr with chemical compounds

  • In conclusion, our studies indicate that the biological effects of activating TSHR mutations vary with the ambient iodide supply and could be masked in regions of high iodine intake [14].
  • The majority (97%) of functional epitopes for stimulating thyrotropin receptor (TSHR) antibodies (stimulating TSHRAbs) in a large cohort (n = 59) of Japanese Graves' patients exists on the N-terminal region of the extracellular domain of TSHR, between residues 25 and 165 numbering from the methionine start site [15].
  • To gain insight into the thyrotropin hormone (TSH) receptor (TSHR) cleavage, we sought to convert the noncleaving luteinizing hormone (LH) receptor (LHR) into a cleaved, two-subunit molecule [16].
  • We first targeted a cluster of three N-linked glycans in the LHR (N295, N303, N317) in a region corresponding to the primary TSHR cleavage site, which has only one N-linked glycan [16].
  • Optimization of the benzoic acid side chains of 1-3 led to gains in selectivity versus activity at the thyroid stimulating hormone (TSH) receptor (TSHR) [17].
 

Other interactions of Tshr

  • The TSH receptor has a stable helical structure, the LH receptor has both helix and beta-sheet structures, and the FSH receptor sorting signal has a main random coil structure [18].
  • TPA-treated PC Cl 3 cells are unable to trap iodide and the expression levels of thyroglobulin, TSH receptor, and TPO genes are drastically reduced by TPA treatment [19].
  • It is suggested, therefore, that there exist in the FRTL5 cell line at least two mechanisms for the regulation of growth, one activated at the level of the IGF-I receptor and the other at the level of the TSH receptor [20].
  • Evidence is additionally provided that TSH receptor mRNA levels are increased by insulin, IGF-I, or calf serum in both Northern and run-on assays [21].
  • The TSH receptor mRNA level correlated to the beta-actin mRNA was 2-fold higher in control cells compared to that in 1,25-(OH)2D3-treated cells 12 h after TSH removal [22].
 

Analytical, diagnostic and therapeutic context of Tshr

  • The formation of thyrotropin receptor (TSHR) antibodies in a Graves' animal model requires the N-terminal segment of the TSHR extracellular domain [23].
  • Thyrotropin receptor (TSH-R) has been thought to be thyroid-specific, but, by Northern blot analysis, we found that rat adipose tissue expressed TSH-R mRNAs in amounts approaching those in the thyroid [9].
  • Deletions, substitutions, or mutations of the rat TSH receptor extracellular domain between residues 20 and 107 (all residue numbers are determined by counting from the methionine start site) have been made by site-directed mutagenesis of receptor cDNA [24].
  • Both deoxyribonuclease I footprint analysis and gel mobility-shift assays indicated that bacterially expressed glutathione S-transferase fusion proteins of GABP subunits bind to a region spanning nucleotides (nt) -116 to -80 of the TSHR gene [25].
  • Recombinant human thyrotropin (TSH) receptor in a radioreceptor assay for the measurement of TSH receptor autoantibodies [26].

References

  1. Mutation of alanine 623 in the third cytoplasmic loop of the rat thyrotropin (TSH) receptor results in a loss in the phosphoinositide but not cAMP signal induced by TSH and receptor autoantibodies. Kosugi, S., Okajima, F., Ban, T., Hidaka, A., Shenker, A., Kohn, L.D. J. Biol. Chem. (1992) [Pubmed]
  2. Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells. Porcellini, A., Ruggiano, G., Pannain, S., Ciullo, I., Amabile, G., Fenzi, G., Avvedimento, E.V. Oncogene (1997) [Pubmed]
  3. p66Shc expression in proliferating thyroid cells is regulated by thyrotropin receptor signaling. Park, Y.J., Kim, T.Y., Lee, S.H., Kim, H., Kim, S.W., Shong, M., Yoon, Y.K., Cho, B.Y., Park, D.J. Endocrinology (2005) [Pubmed]
  4. Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism. Watson, S.G., Radford, A.D., Kipar, A., Ibarrola, P., Blackwood, L. J. Endocrinol. (2005) [Pubmed]
  5. Effect of neonatal treatment with monoclonal antibody to thyrotropin (TSH) receptor on the thyroxin (T4) level and certain parameters of the internal genital organs of adult rats. Karabélyos, C., Nagy, S.U., Csaba, G. Acta physiologica Hungarica. (1996) [Pubmed]
  6. Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor. Lalli, E., Sassone-Corsi, P. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  7. Cloning, chromosomal assignment, and regulation of the rat thyrotropin receptor: expression of the gene is regulated by thyrotropin, agents that increase cAMP levels, and thyroid autoantibodies. Akamizu, T., Ikuyama, S., Saji, M., Kosugi, S., Kozak, C., McBride, O.W., Kohn, L.D. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  8. Reevaluation of the role of gangliosides in the binding and action of thyrotropin. Beckner, S.K., Brady, R.O., Fishman, P.H. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  9. Cloning and functional expression of a thyrotropin receptor cDNA from rat fat cells. Endo, T., Ohta, K., Haraguchi, K., Onaya, T. J. Biol. Chem. (1995) [Pubmed]
  10. Derivation of functional antagonists using N-terminal extracellular domain of gonadotropin and thyrotropin receptors. Osuga, Y., Kudo, M., Kaipia, A., Kobilka, B., Hsueh, A.J. Mol. Endocrinol. (1997) [Pubmed]
  11. Cloning of the single strand DNA-binding protein important for maximal expression and thyrotropin (TSH)-induced negative regulation of the TSH receptor. Ohmori, M., Ohta, M., Shimura, H., Shimurat, Y., Suzuki, K., Kohn, L.D. Mol. Endocrinol. (1996) [Pubmed]
  12. GRK2 and beta-arrestin 1 as negative regulators of thyrotropin receptor-stimulated response. Iacovelli, L., Franchetti, R., Masini, M., De Blasi, A. Mol. Endocrinol. (1996) [Pubmed]
  13. Major histocompatibility complex class I gene expression in rat thyroid cells is regulated by hormones, methimazole, and iodide as well as interferon. Saji, M., Moriarty, J., Ban, T., Singer, D.S., Kohn, L.D. J. Clin. Endocrinol. Metab. (1992) [Pubmed]
  14. Biological activity of activating thyrotrophin receptor mutants: modulation by iodide. Al-Khafaji, F., Wiltshire, M., Fuhrer, D., Mazziotti, G., Lewis, M.D., Smith, P.J., Ludgate, M. J. Mol. Endocrinol. (2005) [Pubmed]
  15. Epitopes for thyroid stimulating and blocking autoantibodies on the extracellular domain of the human thyrotropin receptor. Tahara, K., Ishikawa, N., Yamamoto, K., Hirai, A., Ito, K., Tamura, Y., Yoshida, S., Saito, Y., Kohn, L.D. Thyroid (1997) [Pubmed]
  16. Insight into thyrotropin receptor cleavage by engineering the single polypeptide chain luteinizing hormone receptor into a cleaving, two subunit receptor. Chazenbalk, G.D., McLachlan, S.M., Chen, C.R., Rapoport, B. Eur. J. Biochem. (2001) [Pubmed]
  17. Synthesis of (bis)sulfonic acid, (bis)benzamides as follicle-stimulating hormone (FSH) antagonists. Wrobel, J., Green, D., Jetter, J., Kao, W., Rogers, J., Pérez, M.C., Hardenburg, J., Deecher, D.C., López, F.J., Arey, B.J., Shen, E.S. Bioorg. Med. Chem. (2002) [Pubmed]
  18. The basolateral sorting signals of the thyrotropin and luteinizing hormone receptors: an unusual family of signals sharing an unusual distal intracellular localization, but unrelated in their structures. Beau, I., Groyer-Picard, M.T., Desroches, A., Condamine, E., Leprince, J., Tomé, J.P., Dessen, P., Vaudry, H., Misrahi, M. Mol. Endocrinol. (2004) [Pubmed]
  19. TPA induces a block of differentiation and increases the susceptibility to neoplastic transformation of a rat thyroid epithelial cell line. Portella, G., Vitagliano, D., Li, Z., Sferratore, F., Santoro, M., Vecchio, G., Fusco, A. Oncol. Res. (1998) [Pubmed]
  20. Insulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves'-IgG. Tramontano, D., Cushing, G.W., Moses, A.C., Ingbar, S.H. Endocrinology (1986) [Pubmed]
  21. Regulation of thyrotropin receptor gene expression in rat FRTL-5 thyroid cells. Saji, M., Akamizu, T., Sanchez, M., Obici, S., Avvedimento, E., Gottesman, M.E., Kohn, L.D. Endocrinology (1992) [Pubmed]
  22. 1,25-Dihydroxyvitamin D3 attenuates adenylyl cyclase activity in rat thyroid cells: reduction of thyrotropin receptor number and increase in guanine nucleotide-binding protein Gi-2 alpha. Berg, J.P., Sandvik, J.A., Ree, A.H., Sørnes, G., Bjøro, T., Torjesen, P.A., Gordeladze, J.O., Haug, E. Endocrinology (1994) [Pubmed]
  23. The formation of thyrotropin receptor (TSHR) antibodies in a Graves' animal model requires the N-terminal segment of the TSHR extracellular domain. Kikuoka, S., Shimojo, N., Yamaguchi, K.I., Watanabe, Y., Hoshioka, A., Hirai, A., Saito, Y., Tahara, K., Kohn, L.D., Maruyama, N., Kohno, Y., Niimi, H. Endocrinology (1998) [Pubmed]
  24. Identification of separate determinants on the thyrotropin receptor reactive with Graves' thyroid-stimulating antibodies and with thyroid-stimulating blocking antibodies in idiopathic myxedema: these determinants have no homologous sequence on gonadotropin receptors. Kosugi, S., Ban, T., Akamizu, T., Kohn, L.D. Mol. Endocrinol. (1992) [Pubmed]
  25. Regulation of the rat thyrotropin receptor gene by the methylation-sensitive transcription factor GA-binding protein. Yokomori, N., Tawata, M., Saito, T., Shimura, H., Onaya, T. Mol. Endocrinol. (1998) [Pubmed]
  26. Recombinant human thyrotropin (TSH) receptor in a radioreceptor assay for the measurement of TSH receptor autoantibodies. Filetti, S., Foti, D., Costante, G., Rapoport, B. J. Clin. Endocrinol. Metab. (1991) [Pubmed]
 
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