Functional characterization of five constitutively activating thyrotrophin receptor mutations

Wonerow, Peter; Chey, Soroth; Führer, Dagmar; Holzapfel, H.; Paschke, Ralf

doi:10.1046/j.1365-2265.2000.01119.x

Cited by 32 publications

(23 citation statements)

References 27 publications

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“…Studies showing that TSHR activation can be induced by mutations or deletions in various receptor domains support the model of different active conformations of the TSHR. Moreover, multiple active receptor states underlie coupling of a GPCR to different G proteins (13,224). In certain cases mutation appears to cause an altered receptor conformation that affects TSH binding, but not constitutive activity (98).…”

Section: E Other Concepts Of Tsh-tshr Interactionmentioning

confidence: 99%

Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

Szkudlinski

Frémont²,

Ronin³

et al. 2002

Physiological Reviews

395

256

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This review focuses on recent advances in the structure-function relationships of thyroid-stimulating hormone (TSH) and its receptor. TSH is a member of the glycoprotein hormone family constituting a subset of the cystine-knot growth factor superfamily. TSH is produced by the pituitary thyrotrophs and released to the circulation in a pulsatile manner. It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs). New insights into the structure-function relationships of TSH permitted better understanding of the role of specific protein and carbohydrate domains in the synthesis, bioactivity, and clearance of this hormone. Recent progress in studies on TSHR as well as studies on the other GPCRs provided new clues regarding the molecular mechanisms of receptor activation. Such advances are a result of extensive site-directed mutagenesis, peptide and antibody approaches, detailed sequence analyses, and molecular modeling as well as studies on naturally occurring gain- and loss-of-function mutations. This review integrates expanding information on TSH and TSHR structure-function relationships and summarizes current concepts on ligand-dependent and -independent TSHR activation. Special emphasis has been placed on TSH domains involved in receptor recognition, constitutive activity of TSHR, new insights into the evolution of TSH bioactivity, and the development of high-affinity TSH analogs. Such structural, physiological, pathophysiological, evolutionary, and therapeutic implications of TSH-TSHR structure-function studies are frequently discussed in relation to concomitant progress made in studies on gonadotropins and their receptors.

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Section: E Other Concepts Of Tsh-tshr Interactionmentioning

confidence: 99%

Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

Szkudlinski

Frémont²,

Ronin³

et al. 2002

Physiological Reviews

395

256

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“…The cell surface expression of the TSHR determined by FACS analysis was confirmed by ELISA as previously described (Wonerow et al, 2000).…”

Section: Elisamentioning

confidence: 99%

Gene expression analysis reveals evidence for inactivation of the TGF-β signaling cascade in autonomously functioning thyroid nodules

et al. 2004

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Molecular eventsthat lead to the development of autonomously functioning thyroid nodules (AFTNs) are somatic mutations of the thyrotropin receptor (TSHR) in approximately 60% of the nodules and less frequently, somatic mutations in the G s a protein. However, AFTNs without known mutations indicate that other causes remain to be identified. Moreover, the impact of constitutively activating TSHR mutations on the signal transduction network of the thyroid epithelial cell is unknown. We therefore investigated gene expression in 15 AFTNs and their surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed a changed pattern of gene expression in the TGF-b signaling cascade and 25 differentially regulated genes in AFTNs, including thyroid peroxidase, type I iodothyronine deiodinase and sialyltransferase (SIAT) 1. Strikingly coexpression of SIAT 1 and TSHR in COS-7 cells increased TSH binding and cell surface expression of the TSHR. Moreover, differences in gene expression patterns for AFTNs with and without TSHR mutations indicate specific alterations of signal transduction in AFTNs without TSHR mutations. These results suggest that AFTNs with TSHR mutations harbor further mechanisms of forward stimulation. Furthermore, they give important leads to elucidate the molecular etiology of AFTNs without TSHR mutations.

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“…Subsequently, cells were stimulated with bovine TSH for 1 h as described before (18). Stimulation was terminated by aspiration of the medium and addition of 0.5 ml 3% perchloric acid.…”

Section: Stimulation Of Inositol Phosphate Formationmentioning

confidence: 99%

“…Inositol phosphates were measured as described (18). Forty hours after transfection 2 £ 10 5 COS 7 cells were incubated with 2 mCi/ml [myo-…”

Section: Stimulation Of Inositol Phosphate Formationmentioning

confidence: 99%

Expression of G(alpha)(s) proteins and TSH receptor signalling in hyperfunctioning thyroid nodules with TSH receptor mutations

Holzapfel

Bergner

Wonerow

et al. 2002

European Journal of Endocrinology

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Objective: Constitutively activating mutations of the thyrotrophin receptor (TSHR) are the main molecular cause of hyperfunctioning thyroid nodules (HTNs). The G protein coupling is an important and critical step in the TSHR signalling which mainly includes Gas, Gai and Gaq/11 proteins. Design: We investigated the in vitro consequences of overexpressing Ga proteins on signalling of the wild-type (WT) or mutated TSHR. Moreover, we investigated whether changes in Ga protein expression are pathophysiologically relevant in HTNs or cold thyroid nodules (CTNs).

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Functional characterization of five constitutively activating thyrotrophin receptor mutations

Cited by 32 publications

References 27 publications

Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

Gene expression analysis reveals evidence for inactivation of the TGF-β signaling cascade in autonomously functioning thyroid nodules

Expression of G(alpha)(s) proteins and TSH receptor signalling in hyperfunctioning thyroid nodules with TSH receptor mutations

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