Reactome | TSHR binds TSH/Thyrostimulin

TSHR binds TSH/Thyrostimulin

Stable Identifier

R-HSA-391375

Type

Reaction [transition]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

Synonyms

Thyroid-stimulating hormone receptor can bind TSH, Thyrostimulin

ReviewStatus

4/5

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Thyroid-stimulating hormone (TSH, thyrotropin) binds thyrotropin receptor (TSHR) on the basolateral membrane of thyroid cells (Nagayama Y et al., 1989). The mature TSHR can be either a single chain peptide or a dimer of two subunits linked by disulfide bridges that also exist in the single chain form. In many scores of experiments, the proportion of single-chain TSHR on the cell surface persists in the 30–50% range (reviewed by Rapoport & McLachlan, 2015). As the boundaries of the subunits are unclear we use the single chain form of TSHR. TSH is a dimeric glycoprotein synthesized and secreted by thyrotrope cells in the anterior pituitary gland. TSH regulates the endocrine function of the thyroid gland, mediating the release of the hormones thyroxine (T4) and triiodothyronine (T3). Thyrostimulin is a dimer of Glycoprotein hormone alpha-2 (GPHA2) and Glycoprotein hormone beta-5(GPHB5), comprising the fifth glycoprotein hormone (Nakabayashi et al., 2002), a more potent ligand for the TSH receptor than TSH which has a wider tissue distribution (Huang et al., 2016).

Activation of TSHR leads to dissociation of G proteins into the G protein alpha-s (Gαs) and Gbetagamma (Gβγ) subunits, which in turn trigger several canonical signal transduction cascades. Gαs activates adenylate cyclase and increases intracellular cAMP levels, which ultimately affects the binding of transcription factors to genes expressing thyroid pathway enzymes (Allgeier A et al., 1994; reviewed in Jing & Zhang, 2022).

Mutations in TSHR can cause different phenotypes associated with hyperthyroidism (reviewed in Makkonen et al., 2024) and hypothyroidism (reviewed in Cassio et al., 2012). Defects in TSHR are also a cause of thyroid neoplasms (papillary and follicular cancers) (see, e.g., He et al., 2014; Tong et al., 2015). Finally, autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease (reviewed in Lane et al., 2020). See also Stephenson et al. 2018 for a database of polymorphisms.

Literature References

PubMed ID	Title	Journal	Year
23154162	Current loss-of-function mutations in the thyrotropin receptor gene: when to investigate, clinical effects, and treatment Cassio, A, Nicoletti, A, Rizzello, A, Zazzetta, E, Bal, M, Baldazzi, L	J Clin Res Pediatr Endocrinol	2013
12045258	Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor Nakabayashi, K, Matsumi, H, Bhalla, A, Bae, J, Mosselman, S, Hsu, SY, Hsueh, AJ	J. Clin. Invest.	2002
25303483	Genetic predisposition to papillary thyroid carcinoma: involvement of FOXE1, TSHR, and a novel lincRNA gene, PTCSC2 He, H, Li, W, Liyanarachchi, S, Jendrzejewski, J, Srinivas, M, Davuluri, RV, Nagy, R, de la Chapelle, A	J Clin Endocrinol Metab	2015
27273257	Thyrostimulin-TSHR signaling promotes the proliferation of NIH:OVCAR-3 ovarian cancer cells via trans-regulation of the EGFR pathway Huang, WL, Li, Z, Lin, TY, Wang, SW, Wu, FJ, Luo, CW	Sci Rep	2016
32111150	The Thyrotropin Receptor Mutation Database Update Stephenson, A, Lau, L, Eszlinger, M, Paschke, R	Thyroid	2020
26799472	TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective Rapoport, B, McLachlan, SM	Endocr Rev	2016
32845332	New Therapeutic Horizons for Graves' Hyperthyroidism Lane, LC, Cheetham, TD, Perros, P, Pearce, SHS	Endocr Rev	2020
26260781	Mutations of TSHR and TP53 Genes in an Aggressive Clear Cell Follicular Carcinoma of the Thyroid Tong, GX, Mody, K, Wang, Z, Hamele-Bena, D, Nikiforova, MN, Nikiforov, YE	Endocr Pathol	2015
36187113	Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion Jing, L, Zhang, Q	Front Endocrinol (Lausanne)	2022
8188646	The human thyrotropin receptor activates G-proteins Gs and Gq/11 Allgeier, A, Offermanns, S, Van Sande, J, Spicher, K, Schultz, G, Dumont, JE	J Biol Chem	1994
38194289	Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model Makkonen, K, Jännäri, M, Crisóstomo, L, Kuusi, M, Patyra, K, Melnyk, V, Linnossuo, V, Ojala, J, Ravi, R, Löf, C, Mäkelä, JA, Miettinen, P, Laakso, S, Ojaniemi, M, Jääskeläinen, J, Laakso, M, Bossowski, F, Sawicka, B, Stożek, K, Bossowski, A, Kleinau, G, Scheerer, P, FinnGen, F, Reeve, MP, Kero, J	JCI Insight	2024
2558651	Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor Nagayama, Y, Kaufman, KD, Seto, P, Rapoport, B	Biochem Biophys Res Commun	1989