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Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor
Koji Nakabayashi, … , Sheau Yu Hsu, Aaron J.W. Hsueh
Koji Nakabayashi, … , Sheau Yu Hsu, Aaron J.W. Hsueh
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1445-1452. https://doi.org/10.1172/JCI14340.
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Article Endocrinology

Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor

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Abstract

Human thyrotropin (TSH), luteotropin (LH), follitropin (FSH), and chorionic gonadotropin are members of the heterodimeric glycoprotein hormone family. The common α subunit forms noncovalent heterodimers with different β subunits. Two novel human glycoprotein hormonelike genes, α2 (A2) and β5 (B5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners. Immunological analyses confirmed the heterodimerization of A2 and B5 in transfected cells and their colocalization in the anterior pituitary. Recombinant A2/B5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human TSH receptors, but not LH and FSH receptors, and showed high affinity to TSH receptors in a radioligand receptor assay. The heterodimer also stimulated cAMP production and thymidine incorporation by cultured thyroid cells and increased serum thyroxine levels in TSH-suppressed rats in vivo. This new heterodimeric glycoprotein hormone was named as thyrostimulin based on its thyroid-stimulating activity. The expression of thyrostimulin in the anterior pituitary known to express TSH receptors suggested a paracrine mechanism. The present discovery of a new ligand based on genomic approaches could facilitate the understanding of the physiological roles of extra-thyroid TSH receptor systems and the structural-functional basis of receptor signaling by related glycoprotein hormones.

Authors

Koji Nakabayashi, Hirotaka Matsumi, Alka Bhalla, Jeehyeon Bae, Sietse Mosselman, Sheau Yu Hsu, Aaron J.W. Hsueh

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Figure 1

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Identification of A2 and B5 as potential heterodimerization partners. (a...
Identification of A2 and B5 as potential heterodimerization partners. (a) Comparison of sequences between human B5 and TSH-β as well as A2 and the common α subunit (A). (b) Yeast two-hybrid analyses of interactions between A2 and different subunit genes in the glycoprotein hormone family. Yeast cells were transfected with plasmids encoding A2, and different subunit genes fused to the GAL4 activation domain and the binding domain, respectively. The prominent growth of colonies expressing A2 and B5 indicates a strong interaction between these proteins. Interactions between A2 and CG-β, as well as A2 and FSH-β, were also observed, whereas no growth of yeast colonies was found in cells expressing only A2, thus ruling out self-activation of these constructs.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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