Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor.
Human thyrotropin (TSH), luteotropin (LH), follitropin (FSH), and chorionic gonadotropin are members of the heterodimeric glycoprotein hormone family. The common alpha subunit forms noncovalent heterodimers with different beta subunits. Two novel human glycoprotein hormonelike genes, alpha2 (A2) and beta5 (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.
Nakabayashi
Koji
K
Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California 94305-5317, USA.
Matsumi
Hirotaka
H
Bhalla
Alka
A
Bae
Jeehyeon
J
Mosselman
Sietse
S
Hsu
Sheau Yu
SY
Hsueh
Aaron J W
AJ
D000595:Amino Acid Sequence; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005640:Follicle Stimulating Hormone / Q000737:chemistry* / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D008024:Ligands; D007986:Luteinizing Hormone / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D011869:Radioligand Assay; D011989:Receptors, Thyrotropin / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013972:Thyrotropin / Q000737:chemistry*; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques
D006023:Glycoproteins; D008024:Ligands; D011989:Receptors, Thyrotropin; C458339:thyrostimulin; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013972:Thyrotropin