This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sudo, S. Articles by Hsueh, A. J. W. Search for Related Content PubMed PubMed Citation Articles by Sudo, S. Articles by Hsueh, A. J. W.

Heterodimeric Fly Glycoprotein Hormone-2 (GPA2) and Glycoprotein Hormone-ß5 (GPB5) Activate Fly Leucine-Rich Repeat-Containing G Protein-Coupled Receptor-1 (DLGR1) and Stimulation of Human Thyrotropin Receptors by Chimeric Fly GPA2 and Human GPB5

Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317

Address all correspondence and requests for reprints to: Aaron J. W. Hsueh, Stanford University School of Medicine, Department of Obstetrics and Gynecology, 300 Pasteur Drive, Room A344, Stanford, California 94305-5317. E-mail: aaron.hsueh{at}stanford.edu.

Glycoprotein hormones play important roles in thyroid and gonadal function in vertebrates. The glycoprotein hormone -subunit forms heterodimers with different ß-subunits to activate TSH or gonadotropin (LH and FSH) receptors. Recent genomic analyses allowed the identification of another -subunit, GPA2, and another ß-subunit, GPB5, in human, capable of forming heterodimers to activate TSH receptors. Based on comparative genomic searches, we isolated the fly orthologs for human GPA2 and GPB5, each consisting of 10 cysteine residues likely involved in cystine-knot formation. RT-PCR analyses in Drosophila melanogaster demonstrated the expression of GPA2 and GPB5 at different developmental stages. Immunoblot analyses further showed that fly GPA2 and GPB5 subunit proteins are of approximately 16 kDa, and coexpression of these subunits yielded heterodimers. Purified recombinant fly GPA2/GPB5 heterodimers were found to be glycoproteins with N-linked glycosylated -subunits and nonglycosylated ß-subunits, capable of stimulating cAMP production mediated by fly orphan receptor DLGR1 but not DLGR2. Although the fly GPA2/GPB5 heterodimers did not activate human TSH or gonadotropin receptors, chimeric fly GPA2/human GPB5 heterodimers stimulated human TSH receptors. These findings indicated that fly GPA2/GPB5 is a ligand for DLGR1, thus showing the ancient origin of this glycoprotein hormone-seven transmembrane receptor-G protein signaling system. The fly GPA2 also could form heterodimers with human GPB5 to activate human TSH receptors, indicating the evolutionary conservation of these genes and suggesting that the GPA2 subunit may serve as a scaffold for the ß-subunit to activate downstream G protein-mediated signaling.

This article has been cited by other articles:

				A. Oishi, K. Gengyo-Ando, S. Mitani, A. Mohri-Shiomi, K. D Kimura, T. Ishihara, and I. Katsura FLR-2, the glycoprotein hormone alpha subunit, is involved in the neural control of intestinal functions in Caenorhabditis elegans Genes Cells, October 1, 2009; 14(10): 1141 - 1154. [Abstract] [Full Text] [PDF]

				S. Dos Santos, C. Bardet, S. Bertrand, H. Escriva, D. Habert, and B. Querat Distinct Expression Patterns of Glycoprotein Hormone-{alpha}2 and -{beta}5 in a Basal Chordate Suggest Independent Developmental Functions Endocrinology, August 1, 2009; 150(8): 3815 - 3822. [Abstract] [Full Text] [PDF]

				G. Kleinau and G. Krause Thyrotropin and Homologous Glycoprotein Hormone Receptors: Structural and Functional Aspects of Extracellular Signaling Mechanisms Endocr. Rev., April 1, 2009; 30(2): 133 - 151. [Abstract] [Full Text] [PDF]

				L. Z. Holland, R. Albalat, K. Azumi, E. Benito-Gutierrez, M. J. Blow, M. Bronner-Fraser, F. Brunet, T. Butts, S. Candiani, L. J. Dishaw, et al. The amphioxus genome illuminates vertebrate origins and cephalochordate biology Genome Res., July 1, 2008; 18(7): 1100 - 1111. [Abstract] [Full Text] [PDF]

				F. Hauser, M. Williamson, G. Cazzamali, and C. J. P. Grimmelikhuijzen Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data Brief Funct Genomic Proteomic, February 1, 2006; 4(4): 321 - 330. [Abstract] [Full Text] [PDF]

				A J W Hsueh, P Bouchard, and I Ben-Shlomo Hormonology: a genomic perspective on hormonal research J. Endocrinol., December 1, 2005; 187(3): 333 - 338. [Abstract] [Full Text] [PDF]