Glycoprotein hormones alpha chain (CGA) is the common secreted cystine-knot alpha subunit that non-covalently heterodimerizes with four hormone-specific beta subunitsβTSHB, FSHB, LHB, and chorionic gonadotropin beta (CGB)βto form the active pituitary and placental glycoprotein hormones thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and human chorionic gonadotropin (hCG). Within each heterodimer, the alpha chain directly contacts both the extracellular leucine-rich repeat domain and the hinge region of the cognate G protein-coupled receptor (TSHR, FSHR, or LHCGR), driving receptor activation in the thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone signaling pathways.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | NAS PMID:35002517 Overview of follicle stimulating hormone and its receptors i... | MARK AS OVER ANNOTATED | Summary: Downstream intracellular signaling cascade activated by FSHR/LHCGR/TSHR rather than a direct role of the extracellular hormone subunit CGA. Reason: CGA is an extracellular hormone subunit; MAPK cascade activation is a downstream intracellular consequence of glycoprotein hormone receptor signaling (GO:0038194, GO:0042699, GO:0042700). |
| GO:0001541 ovarian follicle development | NAS PMID:35002517 Overview of follicle stimulating hormone and its receptors i... | KEEP AS NON CORE | Summary: Downstream physiological process regulated by the FSH heterodimer (CGA:FSHB) via FSHR in ovarian granulosa cells. Reason: As the obligate alpha subunit of FSH, CGA is required for ovarian follicle development, which is a physiological outcome downstream of its core role in the follicle-stimulating hormone signaling pathway (GO:0042699). |
| GO:0005179 hormone activity | IEA GO_REF:0000002 | ACCEPT | Summary: Core molecular function of CGA as the common alpha subunit of the pituitary and placental glycoprotein hormones TSH, FSH, LH, and hCG. Reason: InterPro:IPR000476 (Glycoprotein hormone subunit alpha) accurately maps to GO:0005179 (hormone activity); CGA is an obligate receptor-contacting subunit of TSH, FSH, LH, and hCG. Supporting Evidence: PMID:22802634 Each member is a heterodimer composed of a common Ξ±-subunit and a hormone-specific Ξ²-subunit. |
| GO:0005179 hormone activity | IMP PMID:11207219 Molecular biology of channel catfish gonadotropin receptors:... | ACCEPT | Summary: Core molecular function of CGA as an obligate subunit of active glycoprotein hormones. Reason: CGA is essential for the hormone activity (GO:0005179) of heterodimeric glycoprotein hormones (hCG, LH, FSH, and TSH) that activate cognate glycoprotein hormone GPCRs. Supporting Evidence: PMID:11207219 The isolated cDNA encoded an active ccLHR protein, as the recombinant receptor expressed in COS7 cells activated a cAMP response element-driven reporter gene (luciferase) upon exposure to hCG in a dose-dependent manner. |
| GO:0005515 protein binding | IPI PMID:11222739 Three-dimensional structure of human follicle-stimulating ho... | REMOVE | Summary: Crystal structure of human FSH (CGA:FSHB heterodimer); bare protein binding is uninformative and replaced by complex membership and hormone activity. Reason: Per project protein-binding policy, bare GO:0005515 is removed as uninformative; heterodimer assembly with FSHB (UniProtKB:P01225) is captured by part_of GO:0016914 (follicle-stimulating hormone complex). |
| GO:0005515 protein binding | IPI PMID:15662415 Structure of human follicle-stimulating hormone in complex w... | REMOVE | Summary: Crystal structure of human FSH bound to the FSHR ectodomain; bare protein binding is uninformative. Reason: Per project protein-binding policy, bare GO:0005515 is removed as uninformative; heterodimer assembly with FSHB (UniProtKB:P01225) and receptor engagement are captured by GO:0016914 and GO:0016913. |
| GO:0005515 protein binding | IPI PMID:22802634 Structure of follicle-stimulating hormone in complex with th... | REMOVE | Summary: Crystal structure of human FSH (CGA:FSHB) bound to the entire FSHR ectodomain; bare protein binding is uninformative. Reason: Per project protein-binding policy, bare GO:0005515 is removed as uninformative; heterodimer assembly with FSHB (UniProtKB:P01225) is captured by GO:0016914 (follicle-stimulating hormone complex). |
| GO:0005515 protein binding | IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ... | REMOVE | Summary: Binary interactome detection of CGA binding to CGB3; bare protein binding is uninformative. Reason: Per project protein-binding policy, bare GO:0005515 is removed as uninformative; CGA heterodimerization with chorionic gonadotropin beta (UniProtKB:P0DN86) forms the hCG hormone complex enabling hormone activity (GO:0005179). |
| GO:0005515 protein binding | IPI PMID:7922031 Structure of human chorionic gonadotropin at 2.6 A resolutio... | REMOVE | Summary: Crystal structure of human chorionic gonadotropin (CGA:CGB3); bare protein binding is uninformative. Reason: Per project protein-binding policy, bare GO:0005515 is removed as uninformative; CGA:CGB3 heterodimerization is captured by complex membership and hormone activity (GO:0005179). |
| GO:0005576 extracellular region | IDA PMID:24692546 Evidence for Follicle-stimulating Hormone Receptor as a Func... | ACCEPT | Summary: CGA is secreted into the extracellular region as part of recombinant human FSH. Reason: CGA is a secreted glycoprotein hormone subunit that acts in the extracellular space. Supporting Evidence: PMID:24692546 Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor, is an important drug target in the development of novel therapeutics for reproductive indications. |
| GO:0005576 extracellular region | IDA PMID:2494176 Expression of biologically active human follitropin in Chine... | ACCEPT | Summary: Biologically active human follitropin (CGA:FSHB) is secreted into the culture medium. Reason: Direct experimental demonstration of secretion of the CGA-containing FSH heterodimer into the extracellular region. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation to extracellular region from secreted protein keyword and InterPro domain. Reason: CGA has an N-terminal signal peptide (residues 1-24) and is secreted into the extracellular region as part of pituitary and placental glycoprotein hormones. |
| GO:0005576 extracellular region | TAS PMID:27889227 GPCR Signaling and Trafficking: The Long and Short of It. | ACCEPT | Summary: CGA is active in the extracellular region as an obligate subunit of glycoprotein hormones. Reason: CGA functions in the extracellular space where glycoprotein hormone heterodimers bind cell-surface GPCRs. Supporting Evidence: PMID:27889227 The long-accepted paradigm for G protein-coupled receptor (GPCR) activation involves a cyclical model, whereby ligand binding to its cognate receptor promotes transient activation, downstream signaling, followed by inactivation and receptor recycling, setting the stage for another round of stimulation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-378952 | ACCEPT | Summary: Extracellular localization of the thyrotropin (TSH, CGA:TSHB) heterodimer in Reactome. Reason: Correctly captures extracellular localization of CGA within the secreted TSH heterodimer. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-378956 | ACCEPT | Summary: Extracellular localization of the luteinizing hormone (LH, CGA:LHB) heterodimer in Reactome. Reason: Correctly captures extracellular localization of CGA within the secreted LH heterodimer. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-378975 | ACCEPT | Summary: Extracellular localization of the follitropin (FSH, CGA:FSHB) heterodimer in Reactome. Reason: Correctly captures extracellular localization of CGA within the secreted FSH heterodimer. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-378978 | ACCEPT | Summary: Extracellular localization of the human chorionic gonadotropin (hCG, CGA:CGB) heterodimer in Reactome. Reason: Correctly captures extracellular localization of CGA within the secreted hCG heterodimer. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-379044 | ACCEPT | Summary: Extracellular localization of glycoprotein hormone ligands bound to Gs-coupled receptors. Reason: CGA remains in the extracellular region when bound to cell-surface glycoprotein hormone receptors. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-391375 | ACCEPT | Summary: Extracellular localization of CGA during TSH binding to TSHR in Reactome. Reason: CGA acts in the extracellular region as a subunit of TSH binding to TSHR. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-391377 | ACCEPT | Summary: Extracellular localization of CGA during LH binding to LHCGR in Reactome. Reason: CGA acts in the extracellular region as a subunit of LH binding to LHCGR. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-391378 | ACCEPT | Summary: Extracellular localization of CGA during FSH binding to FSHR in Reactome. Reason: CGA acts in the extracellular region as a subunit of FSH binding to FSHR. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-744886 | ACCEPT | Summary: Extracellular localization of CGA in the hormone-receptor signaling complex in Reactome. Reason: CGA is located in the extracellular region when complexed with its cell-surface GPCR. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-744887 | ACCEPT | Summary: Extracellular localization of CGA in liganded Gs-coupled receptor complexes in Reactome. Reason: CGA is located in the extracellular region during glycoprotein hormone receptor activation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8864433 | ACCEPT | Summary: Extracellular localization of secreted CGA protein product in Reactome. Reason: CGA is a secreted protein localized to the extracellular region. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-6786034 | KEEP AS NON CORE | Summary: Biosynthetic transit compartment where CHST8 sulfates N-linked oligosaccharides of lutropin (CGA:LHB) in the Golgi lumen prior to secretion. Reason: CGA transits through the Golgi lumen where its N-glycans undergo GalNAc-4-sulfation during hormone maturation, but its active signaling function occurs in the extracellular region (GO:0005576). |
| GO:0007186 G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: Correct but general PAINT annotation from jawed-vertebrate CGA clade PTN002608947; refine to the three specific glycoprotein hormone signaling pathways in which CGA participates. Reason: CGA is the shared alpha subunit of TSH, FSH, and LH/hCG and participates specifically in the thyroid-stimulating hormone signaling pathway (GO:0038194), follicle-stimulating hormone signaling pathway (GO:0042699, already annotated on CGA), and luteinizing hormone signaling pathway (GO:0042700), all of which are descendants of GO:0007186. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002608947 Β· GLYCOPROTEIN HORMONES ALPHA CHAIN jawed-vertebrate clade SUPPORTS TRANSFER PAINT node PTN002608947 places generic GO:0007186 on the jawed-vertebrate CGA clade rather than the three specific glycoprotein hormone signaling pathways (GO:0038194, GO:0042699, GO:0042700). Proposed replacements: thyroid-stimulating hormone signaling pathway follicle-stimulating hormone signaling pathway luteinizing hormone signaling pathway Supporting Evidence: PMID:36001021 TSH is a member of the glycoprotein hormone family, which includes luteinising hormone, follicle-stimulating hormone, and human chorionic gonadotropin. All are heterodimers of a common Ξ± subunit and subtype-specific Ξ² subunit, which determines the biologic specificity. PMID:36720854 FSH, along with luteinizing hormone (LH), chorionic gonadotropin (CG) and thyroid-stimulating hormone (TSH), constitute the family of glycoprotein hormones14, which share similar 3D architectures and function through binding and activation of a subfamily of G protein-coupled receptors, named glycoprotein hormone receptors15. |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:24692546 Evidence for Follicle-stimulating Hormone Receptor as a Func... | MODIFY | Summary: Experimental demonstration of FSHR activation by recombinant FSH (CGA:FSHB); refine to the specific glycoprotein hormone signaling pathways. Reason: PMID:24692546 assays FSH-mediated activation of FSHR, and across its four heterodimers CGA participates specifically in GO:0038194, GO:0042699, and GO:0042700 rather than generic GPCR signaling. |
| GO:0007186 G protein-coupled receptor signaling pathway | NAS PMID:35002517 Overview of follicle stimulating hormone and its receptors i... | MODIFY | Summary: Review citation for GPCR signaling by FSH; refine to the specific glycoprotein hormone signaling pathways. Reason: GO:0007186 is too general; CGA participates specifically in the thyroid-stimulating hormone (GO:0038194), follicle-stimulating hormone (GO:0042699), and luteinizing hormone (GO:0042700) signaling pathways. |
| GO:0007283 spermatogenesis | NAS PMID:35002517 Overview of follicle stimulating hormone and its receptors i... | KEEP AS NON CORE | Summary: Downstream physiological process regulated by FSH and LH signaling in the testis. Reason: CGA is required for spermatogenesis as the shared alpha subunit of FSH and LH, which is a downstream physiological outcome of gonadotropin signaling (GO:0042699, GO:0042700). |
| GO:0008284 positive regulation of cell population proliferation | NAS PMID:20613903 Follicular stimulating hormone enhances Notch 1 expression i... | MARK AS OVER ANNOTATED | Summary: Downstream cellular response to FSH treatment in ovarian cancer cells. Reason: Cell proliferation in SK-OV-3 cells is an indirect downstream cellular effect of FSHR activation rather than a core function of CGA. |
| GO:0009755 hormone-mediated signaling pathway | NAS PMID:25280580 A review of luteinising hormone and human chorionic gonadotr... | MODIFY | Summary: Correct but overly general hormone signaling annotation; refine to the specific glycoprotein hormone signaling pathways. Reason: GO:0009755 is an ancestor of the three specific glycoprotein hormone signaling pathways in which CGA acts as an obligate ligand subunit: GO:0038194 (thyroid-stimulating hormone signaling pathway), GO:0042699 (follicle-stimulating hormone signaling pathway), and GO:0042700 (luteinizing hormone signaling pathway). |
| GO:0009755 hormone-mediated signaling pathway | NAS PMID:29935915 The forgotten effects of thyrotropin-releasing hormone: Meta... | MODIFY | Summary: Correct but overly general hormone signaling annotation; refine to the specific glycoprotein hormone signaling pathways. Reason: GO:0009755 is too general; CGA acts specifically in the thyroid-stimulating hormone (GO:0038194), follicle-stimulating hormone (GO:0042699), and luteinizing hormone (GO:0042700) signaling pathways. |
| GO:0009755 hormone-mediated signaling pathway | NAS PMID:7922031 Structure of human chorionic gonadotropin at 2.6 A resolutio... | MODIFY | Summary: Correct but overly general hormone signaling annotation from the hCG crystal structure paper; refine to the specific glycoprotein hormone signaling pathways. Reason: GO:0009755 is too general; CGA acts specifically in the thyroid-stimulating hormone (GO:0038194), follicle-stimulating hormone (GO:0042699), and luteinizing hormone (GO:0042700) signaling pathways. |
| GO:0010469 regulation of signaling receptor activity | IDA PMID:24692546 Evidence for Follicle-stimulating Hormone Receptor as a Func... | MODIFY | Summary: Correct but general process annotation for receptor activation by recombinant FSH; refine to the specific glycoprotein hormone signaling pathways. Reason: Direct activation of glycoprotein hormone receptors by CGA-containing heterodimers is more precisely captured by the molecular function hormone activity (GO:0005179 / GO:0016913) and the specific receptor signaling pathways GO:0038194, GO:0042699, and GO:0042700. |
| GO:0010893 positive regulation of steroid biosynthetic process | IDA PMID:2494176 Expression of biologically active human follitropin in Chine... | KEEP AS NON CORE | Summary: Downstream physiological assay (aromatase/estrogen induction in granulosa cells) used to demonstrate bioactivity of recombinant human FSH. Reason: Stimulation of gonadal steroidogenesis is a downstream physiological consequence of FSHR and LHCGR activation by CGA-containing gonadotropins. |
| GO:0016913 follicle-stimulating hormone activity | IDA PMID:24692546 Evidence for Follicle-stimulating Hormone Receptor as a Func... | ACCEPT | Summary: CGA, heterodimerized with FSHB, enables follicle-stimulating hormone activity on FSHR. Reason: Direct experimental demonstration of FSH activity by the recombinant CGA:FSHB heterodimer. Supporting Evidence: PMID:24692546 Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor, is an important drug target in the development of novel therapeutics for reproductive indications. |
| GO:0016913 follicle-stimulating hormone activity | IDA PMID:2494176 Expression of biologically active human follitropin in Chine... | ACCEPT | Summary: Co-expression of human CGA and FSHB in CHO cells produces biologically active follitropin. Reason: Direct experimental demonstration that the CGA:FSHB heterodimer enables follicle-stimulating hormone activity (GO:0016913). |
| GO:0016913 follicle-stimulating hormone activity | IDA PMID:36720854 Mechanism of hormone and allosteric agonist mediated activat... | ACCEPT | Summary: Cryo-EM structure and functional characterization of human FSH (CGA:FSHB) activating FSHR. Reason: PMID:36720854 demonstrates that both the CGA alpha chain and FSHB beta chain directly contact FSHR to contribute to follicle-stimulating hormone activity (GO:0016913). Supporting Evidence: PMID:36720854 FSH, along with luteinizing hormone (LH), chorionic gonadotropin (CG) and thyroid-stimulating hormone (TSH), constitute the family of glycoprotein hormones14, which share similar 3D architectures and function through binding and activation of a subfamily of G protein-coupled receptors, named glycoprotein hormone receptors15. |
| GO:0016913 follicle-stimulating hormone activity | IEA GO_REF:0000117 | ACCEPT | Summary: Automated ARBA annotation for follicle-stimulating hormone activity, consistent with experimental IDA annotations. Reason: Consistent with experimental IDA annotations showing that CGA in complex with FSHB enables follicle-stimulating hormone activity. |
| GO:0016914 follicle-stimulating hormone complex | IBA GO_REF:0000033 | ACCEPT | Summary: Valid PAINT annotation from jawed-vertebrate CGA clade PTN002608947 for membership in the follicle-stimulating hormone heterodimer. Reason: CGA is the obligate alpha subunit of the heterodimeric follicle-stimulating hormone complex (GO:0016914). |
| GO:0016914 follicle-stimulating hormone complex | IDA PMID:24692546 Evidence for Follicle-stimulating Hormone Receptor as a Func... | ACCEPT | Summary: Direct experimental evidence that CGA is part of the human FSH heterodimer. Reason: CGA and FSHB assemble into the follicle-stimulating hormone complex (GO:0016914). Supporting Evidence: PMID:24692546 Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor, is an important drug target in the development of novel therapeutics for reproductive indications. |
| GO:0016914 follicle-stimulating hormone complex | IDA PMID:2494176 Expression of biologically active human follitropin in Chine... | ACCEPT | Summary: Co-expression of CGA and FSHB in CHO cells forms the secreted FSH heterodimer. Reason: Direct experimental evidence that CGA is an obligate subunit of the follicle-stimulating hormone complex. |
| GO:0016914 follicle-stimulating hormone complex | IDA PMID:36720854 Mechanism of hormone and allosteric agonist mediated activat... | ACCEPT | Summary: Cryo-EM structure of the human FSH (CGA:FSHB) heterodimer bound to FSHR. Reason: Direct structural confirmation that CGA is part of the follicle-stimulating hormone complex. Supporting Evidence: PMID:36720854 FSH, along with luteinizing hormone (LH), chorionic gonadotropin (CG) and thyroid-stimulating hormone (TSH), constitute the family of glycoprotein hormones14, which share similar 3D architectures and function through binding and activation of a subfamily of G protein-coupled receptors, named glycoprotein hormone receptors15. |
| GO:0016914 follicle-stimulating hormone complex | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA annotation for follicle-stimulating hormone complex membership, consistent with IDA and IPI evidence. Reason: Consistent with crystal and cryo-EM structures of human FSH (CGA:FSHB). |
| GO:0016914 follicle-stimulating hormone complex | IPI PMID:11222739 Three-dimensional structure of human follicle-stimulating ho... | ACCEPT | Summary: Crystal structure of human follicle-stimulating hormone (CGA:FSHB heterodimer). Reason: Direct structural determination of the CGA:FSHB heterodimeric follicle-stimulating hormone complex. |
| GO:0030335 positive regulation of cell migration | NAS PMID:20613903 Follicular stimulating hormone enhances Notch 1 expression i... | MARK AS OVER ANNOTATED | Summary: Downstream cellular phenotype in ovarian cancer cells treated with FSH. Reason: Cell migration in ovarian cancer cells is an indirect downstream effect of FSHR signaling rather than a core biological role of CGA. |
| GO:0035773 insulin secretion involved in cellular response to glucose stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Insulin secretion involved in cellular response to glucose stimulus (IEA), transferred from mouse Cga, annotated from a study of FSH in glucose-stimulated insulin secretion (PMID:37914684). CGA is the common alpha subunit of FSH. Reason: The row is transferred from mouse Cga, which is annotated by direct assay from a study reporting that follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets (PMID:37914684; not read here beyond its title). CGA is the common alpha subunit of FSH, so the observation concerns the gene product, but the hormone acts on islet cells from outside: it modulates insulin secretion rather than carrying out a step of it. The term as given, the secretion process itself, therefore over-states the role of CGA; a regulatory term would be the accurate form if the finding is confirmed. |
| GO:0042699 follicle-stimulating hormone signaling pathway | NAS PMID:11222739 Three-dimensional structure of human follicle-stimulating ho... | ACCEPT | Summary: Core biological process of CGA as an obligate receptor-contacting subunit of FSH activating FSHR. Reason: As part of the FSH heterodimer (CGA:FSHB), CGA directly contacts and activates FSHR to initiate the follicle-stimulating hormone signaling pathway (GO:0042699). Supporting Evidence: PMID:22802634 Each member is a heterodimer composed of a common Ξ±-subunit and a hormone-specific Ξ²-subunit. PMID:36720854 FSH, along with luteinizing hormone (LH), chorionic gonadotropin (CG) and thyroid-stimulating hormone (TSH), constitute the family of glycoprotein hormones14, which share similar 3D architectures and function through binding and activation of a subfamily of G protein-coupled receptors, named glycoprotein hormone receptors15. |
| GO:0043235 signaling receptor complex | IPI PMID:15662415 Structure of human follicle-stimulating hormone in complex w... | ACCEPT | Summary: Crystal structure of human FSH (CGA:FSHB) in complex with the hormone-binding ectodomain of FSHR. Reason: PMID:15662415 resolves the ternary ligand-receptor complex formed by CGA, FSHB, and FSHR. Supporting Evidence: PMID:15662415 We present here the 2.9-A-resolution structure of a partially deglycosylated complex of human FSH bound to the extracellular hormone-binding domain of its receptor (FSHR(HB)). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | NAS PMID:20613903 Follicular stimulating hormone enhances Notch 1 expression i... | MARK AS OVER ANNOTATED | Summary: Downstream transcriptional consequence (Notch1 expression) of FSH signaling in ovarian cancer cells. Reason: CGA is an extracellular hormone subunit and does not directly regulate RNA polymerase II transcription; gene expression changes are downstream of GPCR second-messenger cascades. |
| GO:0061696 pituitary gonadotropin complex | IPI PMID:7922031 Structure of human chorionic gonadotropin at 2.6 A resolutio... | ACCEPT | Summary: CGA is the common alpha subunit of heterodimeric gonadotropin complexes. Reason: CGA non-covalently pairs with gonadotropin beta subunits to form active gonadotropin heterodimers. |
| GO:0061696 pituitary gonadotropin complex | NAS PMID:25280580 A review of luteinising hormone and human chorionic gonadotr... | ACCEPT | Summary: CGA is the obligate alpha subunit of pituitary gonadotropin complexes (LH and FSH). Reason: CGA heterodimerizes with LHB and FSHB in pituitary gonadotropes to form LH and FSH complexes. Supporting Evidence: PMID:25280580 Products, such as human menopausal gonadotropin (hMG), consist not only of a mixture of the hormones, follicle-stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotropin (hCG) |
| GO:0061696 pituitary gonadotropin complex | NAS PMID:29935915 The forgotten effects of thyrotropin-releasing hormone: Meta... | ACCEPT | Summary: CGA is the common alpha subunit of pituitary glycoprotein hormone complexes. Reason: Correctly captures CGA membership in pituitary gonadotropin heterodimers. |
| GO:0038194 thyroid-stimulating hormone signaling pathway | IC PMID:36001021 Novel TSHB variant (c.217A>C) causing severe central hypothy... | NEW | Summary: As the obligate alpha subunit of thyroid-stimulating hormone (TSH, CGA:TSHB), CGA binds and activates TSHR to initiate the thyroid-stimulating hormone signaling pathway. Reason: GOA currently annotates CGA to GO:0042699 (follicle-stimulating hormone signaling pathway) and generic GO:0007186 (G protein-coupled receptor signaling pathway) but omits GO:0038194 (thyroid-stimulating hormone signaling pathway). Genetic and biochemical studies (PMID:36001021; Reactome:R-HSA-391375) establish that CGA is the shared alpha subunit of active TSH in the thyroid-stimulating hormone signaling pathway. Supporting Evidence: PMID:36001021 TSH is a member of the glycoprotein hormone family, which includes luteinising hormone, follicle-stimulating hormone, and human chorionic gonadotropin. All are heterodimers of a common Ξ± subunit and subtype-specific Ξ² subunit, which determines the biologic specificity. Reactome:R-HSA-391375 Thyroid-stimulating hormone (TSH, thyrotropin) binds thyrotropin receptor (TSHR) on the basolateral membrane of thyroid cells (Nagayama Y et al., 1989). |
| GO:0042700 luteinizing hormone signaling pathway | IC PMID:36720854 Mechanism of hormone and allosteric agonist mediated activat... | NEW | Summary: As the obligate alpha subunit of luteinizing hormone (LH, CGA:LHB) and chorionic gonadotropin (hCG, CGA:CGB), CGA directly binds and activates LHCGR to initiate the luteinizing hormone signaling pathway. Reason: GOA annotates CGA to GO:0061696 (pituitary gonadotropin complex) and GO:0042699 (follicle-stimulating hormone signaling pathway) but omits GO:0042700 (luteinizing hormone signaling pathway). CGA is the shared alpha subunit of LH and hCG that binds and activates LHCGR (PMID:36720854, Reactome:R-HSA-391377). Supporting Evidence: PMID:36720854 FSH, along with luteinizing hormone (LH), chorionic gonadotropin (CG) and thyroid-stimulating hormone (TSH), constitute the family of glycoprotein hormones14, which share similar 3D architectures and function through binding and activation of a subfamily of G protein-coupled receptors, named glycoprotein hormone receptors15. Reactome:R-HSA-391377 Luteininzing hormone (LH, lutropin) is a dimeric glycoprotein synthesized in the anterior pituitary gland. It triggers ovulation in females and stimulates Leydig cell production of testosterone in males. It mediates its action by binding to the LH receptor |
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Download this section (compressed HTML)Q: How do distinct N-glycan sulfation and sialylation patterns on the shared CGA alpha subunit when paired with TSHB, FSHB, LHB, or CGB modulate receptor residence time and Gs versus Gq/11 signaling bias at TSHR, FSHR, and LHCGR?
Experiment: Compare single-molecule FRET conformational dynamics of the TSHR, FSHR, and LHCGR hinge regions upon binding recombinant heterodimers containing site-specific glycan-engineered CGA variants.
Hypothesis: Biantennary N-glycans at Asn52 and Asn78 of CGA sterically tune the lever-like push-pull movement of the receptor extracellular domain relative to the transmembrane bundle across all three glycoprotein hormone receptors.
Type: Single-molecule FRET and GloSensor cAMP/IP1 signaling assays
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