CGA (P01215) Curation Notes

Summary

• Gene: CGA (UniProtKB:P01215; PANTHER PTHR11509:SF0, PAINT node PTN002608947)
• Product: Glycoprotein hormones alpha chain — the common obligate alpha subunit shared by all four human pituitary and placental glycoprotein hormones: thyroid-stimulating hormone (TSH, heterodimer with TSHB), follicle-stimulating hormone (FSH, heterodimer with FSHB), luteinizing hormone (LH, heterodimer with LHB), and chorionic gonadotropin (hCG, heterodimer with CGB3/CGB5/CGB8) [PMID:22802634, PMID:36001021, PMID:36720854].

Key Literature & Structural Evidence

• Shared alpha subunit of heterodimeric glycoprotein hormones:
• PMID:22802634: "The glycoprotein hormone (GPH) family has four members: FSH; two other pituitary hormones, luteinizing hormone and thyroid-stimulating hormone (TSH); and one placental hormone, chorionic gonadotropin. The four members are homologous in sequence, structure, and function. Each member is a heterodimer composed of a common α-subunit and a hormone-specific β-subunit."
• Direct receptor contact and activation in TSH, FSH, and LH/hCG signaling:
• PMID:36001021: "While the β subunit mainly binds to the LRR domain of TSHR, the α subunit simultaneously interacts with the LRR domain and the hinge region of the receptor."
• 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."

Annotation Review Decisions

• Core MF: GO:0005179 (hormone activity, ACCEPT on IEA GO_REF:0000002 and IMP PMID:11207219) and GO:0016913 (follicle-stimulating hormone activity, ACCEPT on IDA PMID:24692546, PMID:2494176, PMID:36720854, and IEA GO_REF:0000117).
• Protein binding (GO:0005515): All five IPI rows with FSHB (UniProtKB:P01225) and CGB3 (UniProtKB:P0DN86) are set to REMOVE per the project protein-binding policy; subunit heterodimerization is captured by the complex annotations (GO:0016914 follicle-stimulating hormone complex and GO:0061696 pituitary gonadotropin complex).
• Signaling pathways:
• GO:0042699 (follicle-stimulating hormone signaling pathway, NAS PMID:11222739) is ACCEPT.
• Broad signaling terms GO:0007186 (G protein-coupled receptor signaling pathway), GO:0009755 (hormone-mediated signaling pathway), and GO:0010469 (regulation of signaling receptor activity) are MODIFY with proposed_replacement_terms listing all three specific glycoprotein hormone signaling pathways in which CGA participates: GO:0038194 (thyroid-stimulating hormone signaling pathway), GO:0042699 (follicle-stimulating hormone signaling pathway), and GO:0042698 (luteinizing hormone signaling pathway).
• Added NEW annotations for GO:0038194 (thyroid-stimulating hormone signaling pathway, supported by PMID:36001021 and Reactome:R-HSA-391375) and GO:0042698 (luteinizing hormone signaling pathway, supported by PMID:36720854 and Reactome:R-HSA-391377).
• Downstream / pleiotropic / over-propagated terms:
• GO:0000165 (MAPK cascade), GO:0008284 (positive regulation of cell population proliferation), GO:0030335 (positive regulation of cell migration), and GO:0045944 (positive regulation of transcription by RNA polymerase II) are set to MARK_AS_OVER_ANNOTATED as downstream intracellular consequences of FSHR/LHCGR/TSHR activation.
• GO:0001541 (ovarian follicle development), GO:0007283 (spermatogenesis), and GO:0010893 (positive regulation of steroid biosynthetic process) are set to KEEP_AS_NON_CORE as downstream physiological processes regulated by gonadotropin signaling.
• GO:0035773 (insulin secretion involved in cellular response to glucose stimulus, IEA Ensembl Compara from mouse Cga) is REMOVE as an unverified electronic transfer unrelated to glycoprotein hormone alpha chain function.