id: MODULE:tsh_signaling title: Thyroid-stimulating hormone signaling pathway module description: >- Secreted heterodimeric thyroid-stimulating hormone (thyrotropin, TSH), assembled in anterior pituitary thyrotrophs from the receptor-specificity-determining beta subunit TSHB (PANTHER:PTHR11515:SF5) and the common glycoprotein hormone alpha subunit CGA (PANTHER:PTHR11509:SF0), binds the extracellular leucine-rich-repeat domain of the thyroid-stimulating hormone receptor (TSHR, PANTHER:PTHR24372:SF0) at the basolateral plasma membrane of thyroid follicular cells. Hormone binding induces a conformational push-pull shift in the TSHR extracellular domain that activates the seven-transmembrane bundle to couple primarily to heterotrimeric Gs (GNAS, PANTHER:PTHR10218:SF357)—stimulating adenylyl cyclase and cAMP-dependent thyroid hormone synthesis and secretion—and at higher hormone occupancy to Gq/11 (GNAQ, PANTHER:PTHR10218:SF329) to activate phospholipase C-beta and dual oxidase-dependent iodide organification, executing the thyroid-stimulating hormone signaling pathway (GO:0038194). status: DRAFT evidence: - source_id: GO:0038194 title: thyroid-stimulating hormone signaling pathway statement: >- The module is grounded in the GO biological process term for thyroid-stimulating hormone signaling pathway (GO:0038194: the series of molecular signals initiated by thyroid-stimulating hormone binding to its receptor on the surface of a target cell). - source_id: PMID:36001021 title: Novel TSHB variant (c.217A>C) causing severe central hypothyroidism and pituitary hyperplasia. supporting_text: >- 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 α subunit and subtype-specific β subunit, which determines the biologic specificity. statement: >- Establishes that TSH is a heterodimer of the common alpha subunit (CGA) and the TSH-specific beta subunit (TSHB) required for thyroid hormone synthesis. - source_id: Reactome:R-HSA-378952 title: Thyrotropin is a heterodimer supporting_text: >- Like other glycoprotein hormones, TSH consists of a common alpha subunit and a beta subunit unique to TSH which determines its specificty. TSH binds to TSH receptor to stimulate the release of the hormones thyroxine (T4) and triiodothyronine (T3) (Chin and Habener 1981). statement: >- Establishes non-covalent heterodimeric assembly of CGA and TSHB into active TSH that binds TSHR. - source_id: Reactome:R-HSA-391375 title: TSHR binds TSH/Thyrostimulin supporting_text: >- Thyroid-stimulating hormone (TSH, thyrotropin) binds thyrotropin receptor (TSHR) on the basolateral membrane of thyroid cells (Nagayama Y et al., 1989). statement: >- Establishes heterodimeric TSH binding to TSHR on thyroid follicular cells and activation of Gs signaling. - source_id: PANTHER:PTN000162063 title: PAINT node PTN000162063 for glycoprotein hormone beta subunits (TSHB) statement: >- Local PAINT IBD node in PTHR11515 with propagated terms C:GO:0005576, F:GO:0005179, P:GO:0007186; PAINT date 20260828. - source_id: PANTHER:PTN002608947 title: PAINT node PTN002608947 for glycoprotein hormone alpha chain (CGA) statement: >- Local PAINT IBD node in PTHR11509 with propagated terms C:GO:0016914, P:GO:0007186; PAINT date 20250320. notes: >- Curated signaling-pathway module for the thyroid-stimulating hormone signaling pathway (GO:0038194) built with PANTHER FAMILY/subfamily selectors, explicit molecular functions, biological processes, and cellular locations across both obligate subunits of heterodimeric thyrotropin—TSHB (PANTHER:PTHR11515:SF5) and CGA (PANTHER:PTHR11509:SF0)—the thyrotropin receptor TSHR (PANTHER:PTHR24372:SF0), and downstream heterotrimeric Gs (GNAS, PANTHER:PTHR10218:SF357) and Gq (GNAQ, PANTHER:PTHR10218:SF329) alpha subunits. module: id: tsh_signaling label: Thyroid-stimulating hormone signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: thyroid-stimulating hormone signaling pathway term: id: GO:0038194 label: thyroid-stimulating hormone signaling pathway description: >- The series of molecular signals initiated by heterodimeric thyroid-stimulating hormone (TSH, composed of CGA and TSHB) binding to the thyroid-stimulating hormone receptor (TSHR) on the surface of a target cell, and ending with the regulation of downstream cellular processes including thyroid hormone generation and secretion. context: taxa: - preferred_term: Euteleostomi term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: heterodimeric TSH ligand-receptor engagement node: id: tsh_receptor_engagement label: Heterodimeric TSH (TSHB:CGA) engagement of TSHR module_type: REGULATORY_STEP description: >- Secreted heterodimeric thyroid-stimulating hormone (composed of non-covalently associated TSHB and CGA subunits) binds the concave surface of the extracellular leucine-rich-repeat domain of TSHR at the plasma membrane of thyroid follicular cells, inducing rotation of the extracellular domain that transitions the 7TM bundle into its active conformation. annotons: - id: tshb_thyrotropin_beta_subunit label: TSHB thyrotropin beta subunit ligand participant: selector_type: FAMILY family: preferred_term: Thyrotropin subunit beta subfamily term: id: PANTHER:PTHR11515:SF5 label: THYROTROPIN SUBUNIT BETA representative_members: - preferred_term: TSHB term: id: UniProtKB:P01222 label: >- Thyrotropin subunit beta (Thyroid-stimulating hormone subunit beta) (TSH-B) (TSH-beta) (Thyrotropin beta chain) [Cleaved into: Thyrotropin subunit beta, N-terminally processed] ancestral_nodes: - preferred_term: PAINT node PTN000162063 for glycoprotein hormone beta subunits term: id: PANTHER:PTN000162063 label: PTN000162063 description: >- Local PAINT IBD node in PTHR11515 with propagated terms C:GO:0005576, F:GO:0005179, P:GO:0007186; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000162063 in PTHR11515. evidence: - source_id: file:interpro/panther/PTHR11515/PTHR11515-review.yaml title: PTHR11515 PANTHER family review statement: >- PTHR11515 review confirms family-wide GO:0005179 (hormone activity) at PTN000162063 and scopes GO:0038194 (thyroid-stimulating hormone signaling pathway) to PANTHER:PTHR11515:SF5 (THYROTROPIN SUBUNIT BETA) and SF2 (GPHB5). function: preferred_term: hormone activity term: id: GO:0005179 label: hormone activity processes: - preferred_term: thyroid-stimulating hormone signaling pathway term: id: GO:0038194 label: thyroid-stimulating hormone signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Hormone-specific beta subunit of thyroid-stimulating hormone (TSH) that heterodimerizes with CGA and confers selective recognition and activation of TSHR on thyrocytes. evidence: - source_id: PMID:36001021 title: Novel TSHB variant (c.217A>C) causing severe central hypothyroidism and pituitary hyperplasia. supporting_text: >- 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 α subunit and subtype-specific β subunit, which determines the biologic specificity. statement: >- Establishes that TSHB is the subtype-specific beta subunit of heterodimeric TSH. - source_id: Reactome:R-HSA-378952 title: Thyrotropin is a heterodimer supporting_text: >- Like other glycoprotein hormones, TSH consists of a common alpha subunit and a beta subunit unique to TSH which determines its specificty. TSH binds to TSH receptor to stimulate the release of the hormones thyroxine (T4) and triiodothyronine (T3) (Chin and Habener 1981). statement: >- Establishes TSHB as the hormone-specific beta chain of heterodimeric TSH. - id: cga_glycoprotein_hormone_alpha_subunit label: CGA glycoprotein hormone alpha subunit ligand participant: selector_type: FAMILY family: preferred_term: Glycoprotein hormones alpha chain subfamily term: id: PANTHER:PTHR11509:SF0 label: GLYCOPROTEIN HORMONES ALPHA CHAIN representative_members: - preferred_term: CGA term: id: UniProtKB:P01215 label: Glycoprotein hormones alpha chain (Anterior pituitary glycoprotein hormones common subunit alpha) (Choriogonadotropin alpha chain) (Chorionic gonadotrophin subunit alpha) (CG-alpha) (Follitropin alpha chain) (Follicle-stimulating hormone alpha chain) (FSH-alpha) (Lutropin alpha chain) (Luteinizing hormone alpha chain) (LSH-alpha) (Thyrotropin alpha chain) (Thyroid-stimulating hormone alpha chain) (TSH-alpha) ancestral_nodes: - preferred_term: PAINT node PTN002608947 for glycoprotein hormone alpha chain term: id: PANTHER:PTN002608947 label: PTN002608947 description: >- Local PAINT IBD node in PTHR11509 with propagated terms C:GO:0016914, P:GO:0007186; PAINT date 20250320. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002608947 in PTHR11509. evidence: - source_id: file:interpro/panther/PTHR11509/PTHR11509-review.yaml title: PTHR11509 PANTHER family review statement: >- PTHR11509 review documents CGA (PANTHER:PTHR11509:SF0) as the shared obligate alpha subunit enabling hormone activity (GO:0005179) in the TSH (GO:0038194), FSH (GO:0042699), and LH (GO:0042700) signaling pathways. function: preferred_term: hormone activity term: id: GO:0005179 label: hormone activity processes: - preferred_term: thyroid-stimulating hormone signaling pathway term: id: GO:0038194 label: thyroid-stimulating hormone signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Common glycoprotein hormone alpha subunit that heterodimerizes with TSHB and directly contacts the TSHR leucine-rich-repeat and hinge domains to drive receptor activation. evidence: - source_id: PMID:36001021 title: Novel TSHB variant (c.217A>C) causing severe central hypothyroidism and pituitary hyperplasia. supporting_text: >- 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 α subunit and subtype-specific β subunit, which determines the biologic specificity. statement: >- Establishes CGA as the common alpha subunit of heterodimeric TSH. - source_id: Reactome:R-HSA-378952 title: Thyrotropin is a heterodimer supporting_text: >- Like other glycoprotein hormones, TSH consists of a common alpha subunit and a beta subunit unique to TSH which determines its specificty. TSH binds to TSH receptor to stimulate the release of the hormones thyroxine (T4) and triiodothyronine (T3) (Chin and Habener 1981). statement: >- Establishes CGA as the obligate alpha subunit of heterodimeric TSH. - id: tshr_thyrotropin_receptor label: TSHR thyrotropin receptor participant: selector_type: FAMILY family: preferred_term: Thyrotropin receptor subfamily term: id: PANTHER:PTHR24372:SF0 label: THYROTROPIN RECEPTOR representative_members: - preferred_term: TSHR term: id: UniProtKB:P16473 label: Thyrotropin receptor (LGR3) (Thyroid-stimulating hormone receptor) (TSH-R) evidence: - source_id: Reactome:R-HSA-391375 title: TSHR binds TSH/Thyrostimulin supporting_text: >- Thyroid-stimulating hormone (TSH, thyrotropin) binds thyrotropin receptor (TSHR) on the basolateral membrane of thyroid cells (Nagayama Y et al., 1989). statement: >- Establishes TSHR as the cell-surface GPCR activated by TSH on thyrocytes. function: preferred_term: thyroid-stimulating hormone receptor activity term: id: GO:0004996 label: thyroid-stimulating hormone receptor activity processes: - preferred_term: thyroid-stimulating hormone signaling pathway term: id: GO:0038194 label: thyroid-stimulating hormone signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Leucine-rich-repeat G protein-coupled receptor on thyroid follicular cells that binds extracellular heterodimeric TSH (and thyrostimulin) and transduces the signal across the plasma membrane via Gs and Gq/11. evidence: - source_id: Reactome:R-HSA-391375 title: TSHR binds TSH/Thyrostimulin supporting_text: >- Thyroid-stimulating hormone (TSH, thyrotropin) binds thyrotropin receptor (TSHR) on the basolateral membrane of thyroid cells (Nagayama Y et al., 1989). statement: >- Establishes TSHR binding to TSH at the basolateral membrane of thyroid follicular cells. - order: 2 role: heterotrimeric Gs and Gq protein coupling node: id: tshr_gs_gq_coupling label: TSHR coupling to heterotrimeric Gs and Gq proteins module_type: REGULATORY_STEP description: >- TSH-activated TSHR acts as a guanine nucleotide exchange factor (GEF) primarily for stimulatory Gs alpha (GNAS) to activate adenylyl cyclase and cAMP-PKA signaling, and for Gq/11 alpha (GNAQ) to stimulate phospholipase C-beta and intracellular calcium/IP3 signaling in thyrocytes. annotons: - id: gnas_gs_alpha_subunit label: GNAS Gs alpha subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(s) subunit alpha subfamily term: id: PANTHER:PTHR10218:SF357 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(S) SUBUNIT ALPHA representative_members: - preferred_term: GNAS term: id: UniProtKB:P63092 label: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (Adenylate cyclase-stimulating G alpha protein) evidence: - source_id: Reactome:R-HSA-391375 title: TSHR binds TSH/Thyrostimulin supporting_text: >- Activation of TSHR leads to dissociation of G proteins into the G protein alpha-s (Gαs) and Gbetagamma (Gβγ) subunits, which in turn trigger several canonical signal transduction cascades. Gαs activates adenylate cyclase and increases intracellular cAMP levels statement: >- Establishes Gs activation downstream of TSH-bound TSHR. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: thyroid-stimulating hormone signaling pathway term: id: GO:0038194 label: thyroid-stimulating hormone signaling pathway - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway term: id: GO:0007189 label: adenylate cyclase-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Stimulatory heterotrimeric G protein alpha subunit (Galpha_s) activated by TSH-bound TSHR to stimulate adenylyl cyclase and cAMP synthesis in thyroid follicular cells. evidence: - source_id: Reactome:R-HSA-391375 title: TSHR binds TSH/Thyrostimulin supporting_text: >- Activation of TSHR leads to dissociation of G proteins into the G protein alpha-s (Gαs) and Gbetagamma (Gβγ) subunits, which in turn trigger several canonical signal transduction cascades. Gαs activates adenylate cyclase and increases intracellular cAMP levels statement: >- Demonstrates Gs coupling and adenylyl cyclase activation downstream of TSHR. - id: gnaq_gq_alpha_subunit label: GNAQ Gq alpha subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(q) subunit alpha subfamily term: id: PANTHER:PTHR10218:SF329 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(Q) SUBUNIT ALPHA representative_members: - preferred_term: GNAQ term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha (Guanine nucleotide-binding protein alpha-q) evidence: - source_id: Reactome:R-HSA-391375 title: TSHR binds TSH/Thyrostimulin supporting_text: >- Activation of TSHR leads to dissociation of G proteins into the G protein alpha-s (Gαs) and Gbetagamma (Gβγ) subunits, which in turn trigger several canonical signal transduction cascades. statement: >- Establishes heterotrimeric G protein activation downstream of TSH-bound TSHR. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: thyroid-stimulating hormone signaling pathway term: id: GO:0038194 label: thyroid-stimulating hormone signaling pathway - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Heterotrimeric Gq alpha subunit activated by TSH-bound TSHR to stimulate phospholipase C-beta and IP3/Ca2+-dependent H2O2 generation for thyroid hormone biosynthesis. evidence: - source_id: Reactome:R-HSA-391375 title: TSHR binds TSH/Thyrostimulin supporting_text: >- Activation of TSHR leads to dissociation of G proteins into the G protein alpha-s (Gαs) and Gbetagamma (Gβγ) subunits, which in turn trigger several canonical signal transduction cascades. statement: >- Demonstrates G protein coupling and canonical signal transduction cascades by TSHR. connections: - source: tsh_receptor_engagement target: tshr_gs_gq_coupling connection_type: CAUSES description: >- Binding of heterodimeric TSH (TSHB:CGA) to the TSHR leucine-rich-repeat domain triggers an extracellular-to-transmembrane conformational transition that catalyzes GDP-to-GTP exchange on Gs and Gq heterotrimeric G proteins.