Thyroid-stimulating hormone signaling pathway module

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).

MODULE:tsh_signalingDRAFTSignaling Pathwaymodules/tsh_signaling.yaml
thyroid-stimulating hormone signaling pathwayGO:0038194
GO:0038194
thyroid-stimulating hormone signaling pathway
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).
PMID:36001021
Novel TSHB variant (c.217A>C) causing severe central hypothyroidism and pituitary hyperplasia.
Establishes that TSH is a heterodimer of the common alpha subunit (CGA) and the TSH-specific beta subunit (TSHB) required for thyroid hormone synthesis.
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.
Reactome:R-HSA-378952
Thyrotropin is a heterodimer
Establishes non-covalent heterodimeric assembly of CGA and TSHB into active TSH that binds TSHR.
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).
Reactome:R-HSA-391375
TSHR binds TSH/Thyrostimulin
Establishes heterodimeric TSH binding to TSHR on thyroid follicular cells and activation of Gs signaling.
Thyroid-stimulating hormone (TSH, thyrotropin) binds thyrotropin receptor (TSHR) on the basolateral membrane of thyroid cells (Nagayama Y et al., 1989).
PANTHER:PTN000162063
PAINT node PTN000162063 for glycoprotein hormone beta subunits (TSHB)
Local PAINT IBD node in PTHR11515 with propagated terms C:GO:0005576, F:GO:0005179, P:GO:0007186; PAINT date 20260828.
PANTHER:PTN002608947
PAINT node PTN002608947 for glycoprotein hormone alpha chain (CGA)
Local PAINT IBD node in PTHR11509 with propagated terms C:GO:0016914, P:GO:0007186; PAINT date 20250320.

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.

3Nodes
2Parts
0Variant Sets
0Variants
5Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:tsh_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 5 evidence or coverage gap(s) (10 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
tshb_thyrotropin_beta_subunit TSHB
UniProtKB:P01222
Family Representative 		hormone activity
GO:0005179 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cga_glycoprotein_hormone_alpha_subunit CGA
UniProtKB:P01215
Family Representative 		hormone activity
GO:0005179 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tshr_thyrotropin_receptor TSHR
UniProtKB:P16473
Family Representative 		thyroid-stimulating hormone receptor activity
GO:0004996 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gnas_gs_alpha_subunit GNAS
UniProtKB:P63092
Family Representative 		G protein activity
GO:0003925 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gnaq_gq_alpha_subunit GNAQ
UniProtKB:P50148
Family Representative 		G protein activity
GO:0003925 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tshb_thyrotropin_beta_subunit Thyrotropin subunit beta subfamily
PANTHER:PTHR11515:SF5
Family 		hormone activity
GO:0005179 		Family Supported
Family review supports GO:0005179 FAMILY_WIDE. All members of PANTHER:PTHR11515 function as secreted beta subunits of heterodimeric glycoprotein hormones (TSH, FSH, LH, hCG, thyrostimulin, bursicon) that enable hormone activity (GO:0005179).
cga_glycoprotein_hormone_alpha_subunit Glycoprotein hormones alpha chain subfamily
PANTHER:PTHR11509:SF0
Family 		hormone activity
GO:0005179 		Family Supported
Family review supports GO:0005179 FAMILY_WIDE. All members of PANTHER:PTHR11509 (both CGA and GPHA2) are obligate alpha subunits of secreted heterodimeric glycoprotein hormones enabling hormone activity (GO:0005179).
tshr_thyrotropin_receptor Thyrotropin receptor subfamily
PANTHER:PTHR24372:SF0
Family 		thyroid-stimulating hormone receptor activity
GO:0004996 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24372:SF0.
gnas_gs_alpha_subunit Guanine nucleotide-binding protein G(s) subunit alpha subfamily
PANTHER:PTHR10218:SF357
Family 		G protein activity
GO:0003925 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10218:SF357.
gnaq_gq_alpha_subunit Guanine nucleotide-binding protein G(q) subunit alpha subfamily
PANTHER:PTHR10218:SF329
Family 		G protein activity
GO:0003925 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10218:SF329.

Gene-review completeness (3/5 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 2 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
CGA P01215 ✓ ✓ ✗
GNAQ P50148 ✓ 111/121 ✗
TSHR P16473 ✗ — —
GNAS P63092 ✗ — —
TSHB P01222 ✓ ✓ ✗

Details

Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829
Thyroid-stimulating hormone signaling pathwaySignaling Pathwaytsh_signaling
thyroid-stimulating hormone signaling pathwayGO:0038194
Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829

Connections

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.
Part 1: heterodimeric TSH ligand-receptor engagement
Heterodimeric TSH (TSHB:CGA) engagement of TSHRRegulatory Steptsh_receptor_engagement

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

TSHB thyrotropin beta subunit ligand
tshb_thyrotropin_beta_subunit
Participant: Family: Thyrotropin subunit beta subfamily
Family:
Thyrotropin subunit beta subfamilyPANTHER:PTHR11515:SF5
Representative Members: TSHBUniProtKB:P01222

Function

hormone activityGO:0005179

Processes

thyroid-stimulating hormone signaling pathwayGO:0038194

Locations

extracellular regionGO:0005576

Hormone-specific beta subunit of thyroid-stimulating hormone (TSH) that heterodimerizes with CGA and confers selective recognition and activation of TSHR on thyrocytes.

PMID:36001021
Novel TSHB variant (c.217A>C) causing severe central hypothyroidism and pituitary hyperplasia.
Establishes that TSHB is the subtype-specific beta subunit of heterodimeric TSH.
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.
Reactome:R-HSA-378952
Thyrotropin is a heterodimer
Establishes TSHB as the hormone-specific beta chain of heterodimeric TSH.
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).
CGA glycoprotein hormone alpha subunit ligand
cga_glycoprotein_hormone_alpha_subunit
Participant: Family: Glycoprotein hormones alpha chain subfamily
Family:
Glycoprotein hormones alpha chain subfamilyPANTHER:PTHR11509:SF0
Representative Members: CGAUniProtKB:P01215

Function

hormone activityGO:0005179

Processes

thyroid-stimulating hormone signaling pathwayGO:0038194

Locations

extracellular regionGO:0005576

Common glycoprotein hormone alpha subunit that heterodimerizes with TSHB and directly contacts the TSHR leucine-rich-repeat and hinge domains to drive receptor activation.

PMID:36001021
Novel TSHB variant (c.217A>C) causing severe central hypothyroidism and pituitary hyperplasia.
Establishes CGA as the common alpha subunit of heterodimeric TSH.
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.
Reactome:R-HSA-378952
Thyrotropin is a heterodimer
Establishes CGA as the obligate alpha subunit of heterodimeric TSH.
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).
TSHR thyrotropin receptor
tshr_thyrotropin_receptor
Participant: Family: Thyrotropin receptor subfamily
Family:
Thyrotropin receptor subfamilyPANTHER:PTHR24372:SF0
Representative Members: TSHRUniProtKB:P16473

Function

thyroid-stimulating hormone receptor activityGO:0004996

Processes

thyroid-stimulating hormone signaling pathwayGO:0038194

Locations

plasma membraneGO:0005886

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.

Reactome:R-HSA-391375
TSHR binds TSH/Thyrostimulin
Establishes TSHR binding to TSH at the basolateral membrane of thyroid follicular cells.
Thyroid-stimulating hormone (TSH, thyrotropin) binds thyrotropin receptor (TSHR) on the basolateral membrane of thyroid cells (Nagayama Y et al., 1989).
Part 2: heterotrimeric Gs and Gq protein coupling
TSHR coupling to heterotrimeric Gs and Gq proteinsRegulatory Steptshr_gs_gq_coupling

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

GNAS Gs alpha subunit
gnas_gs_alpha_subunit
Participant: Family: Guanine nucleotide-binding protein G(s) subunit alpha subfamily
Family:
Guanine nucleotide-binding protein G(s) subunit alpha subfamilyPANTHER:PTHR10218:SF357
Representative Members: GNASUniProtKB:P63092

Function

G protein activityGO:0003925

Processes

thyroid-stimulating hormone signaling pathwayGO:0038194 adenylate cyclase-activating G protein-coupled receptor signaling pathwayGO:0007189

Locations

plasma membraneGO:0005886

Stimulatory heterotrimeric G protein alpha subunit (Galpha_s) activated by TSH-bound TSHR to stimulate adenylyl cyclase and cAMP synthesis in thyroid follicular cells.

Reactome:R-HSA-391375
TSHR binds TSH/Thyrostimulin
Demonstrates Gs coupling and adenylyl cyclase activation downstream of TSHR.
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
GNAQ Gq alpha subunit
gnaq_gq_alpha_subunit
Participant: Family: Guanine nucleotide-binding protein G(q) subunit alpha subfamily
Family:
Guanine nucleotide-binding protein G(q) subunit alpha subfamilyPANTHER:PTHR10218:SF329
Representative Members: GNAQUniProtKB:P50148

Function

G protein activityGO:0003925

Processes

thyroid-stimulating hormone signaling pathwayGO:0038194 phospholipase C-activating G protein-coupled receptor signaling pathwayGO:0007200

Locations

plasma membraneGO:0005886

Heterotrimeric Gq alpha subunit activated by TSH-bound TSHR to stimulate phospholipase C-beta and IP3/Ca2+-dependent H2O2 generation for thyroid hormone biosynthesis.

Reactome:R-HSA-391375
TSHR binds TSH/Thyrostimulin
Demonstrates G protein coupling and canonical signal transduction cascades by TSHR.
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.