Ghr

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GHR is primarily a transmembrane receptor localized to the plasma membrane, but cytosolic localization is plausible for internalized receptor during endocytic trafficking prior to degradation or recycling. The phylogenetic inference from orthologs is reasonable. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-bioreason-sft.md Activated complexes form cytoplasmic signaling hubs that culminate in nuclear signaling via STAT translocation.
GO:0008284 positive regulation of cell population proliferation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GH-GHR signaling promotes cell proliferation through JAK2/STAT5 and MAPK pathways. This is a well-established downstream outcome but is a pleiotropic effect rather than the core function of GHR itself. Supporting Evidence: PMID:8063815 GH-dependent tyrosyl phosphorylation of cellular proteins (p121, p97, p42, and p39) was dependent on the ability to activate JAK2
GO:0019221 cytokine-mediated signaling pathway	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GHR is a class I cytokine receptor and GH signaling is cytokine-mediated. This is accurate and core to receptor function, though the more specific term GO:0060396 (growth hormone receptor signaling pathway) better captures the specificity. Reason: Accurate but the more specific growth hormone receptor signaling pathway term is preferred for the core annotation. Supporting Evidence: PMID:11244571 coprecipitation using an anti-GHR antibody revealed that only Jak1 and Jak2 were associated with the GHR in these tissues
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	IBA GO_REF:0000033	ACCEPT	Summary: GHR activates JAK2/STAT5 signaling upon GH binding. This is a core function of the receptor supported by extensive direct experimental evidence in rat. Supporting Evidence: PMID:8063815 the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2 PMID:11064147 The results show a GH-induced and sustained phosphorylation of Jak2 and Stat5 on tyrosine residues file:rat/Ghr/Ghr-deep-research-falcon.md JAK2 phosphorylates receptor tyrosines and activates STAT5a/STAT5b (dominant), as well as STAT1 and STAT3, which dimerize and translocate to the nucleus to regulate transcription
GO:0009897 external side of plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: The extracellular domain of GHR faces the external side of the plasma membrane where it binds GH. This is consistent with the single-pass type I topology. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-falcon.md Architecture includes an extracellular ligand-binding region with two FNIII-like modules, a single transmembrane helix, and an intracellular domain with Box1 and Box2 motifs important for JAK coupling
GO:0004903 growth hormone receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the defining molecular function of GHR. Extensively validated by direct experiments in rat showing GH binding, JAK2 activation, and downstream signaling. Supporting Evidence: PMID:8063815 Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase. PMID:11244571 coprecipitation using an anti-GHR antibody revealed that only Jak1 and Jak2 were associated with the GHR in these tissues file:rat/Ghr/Ghr-deep-research-falcon.md GHR is a cell-surface receptor whose primary function is to bind circulating growth hormone (GH) and transduce that extracellular hormonal signal into intracellular phosphorylation cascades and gene regulation, notably including induction of hepatic IGF-1 and many other GH-responsive genes
GO:0060396 growth hormone receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: GHR mediates the growth hormone receptor signaling pathway. This is the core biological process annotation, directly supported by multiple rat studies. Supporting Evidence: PMID:8063815 the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2 PMID:11064147 The results show a GH-induced and sustained phosphorylation of Jak2 and Stat5 on tyrosine residues
GO:0019955 cytokine binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GHR binds GH, which is classified as a cytokine. This is accurate but less specific than growth hormone receptor activity (GO:0004903) or peptide hormone binding (GO:0017046). Reason: Accurate but redundant with more specific terms already annotated.
GO:0017046 peptide hormone binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GHR binds GH, a peptide hormone. This is an accurate parent term of the more specific growth hormone receptor activity annotation. Reason: Accurate but subsumed by the more specific GO:0004903 growth hormone receptor activity. Propagation Review Root cause: SOURCE STALE OR MISSING Sources checked: PANTHER:PTHR23037 · PTHR23037 family PAINT slice SOURCE STALE OR MISSING No IBD for GO:0017046 remains anywhere in the current PTHR23037 PAINT slice (snapshot rows dated through 2026-08-28); PAINT has withdrawn or re-scoped this assertion, so this IBA predates a PAINT revision. The biology is independently supported (GHR binds GH; the same term is carried by ISO and IEA rows), so the non-core grading of the GOA row stands.
GO:0070195 growth hormone receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: GHR forms homodimeric complexes upon GH binding. This is a core localization for the active signaling form. Supporting Evidence: PMID:8063815 the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2
GO:0004896 cytokine receptor activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: GHR belongs to the class I cytokine receptor family (IPR003528). Cytokine receptor activity is correct but less specific than growth hormone receptor activity. Reason: Accurate parent term but subsumed by GO:0004903. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-falcon.md a class I/type I cytokine receptor family single-pass transmembrane receptor
GO:0005576 extracellular region	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: The soluble GHBP form (isoform 2 or proteolytically shed ectodomain) is secreted into the extracellular region. Correct for the GHBP product. Reason: Applies to the secreted GHBP form, not the primary membrane-bound receptor.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: GHR is a single-pass type I transmembrane protein localized to the plasma membrane. This is a core localization. Supporting Evidence: PMID:2722883 Expression was detected in 9/12 tissues examined, with the highest levels observed in the liver file:rat/Ghr/Ghr-deep-research-falcon.md GHR is a single-pass plasma-membrane receptor
GO:0016020 membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Correct but overly general. The more specific plasma membrane term is preferred. Reason: Subsumed by more specific GO:0005886 plasma membrane.
GO:0004903 growth hormone receptor activity	IEA GO_REF:0000120	ACCEPT	Summary: Correct. Redundant with the IBA and IDA annotations for the same term.
GO:0005615 extracellular space	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The soluble GHBP (proteolytically shed GHR ectodomain) is found in extracellular space/circulation, so this component annotation is genuine, but it describes the secondary soluble form rather than the signaling-competent transmembrane receptor. Reason: The circulating GHBP localization is genuine. GO has since obsoleted GO:0005615 extracellular space (replaced_by GO:0005576 extracellular region; Ghr-goa.tsv now labels it "obsolete extracellular space"), so this GOA row will map to GO:0005576; an earlier statement here that the term was current was wrong. Kept as non-core because the core receptor function resides in the plasma membrane; the shed GHBP pool is a real but secondary form. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-falcon.md A soluble GH-binding protein (GHBP) corresponds to the extracellular domain of GHR and binds GH with receptor-like affinity
GO:0009986 cell surface	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHR is present at the cell surface where it binds GH. Correct and consistent with the external side of plasma membrane annotation. Reason: Redundant with GO:0009897 external side of plasma membrane.
GO:0017046 peptide hormone binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Correct. Redundant with the IBA annotation for this term.
GO:0032870 cellular response to hormone stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHR mediates cellular response to GH, a hormone stimulus. Correct but general. Reason: Subsumed by the more specific growth hormone receptor signaling pathway.
GO:0040018 positive regulation of multicellular organism growth	IEA GO_REF:0000107	ACCEPT	Summary: GH-GHR signaling is central to postnatal longitudinal growth. This is a key organismal-level outcome of GHR function. Supporting Evidence: PMID:15749813 Linear bone growth depends upon proliferation, maturation, and apoptosis of growth plate chondrocytes, processes regulated by growth hormone (GH) and insulin-like growth factor-I (IGF-I) PMID:12162495 Growth hormone (GH) has direct effects on the growth plate to stimulate longitudinal growth
GO:0042445 hormone metabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHR signaling regulates IGF-1 production and GH clearance, placing it in hormone metabolic processes. However, GHR itself is not a metabolic enzyme; this describes a downstream effect. Reason: Indirect downstream effect rather than direct molecular function.
GO:0042802 identical protein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHR forms homodimers upon GH binding. Identical protein binding is correct but less informative than the more specific protein homodimerization activity term. Reason: Subsumed by GO:0042803 protein homodimerization activity.
GO:0042803 protein homodimerization activity	IEA GO_REF:0000107	ACCEPT	Summary: GHR homodimerizes upon GH binding. This is well established for the GHR family and is essential for signaling. Current mechanistic models hold that GHR exists as a preformed homodimer activated by ligand-induced conformational rearrangement rather than de novo dimerization. Supporting Evidence: PMID:8063815 the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2 file:rat/Ghr/Ghr-deep-research-falcon.md GHR exists as a preformed homodimer at the cell surface
GO:0043235 receptor complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHR forms a signaling receptor complex with JAK2 upon GH binding. Correct annotation. Reason: Subsumed by the more specific GO:0070195 growth hormone receptor complex.
GO:0048009 insulin-like growth factor receptor signaling pathway	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: GHR signaling induces IGF-1 production, which then activates IGF-1R signaling. However, GHR acts upstream of IGF-1R signaling rather than being directly involved in it. This is an over-annotation. Reason: GHR acts upstream of IGF-1 production but is not directly involved in IGF-1R signaling. The relationship is indirect through the somatotropic axis.
GO:0060396 growth hormone receptor signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: Correct. Redundant with IBA and IDA annotations for the same term.
GO:0070195 growth hormone receptor complex	IEA GO_REF:0000107	ACCEPT	Summary: Correct. Redundant with IBA annotation.
GO:0042802 identical protein binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: Correct. GHR forms homodimers. Reason: Redundant with protein homodimerization activity.
GO:0005886 plasma membrane	ISO GO_REF:0000121	ACCEPT	Summary: Correct and core localization.
GO:0004903 growth hormone receptor activity	IDA PMID:8063815 Domains of the growth hormone receptor required for associat...	ACCEPT	Summary: Direct experimental demonstration in rat. VanderKuur et al. showed GH-dependent JAK2 activation and receptor phosphorylation through the Box 1 domain, confirming growth hormone receptor activity. Supporting Evidence: PMID:8063815 Growth hormone (GH) has recently been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2...the N-terminal quarter of the cytoplasmic domain of GHR and within this region, the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	IDA PMID:8063815 Domains of the growth hormone receptor required for associat...	ACCEPT	Summary: Direct demonstration that GH-GHR activates JAK2 and downstream STAT signaling. Core biological process. Supporting Evidence: PMID:8063815 the ability of JAK2 to associate with the mutated GHR was found to correlate with GH-dependent activation of JAK2, tyrosyl phosphorylation of GHR
GO:0030296 protein tyrosine kinase activator activity	IDA PMID:8063815 Domains of the growth hormone receptor required for associat...	ACCEPT	Summary: GHR activates JAK2 tyrosine kinase through its Box 1 domain. This is a core molecular function directly demonstrated in the VanderKuur et al. study. Supporting Evidence: PMID:8063815 the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2 file:rat/Ghr/Ghr-deep-research-falcon.md GHR lacks intrinsic kinase activity; instead its intracellular Box1 (and Box2) region is central for recruiting/coupling to JAK2
GO:0043410 positive regulation of MAPK cascade	IDA PMID:8063815 Domains of the growth hormone receptor required for associat...	KEEP AS NON CORE	Summary: VanderKuur et al. showed GH-dependent phosphorylation of p42 and p39 (MAPK pathway components) dependent on JAK2 activation. GHR acts upstream of MAPK cascade activation. Reason: Downstream effect of GHR-JAK2 signaling rather than core function. Supporting Evidence: PMID:8063815 GH-dependent tyrosyl phosphorylation of cellular proteins (p121, p97, p42, and p39) was dependent on the ability to activate JAK2
GO:0060396 growth hormone receptor signaling pathway	IDA PMID:8063815 Domains of the growth hormone receptor required for associat...	ACCEPT	Summary: Direct experimental evidence for GHR signaling in rat. Core annotation. Supporting Evidence: PMID:8063815 Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase.
GO:1990782 protein tyrosine kinase binding	IDA PMID:8063815 Domains of the growth hormone receptor required for associat...	ACCEPT	Summary: GHR binds JAK2 tyrosine kinase through the Box 1 proline-rich motif. Direct binding demonstrated by coprecipitation. Supporting Evidence: PMID:8063815 JAK2 did not associate with GHR in cells expressing GHR truncated at amino acid 294 (GHR1-294) or when amino acids 297-311 containing a proline-rich motif were deleted (GHR delta P)
GO:0060397 growth hormone receptor signaling pathway via JAK-STAT	ISO GO_REF:0000121	ACCEPT	Summary: GHR signals through JAK-STAT in rat, as directly demonstrated by multiple studies. ISO annotation is well-supported by rat-specific experimental data. Supporting Evidence: PMID:11064147 The results show a GH-induced and sustained phosphorylation of Jak2 and Stat5 on tyrosine residues...DNA binding activity of Stat5 was also observed in response to GH
GO:0004903 growth hormone receptor activity	ISO GO_REF:0000121	ACCEPT	Summary: Correct. Redundant with IDA evidence.
GO:0060396 growth hormone receptor signaling pathway	ISO GO_REF:0000121	ACCEPT	Summary: Correct. Redundant with IDA evidence.
GO:0016020 membrane	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: Correct but overly general. Reason: Subsumed by GO:0005886 plasma membrane.
GO:0008289 lipid binding	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO from human GHR (P10912). The evidence likely relates to GHR association with lipid rafts via extracellular subdomain 2, which mediates targeting to cholesterol-enriched membrane microdomains. This is somewhat indirect as lipid raft association differs from classical lipid binding activity. Mechanistic syntheses of GHR function describe its molecular activity strictly as ligand (GH) binding and JAK2 coupling, with no direct lipid-binding role. Reason: Lipid raft partitioning is not the same as a direct lipid-binding molecular function. The GHR molecular function is GH binding and JAK2 activation, so lipid binding is an over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P10912 · human GHR SUPPORTS SOURCE BUT NOT TARGET Human GHR donor evidence concerns partitioning of the receptor into lipid rafts, conflated with a direct lipid-binding molecular function; GHR's molecular function is GH binding and JAK2 activation. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-falcon.md rat Ghr encodes a non-enzymatic cytokine receptor whose central biochemical role is to organize and activate JAK2 at the plasma membrane in response to GH binding
GO:0009629 response to gravity	IEP PMID:14638460 Alteration of gene expression profiles in skeletal muscle of...	MARK AS OVER ANNOTATED	Summary: Taylor et al. 2002 used DNA microarray on rat skeletal muscle after STS-90 spaceflight and found altered gene expression including growth-related genes. GHR expression was among genes affected by microgravity exposure. IEP evidence based on expression changes during spaceflight. This is a high-throughput expression observation of a non-specific stress condition and does not reflect a function of GHR in gravity sensing; the falcon synthesis frames GHR strictly as a GH-binding JAK2-activating cytokine receptor. Reason: A single high-throughput spaceflight microarray showing altered GHR expression does not establish a role for GHR in response to gravity. This is an over-annotation from a non-specific expression change. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-falcon.md rat Ghr encodes a non-enzymatic cytokine receptor whose central biochemical role is to organize and activate JAK2 at the plasma membrane in response to GH binding PMID:14638460 Spaceflight induced a 19% and 23% loss of tibialis anterior and gastrocnemius muscle mass, respectively, as compared to ground controls...There was inhibition of genes for cell proliferation and growth factor cascades
GO:0019530 taurine metabolic process	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO from mouse. GHR knockout mice show decreased taurine levels and reduced Csad (rate-limiting enzyme for taurine biosynthesis) expression. The qualifier is acts_upstream_of_positive_effect, meaning GHR positively regulates taurine metabolism indirectly. This is a very downstream, tissue-level metabolic consequence of altered GH signaling rather than a function GHR carries out, and it is far removed from the core GH-binding / JAK2-STAT5 role. Reason: Altered taurine metabolism in GHR-knockout animals is an indirect systemic metabolic consequence of disrupted GH signaling, not a function of GHR itself. This is an over-annotation transferred by ISO. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:95708 · mouse Ghr SUPPORTS SOURCE BUT NOT TARGET Mouse donor evidence is altered taurine metabolism in Ghr-knockout animals -- a systemic consequence of lost GH signaling, not a GHR function. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-falcon.md rat Ghr encodes a non-enzymatic cytokine receptor whose central biochemical role is to organize and activate JAK2 at the plasma membrane in response to GH binding
GO:0040014 regulation of multicellular organism growth	ISO GO_REF:0000121	ACCEPT	Summary: GHR is central to regulation of postnatal body growth. Core function. Supporting Evidence: PMID:12162495 Growth hormone (GH) has direct effects on the growth plate to stimulate longitudinal growth
GO:0042445 hormone metabolic process	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: GHR signaling regulates IGF-1 production and GH clearance. Indirect.
GO:0060416 response to growth hormone	IEP PMID:10987684 Autoregulation of growth hormone receptor and growth hormone...	KEEP AS NON CORE	Summary: Hull & Harvey 1998 showed GH acutely upregulates GHR/GHBP transcripts in brain and peripheral tissues, demonstrating autoregulation of GHR expression in response to GH. Reason: Expression response is a regulatory observation rather than a core function. Supporting Evidence: PMID:10987684 GHR and GHBP mRNA content was significantly increased by 25-30% (P < 0.001) in all brain regions and in the spleen of hypophysectomized or sham-hypophysectomized rats
GO:0017046 peptide hormone binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: Correct. GHR binds GH, a peptide hormone. Reason: Subsumed by GO:0004903.
GO:0004903 growth hormone receptor activity	IDA PMID:11244571 Growth hormone receptor interaction with Jak proteins differ...	ACCEPT	Summary: Hellgren et al. 2001 demonstrated GHR function in rat liver and adipose tissue by showing coprecipitation of JAK1 and JAK2 with GHR. Direct experimental evidence. Supporting Evidence: PMID:11244571 coprecipitation using an anti-GHR antibody revealed that only Jak1 and Jak2 were associated with the GHR in these tissues
GO:0042976 activation of Janus kinase activity	IDA PMID:11244571 Growth hormone receptor interaction with Jak proteins differ...	ACCEPT	Summary: Hellgren et al. showed GHR-JAK association in rat tissues. This is a core signaling event directly downstream of receptor activation. Supporting Evidence: PMID:11244571 both Jak1 and Jak2 are associated with the GHR in rat tissues
GO:0005886 plasma membrane	TAS Reactome:R-NUL-1169195	ACCEPT	Summary: Reactome pathway for SOCS binding to GHR places the receptor at the plasma membrane. Correct.
GO:0005886 plasma membrane	TAS Reactome:R-RNO-1168854	ACCEPT	Summary: Reactome pathway for JAK2 phosphorylation of IRS-1/2 places GHR at plasma membrane. Correct.
GO:0005615 extracellular space	IDA PMID:11126270 In rats with sepsis, the acute fall in IGF-I is associated w...	KEEP AS NON CORE	Summary: O'Leary et al. 2000 measured circulating GHBP levels in septic rats, directly demonstrating the soluble GHR ectodomain in extracellular space/circulation. Reason: The circulating soluble GHBP was measured directly in rat, so the localization is genuine. GO has since obsoleted GO:0005615 extracellular space (replaced_by GO:0005576 extracellular region); an earlier statement here that the term was current was wrong. Kept as non-core because the core receptor function resides in the plasma membrane; the shed GHBP pool is a real but secondary form. Supporting Evidence: PMID:11126270 GHBP increased at 24 h following both CLP and LAP
GO:0009725 response to hormone	IEP PMID:12162495 Localization and regulation of the growth hormone receptor a...	KEEP AS NON CORE	Summary: Gevers et al. 2002 showed GHR/GHBP expression in rat growth plate is regulated by GH, thyroid hormones, and dexamethasone. IEP evidence from expression changes in response to hormones. Reason: Expression regulation observation, not core function. Supporting Evidence: PMID:12162495 dexamethasone treatment of normal rats inhibited their growth and reduced GHR and GHBP staining in the growth plate
GO:0032094 response to food	IEP PMID:17634149 Parenteral versus enteral nutrition: effect on serum cytokin...	KEEP AS NON CORE	Summary: O'Leary et al. 2007 compared parenteral vs enteral nutrition effects on hepatic GHR expression in septic rats. GHR expression was affected by nutrition route. Reason: Expression regulation by nutritional status, peripheral to core function. Supporting Evidence: PMID:17634149 hepatic expressions of cytokine-inducible SH2-containing protein, SOCS-2, SOCS-3, IGF-I and the growth hormone receptor (GHR) were measured by real-time quantitative PCR
GO:0032869 cellular response to insulin stimulus	IEP PMID:18040895 Insulin regulation of growth hormone receptor gene expressio...	KEEP AS NON CORE	Summary: Bennett et al. 2007 showed insulin downregulates GHR mRNA and protein via PI-3 kinase and MEK/ERK pathways in rat hepatoma cells. Reason: Expression regulation by insulin, not a core function of GHR. Supporting Evidence: PMID:18040895 insulin treatment reduces GHR mRNA and protein in a time- and concentration-dependent manner, at least in part via down-regulation of GHR transcription...Inhibition of both pathways was necessary to completely block insulin effects
GO:0034097 response to cytokine	IEP PMID:12654216 Growth hormone insensitivity of rats under the endotoxemic c...	KEEP AS NON CORE	Summary: Wang et al. 2002 showed endotoxin, TNF-alpha, and IL-6 downregulate hepatic GHR mRNA and upregulate SOCS-3 in rats. Reason: Expression regulation by cytokines, peripheral to core function. Supporting Evidence: PMID:12654216 liver IGF I and GHR mRNA expressions were obviously down-regulated in endotoxemic rats...Liver GHR mRNA expression was obviously down-regulated after TNF-alpha i.v. injection
GO:0043434 response to peptide hormone	IEP PMID:15334695 Protective effects of recombinant human growth hormone on ci...	KEEP AS NON CORE	Summary: Chen et al. 2004 showed recombinant human GH upregulates GH-binding capacity and GHR mRNA in cirrhotic rats. Reason: Expression regulation by GH treatment in disease model. Supporting Evidence: PMID:15334695 rhGH up-regulated both the GH-binding capacity (R(T)) and the expression of GHR mRNA in vivo
GO:0051384 response to glucocorticoid	IEP PMID:12162495 Localization and regulation of the growth hormone receptor a...	KEEP AS NON CORE	Summary: Gevers et al. 2002 showed dexamethasone treatment reduces GHR/GHBP staining in rat growth plate. Reason: Expression regulation by glucocorticoid, peripheral. Supporting Evidence: PMID:12162495 dexamethasone treatment of normal rats inhibited their growth and reduced GHR and GHBP staining in the growth plate
GO:0060351 cartilage development involved in endochondral bone morphogenesis	IEP PMID:15749813 Spatial distribution of growth hormone receptor, insulin-lik...	KEEP AS NON CORE	Summary: Cruickshank et al. 2005 showed GHR mRNA expression in rat growth plate chondrocytes across developmental stages, with spatial distribution suggesting roles in both proliferation and apoptosis during growth plate development. Reason: Expression in growth plate supports involvement but is a downstream physiological process. Supporting Evidence: PMID:15749813 GHR mRNA was greatest in resting cells with hypertropic cells increasing GHR expression with increasing age...Treating cells in culture with GH increased the number of apoptotic cells across all ages and zones
GO:0070555 response to interleukin-1	IEP PMID:14518239 Pro-inflammatory cytokines IL-1 beta and TNF-alpha reduce gr...	KEEP AS NON CORE	Summary: Bohm et al. 1998 showed IL-1beta and TNF-alpha reduce GHR mRNA in cultured rat hepatocytes. Reason: Expression regulation by cytokines. Supporting Evidence: PMID:14518239 Diminished GHR-mRNA concentrations in response to cytokine stimulation
GO:0070195 growth hormone receptor complex	ISO GO_REF:0000121	ACCEPT	Summary: Correct. Redundant with IBA annotation.
GO:0032355 response to estradiol	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO from human. GHR expression is regulated by estradiol in human. Plausible for rat. Reason: Expression regulation, peripheral.
GO:0043235 receptor complex	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: GHR forms a receptor complex with JAK2. Correct but less specific than GO:0070195. Reason: Subsumed by GO:0070195.
GO:0005615 extracellular space	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO annotation for GHBP in extracellular space, transferred from the ortholog record; consistent with the direct rat IDA evidence for circulating GHBP. Reason: The circulating soluble GHBP localization is genuine. GO has since obsoleted GO:0005615 extracellular space (replaced_by GO:0005576 extracellular region); an earlier statement here that the term was current was wrong. Kept as non-core, aligned with the IEA and IDA rows for the same term. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P10912 · human GHR SUPPORTS TRANSFER Human GHR donor supports the circulating soluble GH-binding protein in extracellular space; the localization transfers validly to rat and is kept as non-core.
GO:0009986 cell surface	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: Correct. GHR is on the cell surface. Reason: Redundant with external side of plasma membrane.
GO:0019838 growth factor binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: GHR binds GH, which acts as a growth factor. Correct but less specific than peptide hormone binding or growth hormone receptor activity. Reason: Subsumed by more specific terms.
GO:0031623 receptor internalization	ISO NOT GO_REF:0000121	KEEP AS NON CORE	Summary: NOT annotation indicating the short isoform (GHBP, isoform 2, lacking transmembrane and cytoplasmic domains) does NOT undergo receptor internalization. Consistent with the lack of transmembrane domain in this isoform. Reason: Isoform-specific negative annotation for receptor trafficking, not a core function. Supporting Evidence: file:rat/Ghr/Ghr-deep-research-bioreason-sft.md The secreted ectodomain (GHRP) modulates hormone bioavailability and receptor occupancy.
GO:0031623 receptor internalization	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: The full-length GHR (isoform 1) undergoes ligand-mediated internalization and down-regulation. Phe-346 is critical for internalization. Well-supported. Reason: Receptor trafficking process, not a core evolved function.
GO:0032870 cellular response to hormone stimulus	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: GHR mediates cellular responses to GH. Correct but general.
GO:0042803 protein homodimerization activity	ISO GO_REF:0000121	ACCEPT	Summary: GHR homodimerizes. Correct.
GO:0046898 response to cycloheximide	ISO NOT GO_REF:0000121	KEEP AS NON CORE	Summary: NOT annotation for the short isoform (GHBP). The soluble isoform does not show response to cycloheximide (translation inhibitor), as it is already secreted. Reason: Isoform-specific negative annotation, peripheral.
GO:0046898 response to cycloheximide	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: The full-length isoform 1 shows response to cycloheximide (translation inhibitor affects receptor levels). This is a pharmacological response, not a core function. Reason: Pharmacological response, not core function.
GO:0048009 insulin-like growth factor receptor signaling pathway	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: GHR acts upstream of IGF-1 production but is not directly involved in IGF-1R signaling itself. Over-annotation. Reason: GHR induces IGF-1 production but does not participate in IGF-1R signal transduction directly. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P10912 · human GHR SUPPORTS SOURCE BUT NOT TARGET Human donor evidence shows GHR induces IGF-1 production upstream of IGF-1R; it does not place GHR within IGF-1R signal transduction itself.
GO:0040018 positive regulation of multicellular organism growth	ISO GO_REF:0000121	ACCEPT	Summary: Correct. Redundant with IEA annotation.
GO:0009755 hormone-mediated signaling pathway	IDA PMID:11064147 Activation of the Jak/Stat signal transduction pathway in GH...	ACCEPT	Summary: Gerland et al. 2000 demonstrated GH-induced JAK2/STAT5 activation in rat osteoblast-like cells, confirming hormone-mediated signaling through GHR. Supporting Evidence: PMID:11064147 The results show a GH-induced and sustained phosphorylation of Jak2 and Stat5 on tyrosine residues
GO:0004903 growth hormone receptor activity	IDA PMID:17258692 Distinct neuronal growth hormone receptor ligand specificity...	ACCEPT	Summary: Moderscheim et al. 2007 confirmed GHR protein on neuronal cell bodies in rat cortex and showed GH-dependent neuroprotective effects via GHR, blocked by GHR antagonist G120D. Supporting Evidence: PMID:17258692 Immunohistochemistry confirmed growth hormone receptor protein on neuronal cell bodies in the rat cortex...This neuroprotective effect was inhibited by the selective growth hormone receptor antagonist G120D (p<0.001)
GO:0019901 protein kinase binding	IPI PMID:11244571 Growth hormone receptor interaction with Jak proteins differ...	ACCEPT	Summary: Hellgren et al. 2001 showed coprecipitation of JAK1 and JAK2 (protein tyrosine kinases) with GHR in rat tissues. Direct physical interaction evidence. Supporting Evidence: PMID:11244571 coprecipitation using an anti-GHR antibody revealed that only Jak1 and Jak2 were associated with the GHR in these tissues
GO:0019903 protein phosphatase binding	IMP PMID:10976913 Mutation of the SHP-2 binding site in growth hormone (GH) re...	ACCEPT	Summary: Stofega et al. 2000 showed that mutation of the SHP-2 binding site (Y595F) on GHR prolonged signaling, demonstrating functional consequence of phosphatase binding. Supporting Evidence: PMID:10976913 Tyrosine-to-phenylalanine mutation of tyrosine 595 of rat GHR greatly diminishes association of the SH2 domains of SHP-2 with GHR
GO:0019903 protein phosphatase binding	IPI PMID:10976913 Mutation of the SHP-2 binding site in growth hormone (GH) re...	ACCEPT	Summary: Direct physical interaction between GHR and SHP-2 phosphatase demonstrated by SH2 domain binding assays. Supporting Evidence: PMID:10976913 the SH2 domains of SHP-2 bind directly to tyrosyl phosphorylated GHR from GH-treated cells
GO:0032107 regulation of response to nutrient levels	IMP PMID:17258692 Distinct neuronal growth hormone receptor ligand specificity...	KEEP AS NON CORE	Summary: Moderscheim et al. 2007 showed rat GH rescued cortical neurons from nutrient deprivation-induced cell death via GHR, indicating GHR regulates cellular response to nutrient levels. Reason: Neuroprotective effect in nutrient deprivation context, downstream of core signaling. Supporting Evidence: PMID:17258692 rat but not bovine growth hormone rescued neurons from nutrient deprivation-induced cell death...This neuroprotective effect was inhibited by the selective growth hormone receptor antagonist G120D (p<0.001)
GO:0042169 SH2 domain binding	IMP PMID:10976913 Mutation of the SHP-2 binding site in growth hormone (GH) re...	ACCEPT	Summary: Stofega et al. showed that GHR phosphotyrosines (Y595, Y487) bind SH2 domains of SHP-2. Functional consequence demonstrated by mutation studies. Supporting Evidence: PMID:10976913 Tyrosine-to-phenylalanine mutation of tyrosine 595 of rat GHR greatly diminishes association of the SH2 domains of SHP-2 with GHR
GO:0042169 SH2 domain binding	IPI PMID:10976913 Mutation of the SHP-2 binding site in growth hormone (GH) re...	ACCEPT	Summary: Direct physical interaction of GHR phosphotyrosines with SH2 domains demonstrated. Supporting Evidence: PMID:10976913 the SH2 domains of SHP-2 bind directly to tyrosyl phosphorylated GHR from GH-treated cells
GO:0043025 neuronal cell body	IDA PMID:17258692 Distinct neuronal growth hormone receptor ligand specificity...	ACCEPT	Summary: Moderscheim et al. 2007 confirmed GHR protein on neuronal cell bodies in rat cortex by immunohistochemistry and immunocytochemistry. Supporting Evidence: PMID:17258692 Immunohistochemistry confirmed growth hormone receptor protein on neuronal cell bodies in the rat cortex...Immunocytochemistry showed growth hormone receptor on neurons within the neuron-enriched cultures
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	IMP PMID:10976913 Mutation of the SHP-2 binding site in growth hormone (GH) re...	ACCEPT	Summary: Stofega et al. showed that disrupting SHP-2 binding prolonged JAK-STAT signaling, demonstrating that GHR positively regulates JAK-STAT pathway with SHP-2 as negative regulator. Supporting Evidence: PMID:10976913 Mutation of tyrosine 595 dramatically prolongs the duration of tyrosyl phosphorylation of the signal transducer and activator of transcription STAT5B in response to GH
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	IDA PMID:11064147 Activation of the Jak/Stat signal transduction pathway in GH...	ACCEPT	Summary: Gerland et al. 2000 directly demonstrated GH-induced JAK2/STAT5 activation in rat osteoblasts. Supporting Evidence: PMID:11064147 The results show a GH-induced and sustained phosphorylation of Jak2 and Stat5 on tyrosine residues. The tyrosine phosphorylation status of Jak2 was increased in a dose-dependent manner
GO:0005634 nucleus	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO from mouse. GHR nuclear localization has been demonstrated in multiple species including evidence of GH-dependent nuclear translocation via the importin system. GHR interacts with HMGN1 in the nucleus. Reasonable annotation. Reason: Nuclear localization is documented but is not the primary site of GHR function.
GO:0042169 SH2 domain binding	IDA PMID:12586763 Interaction of the growth hormone receptor with cytokine-ind...	ACCEPT	Summary: Du et al. 2003 demonstrated interaction of GHR with CIS (cytokine-induced SH2-containing protein) in rat adipocytes. CIS binding to phosphorylated GHR is SH2-domain mediated. Supporting Evidence: PMID:12586763 A tyrosine-phosphorylated protein that appears to be the GHR was coprecipitated from extracts of GH-treated adipocytes with alpha-CIS...Interaction of GHR with CIS peaked between 2 and 10 min after adipocytes were treated with GH
GO:0045597 positive regulation of cell differentiation	TAS PMID:2722883 Regulation of rat growth hormone receptor gene expression.	KEEP AS NON CORE	Summary: Mathews et al. 1989 cloned rat GHR and showed developmental expression regulation. The TAS evidence for differentiation regulation is based on general knowledge that GH promotes cell differentiation. Reason: General downstream effect, not core molecular function. Supporting Evidence: PMID:2722883 Expression in liver, kidney, heart and muscle was developmentally regulated, being low at birth and rising to adult levels in 5 weeks
GO:0004903 growth hormone receptor activity	TAS PMID:12162495 Localization and regulation of the growth hormone receptor a...	ACCEPT	Summary: Gevers et al. 2002 localized GHR in rat growth plate. TAS evidence for receptor activity based on documented function. Supporting Evidence: PMID:12162495 Growth hormone (GH) has direct effects on the growth plate to stimulate longitudinal growth
GO:0045597 positive regulation of cell differentiation	IEP PMID:12162495 Localization and regulation of the growth hormone receptor a...	KEEP AS NON CORE	Summary: Gevers et al. 2002 showed GHR expression in differentiating chondrocytes of the growth plate, with expression highest in early maturing chondrocytes at the proliferative-hypertrophic interface, suggesting a role in chondrocyte differentiation. Reason: Expression pattern suggests involvement but is a downstream physiological effect. Supporting Evidence: PMID:12162495 Both GHR and GHBP were shown in the germinal and proliferative chondrocytes, but most clearly in early maturing chondrocytes at the interface between proliferative and hypertrophic cells

Gene Description

Existing Annotations Review

Core Functions

Growth hormone receptor binds pituitary growth hormone via its extracellular domain and activates JAK2 tyrosine kinase through the cytoplasmic Box 1 proline-rich motif, initiating the JAK-STAT signaling cascade that drives postnatal growth and metabolism.

GHR activates JAK2 tyrosine kinase and provides phosphotyrosine docking sites for SH2 domain-containing signaling proteins including STAT5A/B, SHP-2, and CIS, enabling signal transduction from the cell surface.

References

Deep Research

Bioreason Pro

Falcon

📚 Additional Documentation

Notes

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