Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0009897 external side of plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Conserved receptor topology places the ligand-binding ectodomain on the external side of the plasma membrane. Reason: This is consistent with the biology of the full-length membrane receptor and with accepted plasma-membrane localization.
GO:0019221 cytokine-mediated signaling pathway	IBA GO_REF:0000033	MODIFY	Summary: Broad family-level IBA term transferred from cytokine-receptor ancestry. Ghr has a specific growth-hormone pathway term available. Reason: This is overly broad and likely reflects cytokine-receptor family transfer rather than a precise statement about Ghr. Proposed replacements: growth hormone receptor signaling pathway
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	IBA GO_REF:0000033	ACCEPT	Summary: Conserved statement that activated GHR promotes receptor-proximal JAK-STAT signaling. Reason: This is consistent with the direct mouse JAK-STAT literature and donor traces with real receptor-signaling evidence.
GO:0004903 growth hormone receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: Core receptor molecular function. Reason: Growth hormone receptor activity is directly established in mouse and is the central molecular function of Ghr.
GO:0060396 growth hormone receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: Specific pathway term for the receptor's core biological role. Reason: This specific pathway is strongly supported by direct mouse signaling evidence and is preferable to broader endocrine/cytokine terms.
GO:0008284 positive regulation of cell population proliferation	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Downstream proliferative outcome seen in some contexts, not the core evolved function of Ghr. Reason: This term captures context-dependent downstream physiology rather than receptor-specific molecular function or pathway identity.
GO:0019955 cytokine binding	IBA GO_REF:0000033	MODIFY	Summary: Broad family-level binding term. For Ghr the specific accepted binding activity is peptide hormone binding. Reason: The generic cytokine-binding label is less informative and likely driven by paralog/family transfer. Proposed replacements: peptide hormone binding
GO:0005829 cytosol	IBA GO_REF:0000033	REMOVE	Summary: Family-level non-experimental transfer with no convincing mouse support for Ghr as a cytosolic protein. Reason: Ghr is a membrane receptor/GHBP locus, not a cytosolic protein; this appears to be a low-specificity transfer.
GO:0017046 peptide hormone binding	IBA GO_REF:0000033	ACCEPT	Summary: Specific binding activity for growth hormone. Reason: This is the appropriate specific binding term for Ghr and is supported by direct receptor/hormone interaction evidence.
GO:0070195 growth hormone receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: Conserved receptor-complex term aligned with receptor dimer/complex biology. Reason: The receptor forms signaling-competent complexes and donor traces retain direct experimental support for this term.
GO:0004896 cytokine receptor activity	IEA GO_REF:0000002	MODIFY	Summary: Generic receptor-family term derived from InterPro domain mapping. Reason: Ghr has a specific receptor-activity term that is preferable to the broad cytokine-receptor label. Proposed replacements: growth hormone receptor activity
GO:0004903 growth hormone receptor activity	IEA GO_REF:0000117	ACCEPT	Summary: ARBA prediction agrees with the known core receptor activity. Reason: The term is correct and already supported by stronger mouse experimental evidence.
GO:0005576 extracellular region	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Compatible with the GHBP product and extracellular receptor ectodomain, but not the most informative core location. Reason: The gene produces an extracellular GH-binding product, so the term is not false, but plasma membrane is the clearer core location for the signaling receptor.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: Expected localization for the full-length signaling receptor. Reason: Plasma-membrane localization is directly supported in mouse and is the core cellular location of the signaling receptor isoform.
GO:0006897 endocytosis	IEA GO_REF:0000043	REMOVE	Summary: Keyword-derived process assignment that treats the receptor as though it were an agent of endocytosis. Reason: Internalization of GHR as cargo does not justify a broad gene-level endocytosis annotation.
GO:0016020 membrane	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: True but much less informative than plasma membrane. Reason: The term is correct but too broad to capture the biology better than the accepted plasma-membrane annotation.
GO:0060396 growth hormone receptor signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: ARBA prediction matches the direct experimental literature. Reason: This term is correct and is already supported by stronger mouse and donor experimental evidence.
GO:0004903 growth hormone receptor activity	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer from GHR/P10912. Current donor tracing shows real human experimental support, but the donor also carries circular inferred copies of the same term. Reason: The term itself is correct and directly supported in mouse; the ISO edge is redundant rather than wrong and should not be treated as the primary justification.
GO:0005615 extracellular space	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Human-to-mouse ISO transfer from P10912. Donor support exists, but this fits GHBP/extracellular product biology better than the membrane receptor. Reason: The term is plausible because the locus produces GHBP, but it should not be mistaken for the core location of signaling-competent GHR.
GO:0005886 plasma membrane	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer from P10912 with retained donor-side direct support. Reason: Plasma-membrane localization is correct for the full-length receptor and is independently supported in mouse.
GO:0008289 lipid binding	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer from P10912, but the donor-side support is a non-core assertion that is not corroborated in mouse Ghr biology. Reason: Lipid binding is not part of the established mouse Ghr functional profile and looks like an over-transfer.
GO:0009986 cell surface	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer from P10912 with retained donor-side experimental support. Reason: Cell-surface localization is appropriate for the membrane receptor.
GO:0016020 membrane	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Human-to-mouse ISO transfer from P10912; correct but less informative than plasma membrane. Reason: This broad location term adds little beyond the accepted plasma-membrane annotation.
GO:0017046 peptide hormone binding	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer from P10912 with retained donor-side direct receptor/hormone interaction support. Reason: This is the correct specific binding term for Ghr and is consistent with direct mouse evidence.
GO:0019838 growth factor binding	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer from P10912, but current donor tracing no longer recovers this term on the donor record. Reason: This looks like a stale or overly broad transfer. Peptide hormone binding is the precise accepted term.
GO:0031623 receptor internalization	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer from P10912, but current donor tracing does not recover the term and the rat donor carries a NOT annotation for it. Reason: This is a weak circular/stale transfer and should not be preserved without direct mouse evidence.
GO:0032355 response to estradiol	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer with no current donor-side support recovered. Reason: This appears to be context-heavy endocrine over-transfer rather than core Ghr biology.
GO:0032870 cellular response to hormone stimulus	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Human-to-mouse ISO transfer reflecting broad endocrine physiology rather than a Ghr-specific pathway statement. Reason: The specific accepted pathway terms already capture the relevant biology more cleanly.
GO:0040018 positive regulation of multicellular organism growth	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Human-to-mouse ISO transfer for an organism-level phenotype outcome. Reason: Ghr clearly influences body growth, but this is a downstream whole-animal phenotype rather than the receptor's core molecular role.
GO:0042445 hormone metabolic process	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Human-to-mouse ISO transfer for a broad endocrine-process term. Reason: This is too indirect and process-broad for core Ghr annotation.
GO:0042802 identical protein binding	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer supported by donor-side receptor self- association evidence. Reason: Receptor self-association is consistent with GHR complex/dimer biology.
GO:0042803 protein homodimerization activity	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer with retained donor-side direct support for receptor homodimerization. Reason: Dimerization is a central part of GHR signaling biology.
GO:0043235 receptor complex	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer with retained donor-side experimental support. Reason: GHR functions in a receptor complex/dimer context.
GO:0046898 response to cycloheximide	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer with no current human donor support recovered, and rat donor tracing shows a NOT annotation for the term. Reason: This is a stale and contradicted transfer.
GO:0048009 insulin-like growth factor receptor signaling pathway	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer capturing endocrine cross-talk rather than a Ghr-specific pathway. Reason: Ghr is not an IGF receptor; this is an over-transfer of downstream physiology/cross-talk.
GO:0060396 growth hormone receptor signaling pathway	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer from P10912 with retained donor-side direct pathway support. Reason: The term is correct for mouse Ghr. The donor also carries inferred copies, so the ISO edge is redundant but still directionally right.
GO:0070195 growth hormone receptor complex	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer with donor-side direct support for receptor complex biology. Reason: This is consistent with accepted receptor-complex/dimer annotations.
GO:0005829 cytosol	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer with no convincing donor-side experimental support for GHR as a cytosolic protein. Reason: This appears to be a non-specific transfer inconsistent with receptor topology.
GO:0036464 cytoplasmic ribonucleoprotein granule	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer with no current donor-side support recovered. Reason: There is no coherent Ghr-specific rationale for retaining this term.
GO:0042976 activation of Janus kinase activity	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer from Ghr/P16310. Current donor tracing retains direct rat experimental support. Reason: Activation of JAK kinase activity is part of core GHR signaling biology and the rat donor support is direct rather than purely circular.
GO:0004903 growth hormone receptor activity	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer from P16310. Rat donor retains real experiments but also donor-side ISO copies from mouse/human. Reason: The term itself is correct and directly supported in mouse. The donor chain is partially circular but not enough to overturn the term.
GO:0005615 extracellular space	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Rat-to-mouse ISO transfer from P16310. Rat donor has direct support plus donor-side ISO-from-human copies. Reason: Plausible for GHBP/extracellular product biology, but not the core location of the signaling receptor.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	ISO GO_REF:0000096	MODIFY	Summary: Rat-to-mouse ISO transfer from P16310 with direct donor support, but the mouse-specific pathway term is more precise. Reason: The biology is right, but `growth hormone receptor signaling pathway via JAK-STAT` is the more specific term for Ghr. Proposed replacements: growth hormone receptor signaling pathway via JAK-STAT
GO:0009755 hormone-mediated signaling pathway	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: Rat-to-mouse ISO transfer for a broad endocrine-process label. Reason: Specific Ghr pathway terms already capture the biology more cleanly than this generic hormone-signaling term.
GO:0019901 protein kinase binding	ISO GO_REF:0000096	MODIFY	Summary: Rat-to-mouse ISO transfer from P16310 with interaction evidence, but the more precise retained term is protein tyrosine kinase binding. Reason: GHR engages JAK-family tyrosine kinases; the specific tyrosine-kinase binding term is preferable. Proposed replacements: protein tyrosine kinase binding
GO:0019903 protein phosphatase binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Rat-to-mouse ISO transfer with donor-side support for phosphatase interactions. Reason: Plausible interaction term, but it is secondary to the receptor's core hormone-binding and signaling roles.
GO:0030296 protein tyrosine kinase activator activity	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer with direct donor support for JAK activation by the receptor. Reason: This is a mechanistically informative term for a kinase-less receptor that activates JAK2.
GO:0032107 regulation of response to nutrient levels	ISO GO_REF:0000096	REMOVE	Summary: Rat-to-mouse ISO transfer for contextual physiology rather than core receptor function. Reason: This is too far downstream and context-dependent for a core Ghr annotation.
GO:0042169 SH2 domain binding	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer with donor-side docking evidence for SH2- containing signaling proteins. Reason: This is a mechanistically meaningful interaction term for phosphotyrosine- dependent GHR signaling complexes.
GO:0043025 neuronal cell body	ISO GO_REF:0000096	REMOVE	Summary: Rat-to-mouse ISO transfer from a tissue/context-specific neuronal study. Reason: This is too specific to the donor experimental context to keep as a generic mouse Ghr location.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer with no current donor support recovered and a likely substrate-versus-agent confusion. Reason: GHR is subject to regulated degradation, but that does not make the gene product an agent of the catabolic process.
GO:0043410 positive regulation of MAPK cascade	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer with direct donor support for MAPK-branch signaling. Reason: MAPK activation is part of well-established GHR signaling output.
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer with direct donor support. Reason: This aligns with accepted JAK-STAT signaling biology for Ghr.
GO:0060396 growth hormone receptor signaling pathway	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer from P16310. The rat donor has a direct pathway assertion but also donor-side ISO-from-human copies. Reason: The term is correct for mouse Ghr. The ISO edge is partly circular but the donor set is not purely inferred.
GO:0060397 growth hormone receptor signaling pathway via JAK-STAT	ISO GO_REF:0000119	ACCEPT	Summary: Human-to-mouse ISO transfer no longer recovered as a current human donor annotation, but mouse has direct experimental support for the same term. Reason: Retain the term because it is correct in mouse, while noting that the ISO provenance itself is stale and not the primary evidence.
GO:0060400 negative regulation of growth hormone receptor signaling pathway	ISO GO_REF:0000119	REMOVE	Summary: Human-to-mouse ISO transfer with no current donor support recovered. Reason: This reads as a downstream regulatory consequence rather than a direct core annotation for Ghr.
GO:1990782 protein tyrosine kinase binding	ISO GO_REF:0000096	ACCEPT	Summary: Rat-to-mouse ISO transfer with direct donor support for binding to tyrosine kinases such as JAK2. Reason: This is the preferred specific kinase-binding term for Ghr.
GO:0060397 growth hormone receptor signaling pathway via JAK-STAT	IDA PMID:8702683 Growth hormone promotes the association of transcription fac...	ACCEPT	Summary: Direct mouse evidence that GH promotes STAT5 association with GHR. Reason: This is the strongest direct mouse pathway paper for Ghr and anchors the JAK-STAT branch. Supporting Evidence: PMID:8702683 GH-induced tyrosine phosphorylation of STAT5 and the interaction of STAT5 with GHR can be observed in mouse 3T3-F442A cells which express endogenous mouse GHR.
GO:0016020 membrane	IDA PMID:11834450 Structurally distinct membrane-associated and soluble forms ...	KEEP AS NON CORE	Summary: Direct mouse study of membrane-associated GHBP and soluble GHBP forms. Reason: The paper clearly supports membrane association, but plasma membrane is the more informative core location and the result is entwined with GHBP isoform biology. Supporting Evidence: PMID:11834450 mouse liver GHBP is predominantly present as a membrane-associated protein structurally distinct from the soluble form of GHBP present in serum.
GO:0019530 taurine metabolic process	IMP PMID:18648510 Altered metabolism of growth hormone receptor mutant mice: a...	REMOVE	Summary: Metabolomic consequence of altered GHR signaling in mutant mice, not a direct receptor function. Reason: This is a downstream phenotype/process consequence and should not be kept as a direct Ghr function annotation. Supporting Evidence: PMID:18648510 The systems biology approach applied in this study provides a coherent picture of metabolic changes resulting from impaired STAT5 signalling by the growth hormone receptor, and supports a potentially important role for taurine in enhancing beta-oxidation.
GO:0040014 regulation of multicellular organism growth	IMP PMID:18648510 Altered metabolism of growth hormone receptor mutant mice: a...	KEEP AS NON CORE	Summary: Whole-animal phenotype consequence of altered receptor signaling. Reason: Ghr clearly affects organismal growth, but this is a downstream phenotype rather than the receptor's core molecular role. Supporting Evidence: PMID:18648510 These truncations lead to altered signaling through the GHR in response to hormone binding and allow us to study the contribution of particular GH receptor signaling domains to gene expression and metabolism.
GO:0005615 extracellular space	HDA PMID:24006456 Extracellular matrix secretion by cardiac fibroblasts: role ...	KEEP AS NON CORE	Summary: Proteomic secretome-style evidence from cardiac fibroblasts. Plausible for GHBP/extracellular product biology but not strong Ghr-focused localization. Reason: The term is plausible because of GHBP, but this paper is not a focused Ghr localization study and should not drive core curation. Supporting Evidence: PMID:24006456 Mouse cardiac fibroblasts were transfected with pre-/anti-miR of miR-29b and miR-30c, and their conditioned medium was analyzed by mass spectrometry.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1168790	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1168910	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1168923	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1168927	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1169194	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1169229	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1169240	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1169250	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1169142	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005886 plasma membrane	TAS Reactome:R-MMU-1169206	ACCEPT	Summary: Reactome pathway placement is consistent with accepted receptor localization. Reason: Plasma membrane is the core signaling location for Ghr.
GO:0005576 extracellular region	TAS Reactome:R-MMU-1168790	KEEP AS NON CORE	Summary: Reactome extracellular-region placement is plausible for GHBP/ectodomain biology but not the most informative core location. Reason: The gene produces extracellular GH-binding material, but plasma membrane is the clearer core location.
GO:0005515 protein binding	IPI PMID:8702683 Growth hormone promotes the association of transcription fac...	MODIFY	Summary: Direct interaction paper, but the generic protein-binding term is too uninformative. Reason: The paper is better captured by the more specific SH2-domain-binding concept for receptor docking interactions. Proposed replacements: SH2 domain binding
GO:0004903 growth hormone receptor activity	IDA PMID:6303755 Hepatic binding of human and bovine growth hormones and ovin...	ACCEPT	Summary: Direct mouse receptor-binding evidence from liver membranes. Reason: This is primary experimental mouse evidence for receptor activity. Supporting Evidence: PMID:6303755 GH receptors were at normal levels in lit/lit mice despite their deficiency of pituitary and serum GH. file:mouse/Ghr/Ghr-deep-research-falcon.md GHR is a cell-surface receptor for endocrine and local growth hormone (GH).
GO:0017046 peptide hormone binding	IPI PMID:10556780 Up-regulation of GH-binding protein by mouse GH in transgeni...	ACCEPT	Summary: Mouse GHBP/GH interaction evidence supports the specific hormone-binding activity of the locus. Reason: Whether through receptor or GHBP product, peptide hormone binding is a correct direct activity for Ghr. Supporting Evidence: PMID:10556780 Chromatographic separation of labeled human GH or mGH cross-linked to serum GHBPs showed two GH-binding serum fractions in normal as well as in transgenic mice serum.
GO:0005634 nucleus	IDA PMID:9144201 Functional growth hormone (GH) receptors and GH are expresse...	KEEP AS NON CORE	Summary: Developmental-stage-specific embryo localization with mainly nuclear signal in cleavage-stage embryos. Reason: The observation is experimentally real but context-specific and not the default location for Ghr biology. Supporting Evidence: PMID:9144201 In cleavage-stage embryos this immunoreactivity was localized mainly to the nucleus, but clear evidence of membrane labeling was apparent in blastocysts.
GO:0005886 plasma membrane	IDA PMID:9144201 Functional growth hormone (GH) receptors and GH are expresse...	ACCEPT	Summary: Direct mouse embryo study shows membrane labeling in blastocysts. Reason: This is direct mouse evidence consistent with the core receptor location. Supporting Evidence: PMID:9144201 In cleavage-stage embryos this immunoreactivity was localized mainly to the nucleus, but clear evidence of membrane labeling was apparent in blastocysts.

Core Functions

Full-length mouse GHR binds growth hormone at the plasma membrane and transduces growth-hormone receptor signaling, especially through the JAK-STAT branch.

Molecular Function:

growth hormone receptor activity

Directly Involved In:

growth hormone receptor signaling pathway growth hormone receptor signaling pathway via JAK-STAT

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:6303755
GH receptors were at normal levels in lit/lit mice despite their deficiency of pituitary and serum GH.
PMID:8702683
GH-induced tyrosine phosphorylation of STAT5 and the interaction of STAT5 with GHR can be observed in mouse 3T3-F442A cells which express endogenous mouse GHR.
file:mouse/Ghr/Ghr-notes.md
UniProt records two alternative products: full-length isoform P16882-1 and the shorter P16882-2 GH-binding protein isoform.

References

file:mouse/Ghr/Ghr-notes.md

Curator notes for mouse Ghr review

file:mouse/Ghr/Ghr-iso-donor-trace.md

ISO donor trace for mouse Ghr

file:mouse/Ghr/Ghr-uniprot.txt

UniProtKB P16882 record for mouse Ghr

file:mouse/Ghr/Ghr-goa.tsv

QuickGO export for mouse Ghr

file:mouse/Ghr/Ghr-deep-research-falcon.md

Falcon deep research report for mouse Ghr

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000096

Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000119

Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs

PMID:10556780

Up-regulation of GH-binding protein by mouse GH in transgenic mice overexpressing GH-releasing hormone.

PMID:11834450

Structurally distinct membrane-associated and soluble forms of GH-binding protein in the mouse.

PMID:18648510

Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study.

PMID:24006456

Extracellular matrix secretion by cardiac fibroblasts: role of microRNA-29b and microRNA-30c.

PMID:6303755

Hepatic binding of human and bovine growth hormones and ovine prolactin in the dwarf "little" mouse.

PMID:8702683

Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor.

PMID:9144201

Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: a role for GH in early embryogenesis?

Reactome:R-MMU-1168790

ADAM17 cleavage of Ghr

Reactome:R-MMU-1168910

Stat5 association with Ghr

Reactome:R-MMU-1168923

Stat5 tyrosine phosphorylation

Reactome:R-MMU-1168927

Growth hormone receptor binds Lyn

Reactome:R-MMU-1169142

Jak2 binds Stat1/Stat3

Reactome:R-MMU-1169194

Socs binding to JAK2

Reactome:R-MMU-1169206

Jak2 phosphorylates Stat1/Stat3

Reactome:R-MMU-1169229

Ptp1b dephosphorylates Jak2

Reactome:R-MMU-1169240

Shp1 (Ptpn6) dephosphorylates Jak2

Reactome:R-MMU-1169250

Shp1 binds Jak2 in the receptor complex

Suggested Experiments

Experiment: Express mouse P16882-1 and P16882-2 separately in the same cell system and compare plasma-membrane localization, GH binding, and STAT5 activation.

Hypothesis: Isoform 1 is the signaling-competent receptor whereas isoform 2 primarily contributes extracellular GH-binding/GHBP biology.

Type: isoform-specific expression and signaling assay

Experiment: Measure GH-induced trafficking/internalization of endogenous mouse GHR with isoform-discriminating reagents and quantify receptor versus GHBP pools.

Hypothesis: Receptor internalization should not be retained as a mouse Ghr annotation without direct evidence that distinguishes the full-length receptor from GHBP/shed ectodomain behavior.

Type: ligand-induced trafficking assay

Deep Research

Falcon

(Ghr-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 49 citations 2026-03-21T17:18:57.350313

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Mouse Ghr (Growth Hormone Receptor) — UniProt P16882

1) Target verification (gene/protein identity)

The target gene symbol Ghr (mouse) corresponds to the growth hormone receptor (GHR) and matches UniProt accession P16882, consistent with a class I/type I cytokine receptor-family single-pass transmembrane receptor. The P16882 sequence/topology includes an N-terminal signal peptide, a GH-binding extracellular domain (ECD) containing hallmark cytokine-receptor features such as an FN3-like region and a conserved WSXWS motif, a single transmembrane helix, and a cytoplasmic domain containing a Box 1 motif and a region annotated as required for JAK2 binding—features expected for canonical GHR biology. (gun2022investigationofmonoclonal pages 49-52)

Mouse-focused experimental literature explicitly links GHR (UniProt P16882) to GH-triggered JAK2→STAT5 signaling and IGF-I transcriptional responses. (corrick2013hepaticgrowthhormone pages 1-2)

2) Key concepts and definitions (current understanding)

2.1 Molecular function

GHR is a cell-surface receptor for endocrine and local growth hormone (GH). Ligand binding triggers receptor rearrangements that activate intracellular tyrosine-kinase signaling via associated JAK kinases, especially JAK2, culminating in STAT transcription factor activation (primarily STAT5/STAT5B) and GH-responsive gene regulation including Igf1. (corrick2013hepaticgrowthhormone pages 1-2, petrashen2023aclusterof pages 1-2)

2.2 Receptor activation mechanism

GHR functions as a homodimeric cytokine receptor. GH binding induces conformational changes that reposition the two receptor-associated JAK2 molecules to facilitate trans-phosphorylation, receptor tyrosine phosphorylation, and STAT docking/activation. (storr2019nonclassicalghinsensitivity pages 3-3, storr2019nonclassicalghinsensitivity pages 2-3)

Foundational mechanistic mapping showed that distinct GHR regions support differential STAT responses: the membrane-proximal region required for JAK activation is sufficient for STAT3 activation, whereas C-terminal GHR tyrosines are essential for STAT5 activation through SH2-dependent binding to phosphorylated receptor tyrosines. (sotiropoulos1996differentialactivationof pages 1-2, sotiropoulos1996differentialactivationof pages 2-3)

2.3 Core signaling pathways

The dominant pathway for GH action through GHR is GHR→JAK2→STAT5/STAT5B, regulating hepatic (and extrahepatic) gene programs and systemic growth/metabolism. (corrick2013hepaticgrowthhormone pages 1-2, petrashen2023aclusterof pages 1-2)

Broader pathway usage is supported by authoritative review synthesis: GH–GHR can also activate MAPK, PI3K, and STAT1/3 pathways (with JAK2 described as essential for activation across these branches in rodent/human GHR contexts). (storr2019nonclassicalghinsensitivity pages 3-3)

3) Localization, processing, and trafficking

3.1 Subcellular localization

GHR is a plasma membrane receptor with separable extracellular and cytoplasmic domains detectable by domain-specific antibodies in mouse tissues (e.g., liver), consistent with its role in sensing circulating GH. (corrick2013hepaticgrowthhormone pages 2-3)

3.2 Receptor processing/isoforms and GH-binding protein (GHBP)

A key species distinction relevant to mouse functional annotation is how the circulating growth hormone-binding protein (GHBP) is generated.

In mouse and rat, GHBP is reported to arise from alternative splicing (distinct GHBP mRNA), rather than primarily by proteolytic shedding. (finidori2000regulatorsofgrowth pages 5-8, postelvinay1996growthhormonereceptor pages 1-4)
In non-rodent contexts, GHBP can arise from proteolytic cleavage (shedding) of membrane GHR ectodomain (e.g., ADAM/TACE involvement is discussed in later reviews), providing a circulating GH reservoir/protector. (strous2002theubiquitin–proteasomepathway pages 1-2)

3.3 Endocytosis, ubiquitin/proteasome control, and receptor availability

A foundational review highlights that ubiquitin–proteasome mechanisms regulate GHR availability and that receptor levels can be controlled at multiple cellular locations. In one transfected cell model, receptor availability was attributed approximately 75% to endocytosis, 10% to shedding, and 15% to other mechanisms, providing a quantitative framework for the relative contribution of trafficking routes to surface receptor abundance. (strous2002theubiquitin–proteasomepathway pages 1-2)

3.4 Rapid receptor modification in vivo during stress/injury (mouse liver)

In mouse liver, acute trauma/hemorrhage induces rapid changes in GHR electrophoretic forms (appearance of an ~85 kDa band with reduction of higher-mass forms) without reducing total immunoreactive GHR abundance, consistent with rapid receptor processing/modification. These changes correlate with marked GH resistance, including ~87% reduction of GH-induced STAT5 phosphorylation at 90 minutes after trauma+hemorrhage. (corrick2013hepaticgrowthhormone pages 4-5, corrick2013hepaticgrowthhormone media b16d333b)

4) Negative regulation and expert synthesis

4.1 SOCS2 as a direct negative-feedback regulator of GHR

A 2024 expert review of SOCS-family biology describes SOCS2 as a well-characterized substrate binder of GHR that participates in negative feedback after receptor activation. Mechanistically, SOCS2 suppresses signaling by competing with STATs for binding to phosphorylated receptors via its SH2 domain and is also positioned to regulate signaling through E3 ligase activity. (lynch2024unravellingthedruggability pages 6-7)

The same review reports that SOCS2 knockout mice show gigantism (~30–50% increased size), consistent with loss of negative regulation of GH signaling. (lynch2024unravellingthedruggability pages 6-7)

Structural and biochemical evidence summarized in 2024 further specifies that SOCS2 engages GHR-derived phosphopeptides centered on a GHR phosphotyrosine site (pY595), consistent with a receptor-substrate recognition mechanism that can recruit SOCS2–ElonginB/C–Cullin5 E3 ligase machinery for ubiquitination-linked regulation. (lynch2024unravellingthedruggability pages 7-9)

5) Biological roles and tissue-specific physiology in mouse (selected high-evidence themes)

5.1 Liver: endocrine integration via IGF-1 axis

Mouse liver is a major GH target tissue. GH binding to hepatic GHR activates JAK2 and STAT5b, stimulating IGF-1 expression and broader GH-responsive transcriptional programs. (petrashen2023aclusterof pages 1-2)

Age-associated regulation: a 2023 mouse liver study reports an X-linked miRNA cluster (including mir-465 family) that can attenuate Ghr expression in vitro; in vivo mir-465 upregulation reduces hepatic GHR mRNA and attenuates GH signaling readouts including reduced Igf1/Igfbp3/Als mRNAs and reduced IGF-1 protein in liver and plasma, linking post-transcriptional regulation of Ghr to systemic endocrine outputs in aging contexts. (petrashen2023aclusterof pages 1-2)

5.2 Bone/growth: dependence on intact hepatic GHR–JAK2/STAT5 signaling

A 2024 mouse genetics study reports that deletion of Tmem263 disrupts the GH/IGF-1 axis with reduced hepatic GHR expression and muted GH-induced JAK2/STAT5 signaling, producing low circulating IGF-1, proportional dwarfism, reduced bone mass, and shorter growth plate length; phenotypes emerge strongly by postnatal day 21. (sarver2024tmem263deletiondisrupts pages 1-2)

5.3 Brain/hypothalamus: GHR effects on neuroglia and inflammation markers

A 2023 study using multiple mouse models supports that central GH action is transduced via GHR signaling (with pSTAT5 used to identify GH-responsive cells) and that brain-specific GHR loss reduces hypothalamic expression of several neuroglial markers (e.g., Gfap, Adgre1, Vim), while models with altered systemic GH/IGF-1 signaling show coordinated shifts in neuroglial and proinflammatory marker expression. (wasinski2023centralgrowthhormone pages 1-3)

5.4 Metabolic/aging phenotypes from GHR perturbation (review synthesis)

A 2023 review synthesizing multiple mouse models describes that GHR−/− (Laron) mice show severe postnatal growth retardation, low IGF-1, high GH, and extended lifespan (reported as “almost 5 years” in the review narrative). Adipocyte-specific GHR knockout mice show increased adiposity with improved insulin sensitivity and functional/aging-related benefits. (alsamerria2023exploringthetherapeutic pages 13-15)

6) Recent developments (prioritizing 2023–2024) and real-world implementations

6.1 Cancer applications: GHR antagonism as an adjuvant strategy

A 2024 study reports that GHR is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and that higher GHR expression is a negative prognostic factor; in mouse xenograft models, combining gemcitabine with GHR antagonists (GHRAs) “markedly” improves therapeutic outcomes. Mechanistically, antagonism attenuates multidrug transporter and EMT programs, supporting an emerging translational concept that GH–GHR signaling can promote therapy resistance programs in tumors. The authors note PDAC burden context (>510,000 affected; ~12.5% five-year survival). (basu2024growthhormonereceptor pages 1-2)

6.2 Pharmacologic targeting of GH action in endocrine disease (acromegaly)

A 2024 acromegaly pilot study (n=45) reports that GHR isoforms (full-length vs exon 3-deleted/d3) may stratify incident vertebral fracture (i-VF) risk depending on second-line therapy.

In the fg-SRL + pegvisomant cohort (n=26), i-VFs occurred exclusively in full-length GHR carriers (p=0.039). (chiloiro2024ghreceptorpolymorphisms pages 1-2)
In the pasireotide LAR cohort (n=19), i-VFs occurred exclusively in d3-GHR carriers (p=0.018). (chiloiro2024ghreceptorpolymorphisms pages 1-2)
The study reports OR estimates including increased i-VF risk for full-length GHR patients treated with fg-SRL+pegvisomant (OR 1.6; 95% CI 1.1–2.3). (chiloiro2024ghreceptorpolymorphisms pages 1-2)

6.3 Drug safety/efficacy statistics relevant to GH axis interventions

A 2024 “real-life” safety paper includes quantitative safety/efficacy content extracted from SIGNIFOR LAR (pasireotide) clinical study/label tables: in drug-naïve acromegaly, hyperglycemia occurred in 29% and diabetes mellitus in 26% of pasireotide-treated patients (vs 8% and 4% in active comparator), and the biochemical control endpoint (GH <2.5 mcg/L and normalized IGF-1) was achieved by 31.3% on pasireotide vs 19.2% on active comparator at month 12 (p<0.01 for treatment difference). (ilie2024reallifedataon pages 10-12, ilie2024reallifedataon pages 18-21)

7) Functional annotation summary (for databases/curation)

Gene: Ghr (Mus musculus)

Protein: Growth hormone receptor (GHR); UniProt P16882

Primary molecular function: Cell-surface receptor that binds GH and transduces signals primarily through recruitment/activation of JAK2 and downstream STAT5/STAT5B to regulate gene expression (notably Igf1 axis), with additional pathway branches (MAPK/PI3K/STAT1/3) described in authoritative reviews. (corrick2013hepaticgrowthhormone pages 1-2, storr2019nonclassicalghinsensitivity pages 3-3, petrashen2023aclusterof pages 1-2)

Localization: Plasma membrane; functions at cell surface; undergoes internalization/turnover governed by endocytosis and ubiquitin–proteasome-linked pathways; receptor forms/processing can change rapidly in vivo during stress with signaling consequences. (corrick2013hepaticgrowthhormone pages 2-3, corrick2013hepaticgrowthhormone pages 4-5, strous2002theubiquitin–proteasomepathway pages 1-2)

Negative regulation: SOCS2 binds phosphorylated GHR sites (including pY595) and suppresses signaling (competition with STAT docking; E3 ligase context via Cullin5 complex); SOCS2 loss yields marked overgrowth. (lynch2024unravellingthedruggability pages 7-9, lynch2024unravellingthedruggability pages 6-7)

Rodent-specific note: GH-binding protein (GHBP) is generated via alternative splicing in mouse/rat per foundational reviews, impacting how circulating GH-binding capacity is interpreted in rodent experiments. (finidori2000regulatorsofgrowth pages 5-8, postelvinay1996growthhormonereceptor pages 1-4)

Evidence table

The following table consolidates key functional-annotation facts and supporting sources.

Category	Key points	Key sources
Identity/structure	UniProt P16882 maps to mouse Ghr/GHR, a single-pass class I/type I cytokine receptor with signal peptide, extracellular GH-binding domain containing WSXWS/FN3-like features, one transmembrane helix, and a cytoplasmic Box1/JAK2-binding region required for signaling. (gun2022investigationofmonoclonal pages 49-52, corrick2013hepaticgrowthhormone pages 1-2, gun2022investigationofmonoclonal pages 5-9)	(gun2022investigationofmonoclonal pages 49-52, corrick2013hepaticgrowthhormone pages 1-2, gun2022investigationofmonoclonal pages 5-9)
Ligand & activation	Circulating GH binds the extracellular domain of cell-surface GHR; activation occurs through dimeric receptor rearrangement that repositions receptor-associated JAK2 molecules for trans-phosphorylation rather than simple receptor synthesis at the moment of signaling. (gun2022investigationofmonoclonal pages 13-18, storr2019nonclassicalghinsensitivity pages 3-3, storr2019nonclassicalghinsensitivity pages 2-3)	(gun2022investigationofmonoclonal pages 13-18, storr2019nonclassicalghinsensitivity pages 3-3, storr2019nonclassicalghinsensitivity pages 2-3)
Core signaling	Canonical pathway is GH→GHR→JAK2→STAT5/STAT5B, leading to nuclear transcriptional responses including Igf1, Igfbp3, and Als; additional pathways reported include MAPK, PI3K, and STAT1/3. Mouse liver studies directly show GH-induced JAK2 and STAT5 phosphorylation. (corrick2013hepaticgrowthhormone pages 1-2, corrick2013hepaticgrowthhormone pages 2-3, corrick2013hepaticgrowthhormone pages 3-4, storr2019nonclassicalghinsensitivity pages 3-3, petrashen2023aclusterof pages 1-2)	(corrick2013hepaticgrowthhormone pages 1-2, corrick2013hepaticgrowthhormone pages 2-3, corrick2013hepaticgrowthhormone pages 3-4, storr2019nonclassicalghinsensitivity pages 3-3, petrashen2023aclusterof pages 1-2)
Negative regulation	SOCS2 is a direct negative regulator of GHR signaling: it binds phosphorylated GHR, competes with STAT docking, and can recruit Cullin5 E3 ligase machinery for receptor-associated ubiquitination/degradative control. SOCS2 loss causes GH hypersignaling/gigantism. (lynch2024unravellingthedruggability pages 7-9, lynch2024unravellingthedruggability pages 6-7)	(lynch2024unravellingthedruggability pages 7-9, lynch2024unravellingthedruggability pages 6-7)
Localization/trafficking	GHR functions at the plasma membrane with extracellular and cytoplasmic domains detectable by domain-specific antibodies. Mouse liver studies show multiple receptor species (~95/90 kDa and an injury-associated ~85 kDa band), indicating rapid processing/modification linked to GH resistance; recent work also implicates proper extracellular-domain-dependent trafficking/stability in maintaining hepatic GHR abundance. (corrick2013hepaticgrowthhormone pages 2-3, sarver2024tmem263deletiondisrupts pages 13-15, corrick2013hepaticgrowthhormone pages 4-5, corrick2013hepaticgrowthhormone media b16d333b)	(corrick2013hepaticgrowthhormone pages 2-3, sarver2024tmem263deletiondisrupts pages 13-15, corrick2013hepaticgrowthhormone pages 4-5, corrick2013hepaticgrowthhormone media b16d333b)
Mouse phenotypes	Global or tissue-specific disruption of GH/GHR signaling causes strong postnatal growth and metabolic phenotypes: GHR-deficient mice show severe growth retardation, low IGF-1, high GH, altered adiposity/insulin sensitivity, and extended lifespan; brain GHR affects hypothalamic neuroglial/proinflammatory markers; reduced hepatic GHR signaling lowers IGF-1 and impairs bone growth. (alsamerria2023exploringthetherapeutic pages 13-15, sarver2024tmem263deletiondisrupts pages 1-2, wasinski2023centralgrowthhormone pages 1-3, alsamerria2023exploringthetherapeutic pages 11-13)	(alsamerria2023exploringthetherapeutic pages 13-15, sarver2024tmem263deletiondisrupts pages 1-2, wasinski2023centralgrowthhormone pages 1-3, alsamerria2023exploringthetherapeutic pages 11-13)
2023-2024 developments/applications	Recent studies link GHR to aging-regulated liver miRNAs, hypothalamic inflammation, NAFLD biology, TMEM263-dependent maintenance of hepatic GHR/JAK2-STAT5 signaling, and cancer therapy resistance. GHR antagonism improved gemcitabine response in mouse PDAC xenografts and reduced melanoma chemoresistance signals. (sarver2024tmem263deletiondisrupts pages 1-2, wasinski2023centralgrowthhormone pages 1-3, basu2024growthhormonereceptor pages 1-2, petrashen2023aclusterof pages 1-2)	(sarver2024tmem263deletiondisrupts pages 1-2, wasinski2023centralgrowthhormone pages 1-3, basu2024growthhormonereceptor pages 1-2, petrashen2023aclusterof pages 1-2)
Key quantitative/statistical notes	SOCS2 knockout mice are ~30–50% larger than controls. In trauma/hemorrhage mouse liver, GH-induced STAT5 phosphorylation fell by ~87% at TH90, alongside emergence of an ~85 kDa GHR band. In acromegaly real-world/clinical studies relevant to GHR-targeting therapy: Pegvisomant-associated reports were 1,765 ICSRs and 4,842 ADRs in EudraVigilance; in a 45-patient pilot, incident vertebral fractures under fg-SRL+pegvisomant occurred only in fl-GHR carriers (p=0.039), whereas under pasireotide they occurred only in d3-GHR carriers (p=0.018); reported OR for i-VFs with fl-GHR on fg-SRL+pegvisomant was 1.6 (95% CI 1.1–2.3). (lynch2024unravellingthedruggability pages 6-7, corrick2013hepaticgrowthhormone pages 4-5, chiloiro2024ghreceptorpolymorphisms pages 3-4, chiloiro2024ghreceptorpolymorphisms pages 1-2)	(lynch2024unravellingthedruggability pages 6-7, corrick2013hepaticgrowthhormone pages 4-5, chiloiro2024ghreceptorpolymorphisms pages 3-4, chiloiro2024ghreceptorpolymorphisms pages 1-2)

Table: This table summarizes the functional annotation of mouse Ghr/GHR (UniProt P16882), including receptor identity, activation mechanism, signaling, regulation, localization, phenotypes, and recent applications. It is useful as a compact evidence map for the final research report.

Key visual evidence (mouse liver signaling and receptor processing)

Corrick et al. provide Western blot evidence for the appearance of a hemorrhage-associated ~85 kDa GHR band together with reduced GH-induced STAT5 phosphorylation, supporting rapid receptor modification/processing coupled to functional GH resistance in mouse liver. (corrick2013hepaticgrowthhormone media b16d333b, corrick2013hepaticgrowthhormone media c65a70b8)

References (URLs and publication dates)

(Provided as URLs captured in the evidence context; publication month/year from metadata.)

Postel-Vinay MC, Kelly PA. Growth hormone receptor signalling. Jul 1996. https://doi.org/10.1016/s0950-351x(96)80455-1 (postelvinay1996growthhormonereceptor pages 1-4)
Sotiropoulos A et al. Differential activation of Stat3 and Stat5 by distinct regions of the growth hormone receptor. Aug 1996. https://doi.org/10.1210/mend.10.8.8843416 (sotiropoulos1996differentialactivationof pages 1-2)
Finidori J. Regulators of growth hormone signaling. 2000. https://doi.org/10.1016/s0083-6729(00)59004-9 (finidori2000regulatorsofgrowth pages 5-8)
Strous GJ, van Kerkhof P. The ubiquitin–proteasome pathway and the regulation of growth hormone receptor availability. Nov 2002. https://doi.org/10.1016/s0303-7207(02)00258-7 (strous2002theubiquitin–proteasomepathway pages 1-2)
Corrick RM et al. Hepatic growth hormone resistance after acute injury. Apr 2013. https://doi.org/10.1210/en.2012-2134 (corrick2013hepaticgrowthhormone pages 1-2)
Storr HL et al. Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action. Sep 2019. https://doi.org/10.1210/er.2018-00146 (storr2019nonclassicalghinsensitivity pages 3-3)
Al-Samerria S, Radovick S. Therapeutic potential of targeting GH and IGF-1 in obesity (review). May 2023. https://doi.org/10.3390/ijms24119556 (alsamerria2023exploringthetherapeutic pages 13-15)
Wasinski F et al. Central growth hormone action regulates hypothalamic markers in male mice. May 2023. https://doi.org/10.1016/j.neulet.2023.137236 (wasinski2023centralgrowthhormone pages 1-3)
Petrashen AP et al. X-linked miRNAs de-repressed with age in mouse liver target GH signaling. Oct 2023. https://doi.org/10.3389/fragi.2023.1261121 (petrashen2023aclusterof pages 1-2)
Sarver DC et al. Tmem263 deletion disrupts GH/IGF-1 axis… Jan 2024. https://doi.org/10.7554/elife.90949.2 (sarver2024tmem263deletiondisrupts pages 1-2)
Lynch DM et al. SOCS-family druggability and roles (review). Nov 2024. https://doi.org/10.3389/fimmu.2024.1449397 (lynch2024unravellingthedruggability pages 7-9)
Basu R et al. GHR antagonist improves gemcitabine response in mouse PDAC xenograft. Jul 2024. https://doi.org/10.3390/ijms25137438 (basu2024growthhormonereceptor pages 1-2)
Chiloiro S et al. GHR polymorphisms guide second-line therapies to prevent acromegaly skeletal fragility (pilot). Aug 2024. https://doi.org/10.3389/fendo.2024.1414101 (chiloiro2024ghreceptorpolymorphisms pages 1-2)
Ilie IRP et al. Real-life data on safety of pasireotide… (includes SIGNIFOR LAR trial/label statistics). Dec 2024. https://doi.org/10.3390/ph17121631 (ilie2024reallifedataon pages 10-12)

References

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(ilie2024reallifedataon pages 10-12): Ioana Rada Popa Ilie, Carmen Maximiliana Dobrea, Anca Butuca, Calin Homorodean, Claudiu Morgovan, Andreea Loredana Vonica-Tincu, Felicia Gabriela Gligor, Steliana Ghibu, and Adina Frum. Real-life data on the safety of pasireotide in acromegaly: insights from eudravigilance. Pharmaceuticals, 17:1631, Dec 2024. URL: https://doi.org/10.3390/ph17121631, doi:10.3390/ph17121631. This article has 5 citations.
(ilie2024reallifedataon pages 18-21): Ioana Rada Popa Ilie, Carmen Maximiliana Dobrea, Anca Butuca, Calin Homorodean, Claudiu Morgovan, Andreea Loredana Vonica-Tincu, Felicia Gabriela Gligor, Steliana Ghibu, and Adina Frum. Real-life data on the safety of pasireotide in acromegaly: insights from eudravigilance. Pharmaceuticals, 17:1631, Dec 2024. URL: https://doi.org/10.3390/ph17121631, doi:10.3390/ph17121631. This article has 5 citations.
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(gun2022investigationofmonoclonal pages 13-18): Investigation of monoclonal antibodies generated against the growth hormone receptor on growth hormone signaling This article has 0 citations and is from a peer-reviewed journal.
(corrick2013hepaticgrowthhormone pages 3-4): Ryan M. Corrick, Li Li, Stuart J. Frank, and Joseph L. Messina. Hepatic growth hormone resistance after acute injury. Endocrinology, 154:1577-1588, Apr 2013. URL: https://doi.org/10.1210/en.2012-2134, doi:10.1210/en.2012-2134. This article has 8 citations and is from a domain leading peer-reviewed journal.
(sarver2024tmem263deletiondisrupts pages 13-15): Dylan C. Sarver, Jean Garcia-Diaz, Muzna Saqib, Ryan C. Riddle, and G. William Wong. Tmem263 deletion disrupts the gh/igf-1 axis and causes dwarfism and impairs skeletal acquisition. ArXiv, Jan 2024. URL: https://doi.org/10.7554/elife.90949.2, doi:10.7554/elife.90949.2. This article has 8 citations.
(alsamerria2023exploringthetherapeutic pages 11-13): Sarmed Al-Samerria and Sally Radovick. Exploring the therapeutic potential of targeting gh and igf-1 in the management of obesity: insights from the interplay between these hormones and metabolism. International Journal of Molecular Sciences, 24:9556, May 2023. URL: https://doi.org/10.3390/ijms24119556, doi:10.3390/ijms24119556. This article has 33 citations.
(chiloiro2024ghreceptorpolymorphisms pages 3-4): Sabrina Chiloiro, Flavia Costanza, Antonella Giampietro, Amato Infante, Pier Paolo Mattogno, Flavia Angelini, Consolato Gullì, Liverana Lauretti, Mario Rigante, Alessandro Olivi, Laura De Marinis, Francesco Doglietto, Antonio Bianchi, and Alfredo Pontecorvi. Gh receptor polymorphisms guide second-line therapies to prevent acromegaly skeletal fragility: preliminary results of a pilot study. Frontiers in Endocrinology, Aug 2024. URL: https://doi.org/10.3389/fendo.2024.1414101, doi:10.3389/fendo.2024.1414101. This article has 5 citations.
(corrick2013hepaticgrowthhormone media c65a70b8): Ryan M. Corrick, Li Li, Stuart J. Frank, and Joseph L. Messina. Hepatic growth hormone resistance after acute injury. Endocrinology, 154:1577-1588, Apr 2013. URL: https://doi.org/10.1210/en.2012-2134, doi:10.1210/en.2012-2134. This article has 8 citations and is from a domain leading peer-reviewed journal.

Citations

gun2022investigationofmonoclonal pages 49-52
corrick2013hepaticgrowthhormone pages 1-2
storr2019nonclassicalghinsensitivity pages 3-3
corrick2013hepaticgrowthhormone pages 2-3
lynch2024unravellingthedruggability pages 6-7
lynch2024unravellingthedruggability pages 7-9
petrashen2023aclusterof pages 1-2
wasinski2023centralgrowthhormone pages 1-3
alsamerria2023exploringthetherapeutic pages 13-15
basu2024growthhormonereceptor pages 1-2
chiloiro2024ghreceptorpolymorphisms pages 1-2
postelvinay1996growthhormonereceptor pages 1-4
sotiropoulos1996differentialactivationof pages 1-2
finidori2000regulatorsofgrowth pages 5-8
ilie2024reallifedataon pages 10-12
storr2019nonclassicalghinsensitivity pages 2-3
sotiropoulos1996differentialactivationof pages 2-3
corrick2013hepaticgrowthhormone pages 4-5
ilie2024reallifedataon pages 18-21
gun2022investigationofmonoclonal pages 5-9
gun2022investigationofmonoclonal pages 13-18
corrick2013hepaticgrowthhormone pages 3-4
alsamerria2023exploringthetherapeutic pages 11-13
chiloiro2024ghreceptorpolymorphisms pages 3-4
https://doi.org/10.1016/s0950-351x(96
https://doi.org/10.1210/mend.10.8.8843416
https://doi.org/10.1016/s0083-6729(00
https://doi.org/10.1016/s0303-7207(02
https://doi.org/10.1210/en.2012-2134
https://doi.org/10.1210/er.2018-00146
https://doi.org/10.3390/ijms24119556
https://doi.org/10.1016/j.neulet.2023.137236
https://doi.org/10.3389/fragi.2023.1261121
https://doi.org/10.7554/elife.90949.2
https://doi.org/10.3389/fimmu.2024.1449397
https://doi.org/10.3390/ijms25137438
https://doi.org/10.3389/fendo.2024.1414101
https://doi.org/10.3390/ph17121631
https://doi.org/10.1210/en.2012-2134,
https://doi.org/10.3389/fragi.2023.1261121,
https://doi.org/10.1210/er.2018-00146,
https://doi.org/10.1210/mend.10.8.8843416,
https://doi.org/10.3389/fimmu.2024.1449397,
https://doi.org/10.7554/elife.90949.2,
https://doi.org/10.1016/j.neulet.2023.137236,
https://doi.org/10.3390/ijms24119556,
https://doi.org/10.3390/ijms25137438,
https://doi.org/10.3389/fendo.2024.1414101,
https://doi.org/10.3390/ph17121631,

📚 Additional Documentation

Notes

(Ghr-notes.md)

Ghr notes

Core mouse biology

Mouse Ghr encodes a bona fide growth hormone receptor with direct receptor/binding evidence in mouse liver membranes [PMID:6303755 Hepatic binding of human and bovine growth hormones and ovine prolactin in the dwarf "little" mouse., "GH receptors were at normal levels in lit/lit mice despite their deficiency of pituitary and serum GH."].
GH induces STAT5 association with GHR in mouse cells, making the JAK-STAT branch the strongest directly supported signaling output in mouse [PMID:8702683 Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor., "GH-induced tyrosine phosphorylation of STAT5 and the interaction of STAT5 with GHR can be observed in mouse 3T3-F442A cells which express endogenous mouse GHR."].
The embryo staining paper reports mainly nuclear signal in cleavage-stage embryos but membrane signal in blastocysts, so nuclear localization should be treated as developmental/context-specific rather than the default location [PMID:9144201 Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: a role for GH in early embryogenesis?, "In cleavage-stage embryos this immunoreactivity was localized mainly to the nucleus, but clear evidence of membrane labeling was apparent in blastocysts."].

Isoform biology relevant to annotation review

UniProt records two alternative products: full-length isoform P16882-1 and the shorter P16882-2 GH-binding protein isoform [file:mouse/Ghr/Ghr-uniprot.txt, "Event=Alternative splicing; Named isoforms=2;"].
Mouse GH-binding protein biology matters for localization curation. Mouse liver GHBP is structurally distinct from serum GHBP and is found on intracellular membranes and plasma membrane [PMID:11834450 Structurally distinct membrane-associated and soluble forms of GH-binding protein in the mouse., "mouse liver GHBP is predominantly present as a membrane-associated protein structurally distinct from the soluble form of GHBP present in serum. Liver GHBP is associated with both intracellular membranes and the plasma membrane."].
This isoform split argues against blindly attaching every signaling term to the gene product without asking whether the evidence concerns the signaling-competent membrane receptor or the shorter GHBP product [file:mouse/Ghr/Ghr-uniprot.txt, "The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling."].

ISO donor-trace conclusions

Every mouse ISO annotation in Ghr-goa.tsv traces to either human UniProtKB:P10912 or rat RGD:2687/UniProtKB:P16310 [file:mouse/Ghr/Ghr-goa.tsv, "ISO rows use WITH/FROM values pointing to human P10912 or rat RGD:2687."].
The detailed donor trace is in [file:mouse/Ghr/Ghr-iso-donor-trace.md, "Current donor tracing distinguishes direct donor experiments from circular or stale ISO chains."].
Rat donor P16310 is the main circularity problem: it has genuine direct experimental support for JAK2/STAT5-oriented terms, but several rat donor annotations are themselves ISO from human GHR, and rat also carries NOT annotations for receptor internalization and cycloheximide response [file:mouse/Ghr/Ghr-iso-donor-trace.md, "Rat donor P16310 carries direct JAK2/STAT5 experiments but also multiple ISO-from-human terms and NOT annotations for GO:0031623 and GO:0046898."].
Broad cytokine-family IBA terms need extra skepticism. The mouse UniProt record places GHR in PANTHER subfamily PTHR23037:SF46 INTERLEUKIN 5 RECEPTOR SUBUNIT ALPHA, which is a clear warning sign for paralog-driven over-transfer of generic cytokine receptor terms [file:mouse/Ghr/Ghr-uniprot.txt, "PANTHER; PTHR23037:SF46; INTERLEUKIN 5 RECEPTOR SUBUNIT ALPHA; 1."].

Downstream phenotype caution

The metabolomics paper is useful for consequences of altered signaling, not direct receptor function. It studies mice with altered intracellular GHR signaling and reports altered taurine/choline/creatinine metabolism plus obesity and insulin resistance as downstream outcomes [PMID:18648510 Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study., "These mutations result in altered liver metabolism, obesity and insulin resistance."].
That same paper explicitly frames the altered metabolites as consequences of impaired STAT5 signaling, so terms such as taurine metabolic process or broad organismal growth regulation should be treated as downstream/non-core rather than direct receptor activity [PMID:18648510 Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study., "provides a coherent picture of metabolic changes resulting from impaired STAT5 signalling by the growth hormone receptor"].
The HDA extracellular-space annotation comes from a cardiac fibroblast secretome paper that is not centered on GHR biology and should not outweigh the receptor/GHBP literature [PMID:24006456 Extracellular matrix secretion by cardiac fibroblasts: role of microRNA-29b and microRNA-30c., "Mouse cardiac fibroblasts were transfected with pre-/anti-miR of miR-29b and miR-30c, and their conditioned medium was analyzed by mass spectrometry."].

Iso Donor Trace

(Ghr-iso-donor-trace.md)

Ghr ISO donor trace

Trace performed on 2026-03-21 by matching each mouse ISO row in genes/mouse/Ghr/Ghr-goa.tsv to the current donor-side annotations on human GHR (UniProtKB:P10912) or rat Ghr (UniProtKB:P16310, mapped from RGD:2687).

Human donor `UniProtKB:P10912`

GO:0004903 growth hormone receptor activity: donor retains direct human experimental support. Keep. Mouse also has direct mouse IDA, so the ISO edge is redundant and partly circular rather than wrong.
GO:0005615 extracellular space: donor retains direct support, but this mainly fits the soluble GHBP product rather than the signaling receptor. Keep as non-core.
GO:0005886 plasma membrane with mouse qualifier is_active_in: donor retains direct support. Keep.
GO:0005886 plasma membrane with mouse qualifier located_in: donor retains direct support. Keep.
GO:0008289 lipid binding: donor trace recovers only a non-core human assertion, with no mouse support and no role in established mouse Ghr biology. Remove as over-transfer.
GO:0009986 cell surface: donor retains direct support. Keep.
GO:0016020 membrane: donor support exists, but the term is too broad given the stronger plasma-membrane annotations and GHBP membrane-association context. Keep as non-core.
GO:0017046 peptide hormone binding: donor retains direct support. Keep.
GO:0019838 growth factor binding: no current donor-side support recovered; the specific accepted term is peptide hormone binding. Remove.
GO:0031623 receptor internalization: no current human donor support recovered. Remove.
GO:0032355 response to estradiol: no current human donor support recovered. Remove.
GO:0032870 cellular response to hormone stimulus: donor support is broad endocrine physiology, not a Ghr-specific core function. Mark as over-annotated.
GO:0040018 positive regulation of multicellular organism growth: biologically plausible but phenotype-level and non-core. Keep as non-core.
GO:0042445 hormone metabolic process: broad downstream/endocrine-context term, not direct receptor function. Mark as over-annotated.
GO:0042802 identical protein binding: donor retains direct support for receptor self-association. Keep.
GO:0042803 protein homodimerization activity: donor retains direct support. Keep.
GO:0043235 receptor complex: donor retains direct support. Keep.
GO:0046898 response to cycloheximide: no current human donor support recovered. Remove.
GO:0048009 insulin-like growth factor receptor signaling pathway: this is pathway cross-talk/physiology, not Ghr core function. Remove.
GO:0060396 growth hormone receptor signaling pathway: donor retains direct support. Keep.
GO:0070195 growth hormone receptor complex: donor retains direct support. Keep.
GO:0005829 cytosol: donor trace only recovers non-experimental family-level support. Remove.
GO:0036464 cytoplasmic ribonucleoprotein granule: no current donor-side support recovered. Remove.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process: no current donor-side support recovered, and the receptor is more plausibly the substrate than the agent of this process. Remove.
GO:0060397 growth hormone receptor signaling pathway via JAK-STAT: no current donor-side support recovered, but mouse has direct IDA support for the same term. Keep the term, but do not rely on the ISO edge.
GO:0060400 negative regulation of growth hormone receptor signaling pathway: no current donor-side support recovered and the term reads as a downstream regulatory consequence rather than core receptor function. Remove.

Rat donor `UniProtKB:P16310` mapped from `RGD:2687`

GO:0042976 activation of Janus kinase activity: donor retains direct rat experimental support. Keep.
GO:0004903 growth hormone receptor activity: donor has direct rat experiments, but also donor-side ISO copies from mouse and human. Keep the term but flag the ISO chain as circular/redundant.
GO:0005615 extracellular space: donor includes direct rat support plus donor-side ISO-from-human copies. Keep as non-core and note circularity.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT: donor retains direct rat support, but the mouse-specific term GO:0060397 is better. Modify.
GO:0009755 hormone-mediated signaling pathway: donor support is too broad compared with specific growth-hormone signaling terms. Mark as over-annotated.
GO:0019901 protein kinase binding: donor retains rat interaction evidence, but the more precise term on this receptor is protein tyrosine kinase binding. Modify.
GO:0019903 protein phosphatase binding: donor retains rat support for phosphatase interactions. Keep as non-core.
GO:0030296 protein tyrosine kinase activator activity: donor retains direct rat experimental support. Keep.
GO:0032107 regulation of response to nutrient levels: donor support is contextual physiology rather than core receptor function. Remove.
GO:0042169 SH2 domain binding: donor retains direct rat support for phosphotyrosine docking interactions. Keep.
GO:0043025 neuronal cell body: donor support is tissue/context-specific rat neuroanatomy and should not be transferred as a generic mouse Ghr location. Remove.
GO:0043410 positive regulation of MAPK cascade: donor retains direct rat support. Keep.
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT: donor retains direct rat support. Keep.
GO:0060396 growth hormone receptor signaling pathway: donor includes a direct rat pathway assertion, but also donor-side ISO-from-human copies. Keep the term while flagging the rat ISO chain as circular.
GO:1990782 protein tyrosine kinase binding: donor retains direct rat support. Keep.

Important circularity and stale-transfer findings

Rat donor P16310 carries donor-side NOT|involved_in annotations for GO:0031623 receptor internalization and GO:0046898 response to cycloheximide. Those negatives make the corresponding mouse ISO transfers especially weak.
Several mouse ISO rows are best interpreted as transfer-of-transfer artifacts: mouse ISO <- rat ISO <- human, rather than mouse ISO <- direct donor experiment.
No evidence of classic paralog mix-up with prolactin receptor was needed to explain the worst rows; the bigger problem is cytokine-receptor family over-generalization plus circular donor propagation.

📄 View Raw YAML

id: P16882
gene_symbol: Ghr
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: >-
  Ghr encodes the mouse growth hormone receptor, a single-pass type I cytokine
  receptor whose full-length membrane isoform binds growth hormone at the plasma
  membrane and activates JAK2/STAT5-centered signaling. The locus also produces
  a shorter GH-binding protein isoform (GHBP), so extracellular-space and
  hormone-buffering annotations need to be interpreted in the context of
  alternative splicing rather than assumed to describe the signaling receptor.
  Direct mouse evidence strongly supports receptor activity, plasma-membrane
  localization, and growth-hormone-triggered JAK-STAT signaling, whereas many
  transferred ISO and IBA terms are broad cytokine-family, downstream
  physiology, or circular donor-propagation artifacts.
functional_isoforms:
  - id: GHR_MEMBRANE_RECEPTOR
    name: Full-length signaling receptor isoform
    type: SPLICE_VARIANT
    maps_to:
      - type: UNIPROT_ISOFORM
        ids:
          - P16882-1
    description: >-
      Full-length membrane GHR. This is the signaling-competent form that binds
      growth hormone at the plasma membrane and activates JAK2/STAT signaling.
      Core receptor activity and pathway annotations should be interpreted
      primarily through this isoform.
    isoform_specific_terms:
      - id: GO:0004903
        label: growth hormone receptor activity
      - id: GO:0017046
        label: peptide hormone binding
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0060396
        label: growth hormone receptor signaling pathway
      - id: GO:0060397
        label: growth hormone receptor signaling pathway via JAK-STAT
  - id: GHR_GHBP
    name: GH-binding protein isoform
    type: SPLICE_VARIANT
    maps_to:
      - type: UNIPROT_ISOFORM
        ids:
          - P16882-2
    description: >-
      Shorter alternative product corresponding to the GH-binding protein (GHBP).
      This form contributes extracellular hormone-binding/reservoir biology and
      should not be conflated with the signaling-competent membrane receptor when
      reviewing transferred signaling annotations.
    isoform_specific_terms:
      - id: GO:0005576
        label: extracellular region
      - id: GO:0005615
        label: extracellular space
existing_annotations:
  - term:
      id: GO:0009897
      label: external side of plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Conserved receptor topology places the ligand-binding ectodomain on the
        external side of the plasma membrane.
      action: ACCEPT
      reason: >-
        This is consistent with the biology of the full-length membrane receptor
        and with accepted plasma-membrane localization.
  - term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Broad family-level IBA term transferred from cytokine-receptor ancestry.
        Ghr has a specific growth-hormone pathway term available.
      action: MODIFY
      reason: >-
        This is overly broad and likely reflects cytokine-receptor family
        transfer rather than a precise statement about Ghr.
      proposed_replacement_terms:
        - id: GO:0060396
          label: growth hormone receptor signaling pathway
  - term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Conserved statement that activated GHR promotes receptor-proximal
        JAK-STAT signaling.
      action: ACCEPT
      reason: >-
        This is consistent with the direct mouse JAK-STAT literature and donor
        traces with real receptor-signaling evidence.
  - term:
      id: GO:0004903
      label: growth hormone receptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Core receptor molecular function.
      action: ACCEPT
      reason: >-
        Growth hormone receptor activity is directly established in mouse and is
        the central molecular function of Ghr.
  - term:
      id: GO:0060396
      label: growth hormone receptor signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Specific pathway term for the receptor's core biological role.
      action: ACCEPT
      reason: >-
        This specific pathway is strongly supported by direct mouse signaling
        evidence and is preferable to broader endocrine/cytokine terms.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Downstream proliferative outcome seen in some contexts, not the core
        evolved function of Ghr.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        This term captures context-dependent downstream physiology rather than
        receptor-specific molecular function or pathway identity.
  - term:
      id: GO:0019955
      label: cytokine binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Broad family-level binding term. For Ghr the specific accepted binding
        activity is peptide hormone binding.
      action: MODIFY
      reason: >-
        The generic cytokine-binding label is less informative and likely driven
        by paralog/family transfer.
      proposed_replacement_terms:
        - id: GO:0017046
          label: peptide hormone binding
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Family-level non-experimental transfer with no convincing mouse support
        for Ghr as a cytosolic protein.
      action: REMOVE
      reason: >-
        Ghr is a membrane receptor/GHBP locus, not a cytosolic protein; this
        appears to be a low-specificity transfer.
  - term:
      id: GO:0017046
      label: peptide hormone binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Specific binding activity for growth hormone.
      action: ACCEPT
      reason: >-
        This is the appropriate specific binding term for Ghr and is supported by
        direct receptor/hormone interaction evidence.
  - term:
      id: GO:0070195
      label: growth hormone receptor complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Conserved receptor-complex term aligned with receptor dimer/complex
        biology.
      action: ACCEPT
      reason: >-
        The receptor forms signaling-competent complexes and donor traces retain
        direct experimental support for this term.
  - term:
      id: GO:0004896
      label: cytokine receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Generic receptor-family term derived from InterPro domain mapping.
      action: MODIFY
      reason: >-
        Ghr has a specific receptor-activity term that is preferable to the broad
        cytokine-receptor label.
      proposed_replacement_terms:
        - id: GO:0004903
          label: growth hormone receptor activity
  - term:
      id: GO:0004903
      label: growth hormone receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        ARBA prediction agrees with the known core receptor activity.
      action: ACCEPT
      reason: >-
        The term is correct and already supported by stronger mouse experimental
        evidence.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Compatible with the GHBP product and extracellular receptor ectodomain,
        but not the most informative core location.
      action: KEEP_AS_NON_CORE
      reason: >-
        The gene produces an extracellular GH-binding product, so the term is not
        false, but plasma membrane is the clearer core location for the signaling
        receptor.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Expected localization for the full-length signaling receptor.
      action: ACCEPT
      reason: >-
        Plasma-membrane localization is directly supported in mouse and is the
        core cellular location of the signaling receptor isoform.
  - term:
      id: GO:0006897
      label: endocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        Keyword-derived process assignment that treats the receptor as though it
        were an agent of endocytosis.
      action: REMOVE
      reason: >-
        Internalization of GHR as cargo does not justify a broad gene-level
        endocytosis annotation.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        True but much less informative than plasma membrane.
      action: KEEP_AS_NON_CORE
      reason: >-
        The term is correct but too broad to capture the biology better than the
        accepted plasma-membrane annotation.
  - term:
      id: GO:0060396
      label: growth hormone receptor signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        ARBA prediction matches the direct experimental literature.
      action: ACCEPT
      reason: >-
        This term is correct and is already supported by stronger mouse and donor
        experimental evidence.
  - term:
      id: GO:0004903
      label: growth hormone receptor activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from GHR/P10912. Current donor tracing shows
        real human experimental support, but the donor also carries circular
        inferred copies of the same term.
      action: ACCEPT
      reason: >-
        The term itself is correct and directly supported in mouse; the ISO edge
        is redundant rather than wrong and should not be treated as the primary
        justification.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912. Donor support exists, but this
        fits GHBP/extracellular product biology better than the membrane receptor.
      action: KEEP_AS_NON_CORE
      reason: >-
        The term is plausible because the locus produces GHBP, but it should not
        be mistaken for the core location of signaling-competent GHR.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912 with retained donor-side direct
        support.
      action: ACCEPT
      reason: >-
        Plasma-membrane localization is correct for the full-length receptor and
        is independently supported in mouse.
  - term:
      id: GO:0008289
      label: lipid binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912, but the donor-side support is a
        non-core assertion that is not corroborated in mouse Ghr biology.
      action: REMOVE
      reason: >-
        Lipid binding is not part of the established mouse Ghr functional profile
        and looks like an over-transfer.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912 with retained donor-side
        experimental support.
      action: ACCEPT
      reason: >-
        Cell-surface localization is appropriate for the membrane receptor.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912; correct but less informative than
        plasma membrane.
      action: KEEP_AS_NON_CORE
      reason: >-
        This broad location term adds little beyond the accepted plasma-membrane
        annotation.
  - term:
      id: GO:0017046
      label: peptide hormone binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912 with retained donor-side direct
        receptor/hormone interaction support.
      action: ACCEPT
      reason: >-
        This is the correct specific binding term for Ghr and is consistent with
        direct mouse evidence.
  - term:
      id: GO:0019838
      label: growth factor binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912, but current donor tracing no
        longer recovers this term on the donor record.
      action: REMOVE
      reason: >-
        This looks like a stale or overly broad transfer. Peptide hormone binding
        is the precise accepted term.
  - term:
      id: GO:0031623
      label: receptor internalization
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912, but current donor tracing does
        not recover the term and the rat donor carries a NOT annotation for it.
      action: REMOVE
      reason: >-
        This is a weak circular/stale transfer and should not be preserved
        without direct mouse evidence.
  - term:
      id: GO:0032355
      label: response to estradiol
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with no current donor-side support recovered.
      action: REMOVE
      reason: >-
        This appears to be context-heavy endocrine over-transfer rather than core
        Ghr biology.
  - term:
      id: GO:0032870
      label: cellular response to hormone stimulus
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer reflecting broad endocrine physiology rather
        than a Ghr-specific pathway statement.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        The specific accepted pathway terms already capture the relevant biology
        more cleanly.
  - term:
      id: GO:0040018
      label: positive regulation of multicellular organism growth
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer for an organism-level phenotype outcome.
      action: KEEP_AS_NON_CORE
      reason: >-
        Ghr clearly influences body growth, but this is a downstream whole-animal
        phenotype rather than the receptor's core molecular role.
  - term:
      id: GO:0042445
      label: hormone metabolic process
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer for a broad endocrine-process term.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        This is too indirect and process-broad for core Ghr annotation.
      additional_reference_ids:
        - file:mouse/Ghr/Ghr-iso-donor-trace.md
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer supported by donor-side receptor self-
        association evidence.
      action: ACCEPT
      reason: >-
        Receptor self-association is consistent with GHR complex/dimer biology.
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with retained donor-side direct support for
        receptor homodimerization.
      action: ACCEPT
      reason: >-
        Dimerization is a central part of GHR signaling biology.
  - term:
      id: GO:0043235
      label: receptor complex
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with retained donor-side experimental support.
      action: ACCEPT
      reason: >-
        GHR functions in a receptor complex/dimer context.
  - term:
      id: GO:0046898
      label: response to cycloheximide
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with no current human donor support recovered,
        and rat donor tracing shows a NOT annotation for the term.
      action: REMOVE
      reason: >-
        This is a stale and contradicted transfer.
  - term:
      id: GO:0048009
      label: insulin-like growth factor receptor signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer capturing endocrine cross-talk rather than a
        Ghr-specific pathway.
      action: REMOVE
      reason: >-
        Ghr is not an IGF receptor; this is an over-transfer of downstream
        physiology/cross-talk.
  - term:
      id: GO:0060396
      label: growth hormone receptor signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer from P10912 with retained donor-side direct
        pathway support.
      action: ACCEPT
      reason: >-
        The term is correct for mouse Ghr. The donor also carries inferred copies,
        so the ISO edge is redundant but still directionally right.
  - term:
      id: GO:0070195
      label: growth hormone receptor complex
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with donor-side direct support for receptor
        complex biology.
      action: ACCEPT
      reason: >-
        This is consistent with accepted receptor-complex/dimer annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with no convincing donor-side experimental
        support for GHR as a cytosolic protein.
      action: REMOVE
      reason: >-
        This appears to be a non-specific transfer inconsistent with receptor
        topology.
  - term:
      id: GO:0036464
      label: cytoplasmic ribonucleoprotein granule
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with no current donor-side support recovered.
      action: REMOVE
      reason: >-
        There is no coherent Ghr-specific rationale for retaining this term.
  - term:
      id: GO:0042976
      label: activation of Janus kinase activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer from Ghr/P16310. Current donor tracing retains
        direct rat experimental support.
      action: ACCEPT
      reason: >-
        Activation of JAK kinase activity is part of core GHR signaling biology
        and the rat donor support is direct rather than purely circular.
  - term:
      id: GO:0004903
      label: growth hormone receptor activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer from P16310. Rat donor retains real experiments
        but also donor-side ISO copies from mouse/human.
      action: ACCEPT
      reason: >-
        The term itself is correct and directly supported in mouse. The donor
        chain is partially circular but not enough to overturn the term.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer from P16310. Rat donor has direct support plus
        donor-side ISO-from-human copies.
      action: KEEP_AS_NON_CORE
      reason: >-
        Plausible for GHBP/extracellular product biology, but not the core
        location of the signaling receptor.
  - term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer from P16310 with direct donor support, but the
        mouse-specific pathway term is more precise.
      action: MODIFY
      reason: >-
        The biology is right, but `growth hormone receptor signaling pathway via
        JAK-STAT` is the more specific term for Ghr.
      proposed_replacement_terms:
        - id: GO:0060397
          label: growth hormone receptor signaling pathway via JAK-STAT
  - term:
      id: GO:0009755
      label: hormone-mediated signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer for a broad endocrine-process label.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Specific Ghr pathway terms already capture the biology more cleanly than
        this generic hormone-signaling term.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer from P16310 with interaction evidence, but the
        more precise retained term is protein tyrosine kinase binding.
      action: MODIFY
      reason: >-
        GHR engages JAK-family tyrosine kinases; the specific tyrosine-kinase
        binding term is preferable.
      proposed_replacement_terms:
        - id: GO:1990782
          label: protein tyrosine kinase binding
  - term:
      id: GO:0019903
      label: protein phosphatase binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer with donor-side support for phosphatase
        interactions.
      action: KEEP_AS_NON_CORE
      reason: >-
        Plausible interaction term, but it is secondary to the receptor's core
        hormone-binding and signaling roles.
  - term:
      id: GO:0030296
      label: protein tyrosine kinase activator activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer with direct donor support for JAK activation by
        the receptor.
      action: ACCEPT
      reason: >-
        This is a mechanistically informative term for a kinase-less receptor that
        activates JAK2.
  - term:
      id: GO:0032107
      label: regulation of response to nutrient levels
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer for contextual physiology rather than core
        receptor function.
      action: REMOVE
      reason: >-
        This is too far downstream and context-dependent for a core Ghr annotation.
  - term:
      id: GO:0042169
      label: SH2 domain binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer with donor-side docking evidence for SH2-
        containing signaling proteins.
      action: ACCEPT
      reason: >-
        This is a mechanistically meaningful interaction term for phosphotyrosine-
        dependent GHR signaling complexes.
  - term:
      id: GO:0043025
      label: neuronal cell body
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer from a tissue/context-specific neuronal study.
      action: REMOVE
      reason: >-
        This is too specific to the donor experimental context to keep as a
        generic mouse Ghr location.
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with no current donor support recovered and a
        likely substrate-versus-agent confusion.
      action: REMOVE
      reason: >-
        GHR is subject to regulated degradation, but that does not make the gene
        product an agent of the catabolic process.
  - term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer with direct donor support for MAPK-branch
        signaling.
      action: ACCEPT
      reason: >-
        MAPK activation is part of well-established GHR signaling output.
  - term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer with direct donor support.
      action: ACCEPT
      reason: >-
        This aligns with accepted JAK-STAT signaling biology for Ghr.
  - term:
      id: GO:0060396
      label: growth hormone receptor signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer from P16310. The rat donor has a direct pathway
        assertion but also donor-side ISO-from-human copies.
      action: ACCEPT
      reason: >-
        The term is correct for mouse Ghr. The ISO edge is partly circular but the
        donor set is not purely inferred.
  - term:
      id: GO:0060397
      label: growth hormone receptor signaling pathway via JAK-STAT
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer no longer recovered as a current human donor
        annotation, but mouse has direct experimental support for the same term.
      action: ACCEPT
      reason: >-
        Retain the term because it is correct in mouse, while noting that the ISO
        provenance itself is stale and not the primary evidence.
  - term:
      id: GO:0060400
      label: negative regulation of growth hormone receptor signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000119
    review:
      summary: >-
        Human-to-mouse ISO transfer with no current donor support recovered.
      action: REMOVE
      reason: >-
        This reads as a downstream regulatory consequence rather than a direct core
        annotation for Ghr.
  - term:
      id: GO:1990782
      label: protein tyrosine kinase binding
    evidence_type: ISO
    original_reference_id: GO_REF:0000096
    review:
      summary: >-
        Rat-to-mouse ISO transfer with direct donor support for binding to
        tyrosine kinases such as JAK2.
      action: ACCEPT
      reason: >-
        This is the preferred specific kinase-binding term for Ghr.
  - term:
      id: GO:0060397
      label: growth hormone receptor signaling pathway via JAK-STAT
    evidence_type: IDA
    original_reference_id: PMID:8702683
    review:
      summary: >-
        Direct mouse evidence that GH promotes STAT5 association with GHR.
      action: ACCEPT
      reason: >-
        This is the strongest direct mouse pathway paper for Ghr and anchors the
        JAK-STAT branch.
      supported_by:
        - reference_id: PMID:8702683
          supporting_text: >-
            GH-induced tyrosine phosphorylation of STAT5 and the interaction of
            STAT5 with GHR can be observed in mouse 3T3-F442A cells which express
            endogenous mouse GHR.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IDA
    original_reference_id: PMID:11834450
    review:
      summary: >-
        Direct mouse study of membrane-associated GHBP and soluble GHBP forms.
      action: KEEP_AS_NON_CORE
      reason: >-
        The paper clearly supports membrane association, but plasma membrane is
        the more informative core location and the result is entwined with GHBP
        isoform biology.
      supported_by:
        - reference_id: PMID:11834450
          supporting_text: >-
            mouse liver GHBP is predominantly present as a membrane-associated
            protein structurally distinct from the soluble form of GHBP present in
            serum.
  - term:
      id: GO:0019530
      label: taurine metabolic process
    evidence_type: IMP
    original_reference_id: PMID:18648510
    review:
      summary: >-
        Metabolomic consequence of altered GHR signaling in mutant mice, not a
        direct receptor function.
      action: REMOVE
      reason: >-
        This is a downstream phenotype/process consequence and should not be kept
        as a direct Ghr function annotation.
      supported_by:
        - reference_id: PMID:18648510
          supporting_text: >-
            The systems biology approach applied in this study provides a
            coherent picture of metabolic changes resulting from impaired STAT5
            signalling by the growth hormone receptor, and supports a
            potentially important role for taurine in enhancing beta-oxidation.
  - term:
      id: GO:0040014
      label: regulation of multicellular organism growth
    evidence_type: IMP
    original_reference_id: PMID:18648510
    review:
      summary: >-
        Whole-animal phenotype consequence of altered receptor signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Ghr clearly affects organismal growth, but this is a downstream phenotype
        rather than the receptor's core molecular role.
      supported_by:
        - reference_id: PMID:18648510
          supporting_text: >-
            These truncations lead to altered signaling through the GHR in
            response to hormone binding and allow us to study the contribution
            of particular GH receptor signaling domains to gene expression and
            metabolism.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: HDA
    original_reference_id: PMID:24006456
    review:
      summary: >-
        Proteomic secretome-style evidence from cardiac fibroblasts. Plausible for
        GHBP/extracellular product biology but not strong Ghr-focused localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        The term is plausible because of GHBP, but this paper is not a focused Ghr
        localization study and should not drive core curation.
      supported_by:
        - reference_id: PMID:24006456
          supporting_text: >-
            Mouse cardiac fibroblasts were transfected with pre-/anti-miR of
            miR-29b and miR-30c, and their conditioned medium was analyzed by mass
            spectrometry.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1168790
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1168910
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1168923
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1168927
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1169194
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1169229
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1169240
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1169250
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1169142
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1169206
    review:
      summary: Reactome pathway placement is consistent with accepted receptor localization.
      action: ACCEPT
      reason: Plasma membrane is the core signaling location for Ghr.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-MMU-1168790
    review:
      summary: >-
        Reactome extracellular-region placement is plausible for GHBP/ectodomain
        biology but not the most informative core location.
      action: KEEP_AS_NON_CORE
      reason: >-
        The gene produces extracellular GH-binding material, but plasma membrane
        is the clearer core location.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8702683
    review:
      summary: >-
        Direct interaction paper, but the generic protein-binding term is too
        uninformative.
      action: MODIFY
      reason: >-
        The paper is better captured by the more specific SH2-domain-binding
        concept for receptor docking interactions.
      proposed_replacement_terms:
        - id: GO:0042169
          label: SH2 domain binding
  - term:
      id: GO:0004903
      label: growth hormone receptor activity
    evidence_type: IDA
    original_reference_id: PMID:6303755
    review:
      summary: >-
        Direct mouse receptor-binding evidence from liver membranes.
      action: ACCEPT
      reason: >-
        This is primary experimental mouse evidence for receptor activity.
      supported_by:
        - reference_id: PMID:6303755
          supporting_text: >-
            GH receptors were at normal levels in lit/lit mice despite their
            deficiency of pituitary and serum GH.
        - reference_id: file:mouse/Ghr/Ghr-deep-research-falcon.md
          supporting_text: >-
            GHR is a cell-surface receptor for endocrine and local growth
            hormone (GH).
  - term:
      id: GO:0017046
      label: peptide hormone binding
    evidence_type: IPI
    original_reference_id: PMID:10556780
    review:
      summary: >-
        Mouse GHBP/GH interaction evidence supports the specific hormone-binding
        activity of the locus.
      action: ACCEPT
      reason: >-
        Whether through receptor or GHBP product, peptide hormone binding is a
        correct direct activity for Ghr.
      supported_by:
        - reference_id: PMID:10556780
          supporting_text: >-
            Chromatographic separation of labeled human GH or mGH cross-linked to
            serum GHBPs showed two GH-binding serum fractions in normal as well as
            in transgenic mice serum.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:9144201
    review:
      summary: >-
        Developmental-stage-specific embryo localization with mainly nuclear
        signal in cleavage-stage embryos.
      action: KEEP_AS_NON_CORE
      reason: >-
        The observation is experimentally real but context-specific and not the
        default location for Ghr biology.
      supported_by:
        - reference_id: PMID:9144201
          supporting_text: >-
            In cleavage-stage embryos this immunoreactivity was localized mainly
            to the nucleus, but clear evidence of membrane labeling was apparent
            in blastocysts.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:9144201
    review:
      summary: >-
        Direct mouse embryo study shows membrane labeling in blastocysts.
      action: ACCEPT
      reason: >-
        This is direct mouse evidence consistent with the core receptor location.
      supported_by:
        - reference_id: PMID:9144201
          supporting_text: >-
            In cleavage-stage embryos this immunoreactivity was localized mainly
            to the nucleus, but clear evidence of membrane labeling was apparent
            in blastocysts.
core_functions:
  - description: >-
      Full-length mouse GHR binds growth hormone at the plasma membrane and
      transduces growth-hormone receptor signaling, especially through the
      JAK-STAT branch.
    molecular_function:
      id: GO:0004903
      label: growth hormone receptor activity
    directly_involved_in:
      - id: GO:0060396
        label: growth hormone receptor signaling pathway
      - id: GO:0060397
        label: growth hormone receptor signaling pathway via JAK-STAT
    locations:
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: PMID:6303755
        supporting_text: >-
          GH receptors were at normal levels in lit/lit mice despite their
          deficiency of pituitary and serum GH.
      - reference_id: PMID:8702683
        supporting_text: >-
          GH-induced tyrosine phosphorylation of STAT5 and the interaction of
          STAT5 with GHR can be observed in mouse 3T3-F442A cells which express
          endogenous mouse GHR.
      - reference_id: file:mouse/Ghr/Ghr-notes.md
        supporting_text: >-
          UniProt records two alternative products: full-length isoform P16882-1
          and the shorter P16882-2 GH-binding protein isoform.
suggested_questions:
  - question: >-
      Should extracellular-space annotations for mouse Ghr be made explicitly
      isoform-aware, so that GHBP biology is separated from the full-length
      signaling receptor?
  - question: >-
      Which ortholog-derived GHR ISO annotations should be globally pruned
      because the donor is itself ISO or explicitly NOT?
suggested_experiments:
  - hypothesis: >-
      Isoform 1 is the signaling-competent receptor whereas isoform 2 primarily
      contributes extracellular GH-binding/GHBP biology.
    description: >-
      Express mouse P16882-1 and P16882-2 separately in the same cell system and
      compare plasma-membrane localization, GH binding, and STAT5 activation.
    experiment_type: isoform-specific expression and signaling assay
  - hypothesis: >-
      Receptor internalization should not be retained as a mouse Ghr annotation
      without direct evidence that distinguishes the full-length receptor from
      GHBP/shed ectodomain behavior.
    description: >-
      Measure GH-induced trafficking/internalization of endogenous mouse GHR with
      isoform-discriminating reagents and quantify receptor versus GHBP pools.
    experiment_type: ligand-induced trafficking assay
references:
  - id: file:mouse/Ghr/Ghr-notes.md
    title: Curator notes for mouse Ghr review
    findings: []
  - id: file:mouse/Ghr/Ghr-iso-donor-trace.md
    title: ISO donor trace for mouse Ghr
    findings: []
  - id: file:mouse/Ghr/Ghr-uniprot.txt
    title: UniProtKB P16882 record for mouse Ghr
    findings: []
  - id: file:mouse/Ghr/Ghr-goa.tsv
    title: QuickGO export for mouse Ghr
    findings: []
  - id: file:mouse/Ghr/Ghr-deep-research-falcon.md
    title: Falcon deep research report for mouse Ghr
    findings: []
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
      Location vocabulary mapping, accompanied by conservative changes to GO
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000096
    title: Automated transfer of experimentally-verified manual GO annotation
      data to mouse-rat orthologs
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000119
    title: Automated transfer of experimentally-verified manual GO annotation
      data to mouse-human orthologs
    findings: []
  - id: PMID:10556780
    title: Up-regulation of GH-binding protein by mouse GH in transgenic mice
      overexpressing GH-releasing hormone.
    findings: []
  - id: PMID:11834450
    title: Structurally distinct membrane-associated and soluble forms of
      GH-binding protein in the mouse.
    findings: []
  - id: PMID:18648510
    title: 'Altered metabolism of growth hormone receptor mutant mice: a combined
      NMR metabonomics and microarray study.'
    findings: []
  - id: PMID:24006456
    title: 'Extracellular matrix secretion by cardiac fibroblasts: role of
      microRNA-29b and microRNA-30c.'
    findings: []
  - id: PMID:6303755
    title: Hepatic binding of human and bovine growth hormones and ovine
      prolactin in the dwarf "little" mouse.
    findings: []
  - id: PMID:8702683
    title: Growth hormone promotes the association of transcription factor STAT5
      with the growth hormone receptor.
    findings: []
  - id: PMID:9144201
    title: 'Functional growth hormone (GH) receptors and GH are expressed by
      preimplantation mouse embryos: a role for GH in early embryogenesis?'
    findings: []
  - id: Reactome:R-MMU-1168790
    title: ADAM17 cleavage of Ghr
    findings: []
  - id: Reactome:R-MMU-1168910
    title: Stat5 association with Ghr
    findings: []
  - id: Reactome:R-MMU-1168923
    title: Stat5 tyrosine phosphorylation
    findings: []
  - id: Reactome:R-MMU-1168927
    title: Growth hormone receptor binds Lyn
    findings: []
  - id: Reactome:R-MMU-1169142
    title: Jak2 binds Stat1/Stat3
    findings: []
  - id: Reactome:R-MMU-1169194
    title: Socs binding to JAK2
    findings: []
  - id: Reactome:R-MMU-1169206
    title: Jak2 phosphorylates Stat1/Stat3
    findings: []
  - id: Reactome:R-MMU-1169229
    title: Ptp1b dephosphorylates Jak2
    findings: []
  - id: Reactome:R-MMU-1169240
    title: Shp1 (Ptpn6) dephosphorylates Jak2
    findings: []
  - id: Reactome:R-MMU-1169250
    title: Shp1 binds Jak2 in the receptor complex
    findings: []

Ghr

Gene Description

Functional Isoforms

Existing Annotations Review

Core Functions

Full-length mouse GHR binds growth hormone at the plasma membrane and transduces growth-hormone receptor signaling, especially through the JAK-STAT branch.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Mouse Ghr (Growth Hormone Receptor) — UniProt P16882

1) Target verification (gene/protein identity)

2) Key concepts and definitions (current understanding)

2.1 Molecular function

2.2 Receptor activation mechanism

2.3 Core signaling pathways

3) Localization, processing, and trafficking

3.1 Subcellular localization

3.2 Receptor processing/isoforms and GH-binding protein (GHBP)

3.3 Endocytosis, ubiquitin/proteasome control, and receptor availability

3.4 Rapid receptor modification in vivo during stress/injury (mouse liver)

4) Negative regulation and expert synthesis

4.1 SOCS2 as a direct negative-feedback regulator of GHR

5) Biological roles and tissue-specific physiology in mouse (selected high-evidence themes)

5.1 Liver: endocrine integration via IGF-1 axis

5.2 Bone/growth: dependence on intact hepatic GHR–JAK2/STAT5 signaling

5.3 Brain/hypothalamus: GHR effects on neuroglia and inflammation markers

5.4 Metabolic/aging phenotypes from GHR perturbation (review synthesis)

6) Recent developments (prioritizing 2023–2024) and real-world implementations

6.1 Cancer applications: GHR antagonism as an adjuvant strategy

6.2 Pharmacologic targeting of GH action in endocrine disease (acromegaly)

6.3 Drug safety/efficacy statistics relevant to GH axis interventions

7) Functional annotation summary (for databases/curation)

Evidence table

Key visual evidence (mouse liver signaling and receptor processing)

References (URLs and publication dates)

Citations

📚 Additional Documentation

Notes

Ghr notes

Core mouse biology

Isoform biology relevant to annotation review

ISO donor-trace conclusions

Downstream phenotype caution

Iso Donor Trace

Ghr ISO donor trace

Human donor UniProtKB:P10912

Rat donor UniProtKB:P16310 mapped from RGD:2687

Important circularity and stale-transfer findings

📄 View Raw YAML

Human donor `UniProtKB:P10912`

Rat donor `UniProtKB:P16310` mapped from `RGD:2687`