| Aspect | Key points | Best supporting citations | Source details |
|---|---|---|---|
| Identity / domains | Rat **Ghr** (UniProt **P16310**) matches the canonical **growth hormone receptor (GHR)**, a **class I/type I cytokine receptor**. Architecture includes an **extracellular ligand-binding region with two FNIII-like modules**, a **single transmembrane helix**, and an **intracellular domain** with **Box1** and **Box2** motifs important for JAK coupling. A domain schematic also identifies ECD ~19–262, TMD ~263–288, ICD ~289–638 in a conserved GHR framework. | (pqac-00000001, pqac-00000015, pqac-00000016) | Gün, 2022, DOI: https://doi.org/10.17185/duepublico/46490 |
| Ligand / stoichiometry | The ligand is **growth hormone (GH)**. Structural and mechanistic sources support **1 GH : 2 GHR** binding, with **site 1** binding one receptor first and **site 2** engaging the second receptor. Reviews also describe the receptor:ligand complex as **2:1 GHR:GH**. | (pqac-00000002, pqac-00000011, pqac-00000012) | Dehkhoda, 2018, DOI: https://doi.org/10.3389/fendo.2018.00035; Wójcik, 2018, DOI: https://doi.org/10.3390/ijms19071843 |
| Activation mechanism | Older models proposed ligand-induced dimerization, but current understanding favors **preformed GHR homodimers** at the cell surface and even in the ER. GH binding induces a **conformational rearrangement** of the dimer rather than creating the dimer de novo. This reorientation separates/releases intracellular restraints so **JAK2 molecules trans-phosphorylate** and initiate signaling. | (pqac-00000009, pqac-00000012, pqac-00000013) | Dehkhoda, 2018, DOI: https://doi.org/10.3389/fendo.2018.00035; Ortiz, 2014, no DOI in evidence |
| Key pathways | The dominant signaling output is **JAK2 → STAT5a/STAT5b**, with additional activation of **STAT1** and **STAT3**. GHR also signals through **MAPK/ERK** via Shc/Grb2/SOS/Ras/Raf/MEK and through **IRS-PI3K-Akt** pathways. These pathways link GHR to growth, metabolism, and transcriptional regulation including **IGF-1** production. | (pqac-00000007, pqac-00000008, pqac-00000009, pqac-00000013) | Carter-Su, 2016, DOI: https://doi.org/10.1016/j.ghir.2015.09.002; Dehkhoda, 2018, DOI: https://doi.org/10.3389/fendo.2018.00035 |
| Negative regulation | Multiple post-receptor brakes constrain signaling: **SOCS2**, **SOCS1**, **SOCS3**, **CIS**, **PIAS**, **PTP1B**, **PTP-H1**, **SHP1**, **SHP2**, and **SIRPα1**. **SOCS2** is especially important: it binds phosphorylated GHR, helps recruit an E3 ubiquitin ligase complex, and promotes **GHR internalization/degradation**. Signaling is transient, with maximal activation around **~30 min** and a refractory period of **~3–4 h** in one review. | (pqac-00000010, pqac-00000011) | Fernández-Pérez, 2016, DOI: https://doi.org/10.5772/64606; Wójcik, 2018, DOI: https://doi.org/10.3390/ijms19071843 |
| GH-binding protein (GHBP) | A **soluble GH-binding protein (GHBP)** corresponds to the **extracellular domain** of GHR and binds GH with receptor-like affinity. Literature and knockout genetics treat **GHR and GHBP as products of the same gene system**. GHBP modulates GH bioavailability in circulation, and schematic work highlights extracellular-domain shedding / soluble release. | (pqac-00000004, pqac-00000006, pqac-00000001) | List, 2001, DOI: https://doi.org/10.1006/mgme.2001.3164; Gün, 2022, DOI: https://doi.org/10.17185/duepublico/46490 |
| Localization / trafficking | GHR is primarily a **plasma-membrane single-pass receptor**, but preformed dimers are reported to assemble in the **endoplasmic reticulum** before surface expression. JAK2 can remain associated during **internalization**, suggesting some **endosomal signaling**. 2024 work also indicates ligand-dependent changes in **surface availability** and crosstalk with **PRLR**, with Box1/JAK2 coupling affecting receptor trafficking behavior. | (pqac-00000012, pqac-00000011, pqac-00000003) | Wójcik, 2018, DOI: https://doi.org/10.3390/ijms19071843; Chen, 2024, DOI: https://doi.org/10.1101/2023.09.01.555812 |
| Rodent phenotypes / quantitative data | Rodent genetics show that loss of **JAK2/STAT5** signaling strongly impairs postnatal growth. Liver-focused disruption of GH-GHR signaling can reduce circulating **IGF-1 by ~80%** or **>90%** depending on model, with metabolic effects including steatosis and insulin resistance. **SOCS2 knockout mice are ~40% larger**, underscoring negative regulation. GHR/BP knockout models also show **undetectable serum IGF-I** and elevated GH. | (pqac-00000014, pqac-00000010, pqac-00000006) | Dehkhoda, 2018, DOI: https://doi.org/10.3389/fendo.2018.00035; Fernández-Pérez, 2016, DOI: https://doi.org/10.5772/64606; List, 2001, DOI: https://doi.org/10.1006/mgme.2001.3164 |
| Rat-specific / rodent signaling observations | In rat liver hepatocytes during early life, one study reported GH did **not** activate expected intracellular mediators, highlighting developmental context dependence of GHR responsiveness. Reviews also note that **male rat GH secretion is pulsatile**, shaping **STAT5b** activation differently from more continuous female patterns. Thus, rat Ghr function is conserved, but pathway output is strongly conditioned by age and endocrine context. | (pqac-00000010) | Fernández-Pérez, 2016, DOI: https://doi.org/10.5772/64606 |
| Recent 2024 developments | 2024 work refines GHR biology in two ways: (1) **branch-specific signaling** studies indicate **Box1/JAK2/STAT5** and **LYN/ERK** outputs can be genetically uncoupled, with STAT5 being the key growth-driving branch; (2) super-resolution / membrane studies suggest **JAK2 and Box1 are important for reciprocal surface regulation of GHR and PRLR**. These studies update trafficking/crosstalk and pathway specificity rather than overturning the core GHR model. | (pqac-00000003, pqac-00000005) | Chhabra, 2024, DOI unavailable in evidence; Chen, 2024, DOI: https://doi.org/10.1101/2023.09.01.555812 |


*Table: This table summarizes the verified identity, structure, signaling, regulation, localization, and phenotype evidence for rat Ghr/GHR. It is useful as a compact functional-annotation reference with direct context-ID support for each major claim.*