Disease relevance of GHR

• The use of FITC-labeled mAb263 and hGH is of potential use for the study of GHR levels in patients exhibiting different types of growth disorders [1].
• We have previously described two families (H and M) with GH binding protein-positive Laron Syndrome (LS), proposed to have one or more post GHR signaling defects [2].
• In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer [3].
• We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines [3].
• Synthesis of the GHR antagonist pegvisomant has provided another agent with which to treat patients with acromegaly [4].

Psychiatry related information on GHR

• The effects of food deprivation on the hepatic level growth hormone receptor (GHR) were investigated in black seabream (Acanthopagrus schlegeli) both at the protein level (by radioreceptor assay) and at the mRNA level (by ribonuclease protection assay) [5].
• RESULTS: GHR adolescents showed impairments in immediate logical memory, verbal working memory, CPT-IP performance, and fine motor skills [6].

High impact information on GHR

• Briefly, binding of GH to GH receptor induces receptor dimerization and activation of the tyrosine kinase JAK2 [7].
• In transfection experiments, the transduction of growth hormone signaling through d3-GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (P < 0.0001) [8].
• These observations suggest that the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics [8].
• Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene [9].
• Growth hormone-receptor gene in Laron dwarfism [10].

Chemical compound and disease context of GHR

• To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells [11].
• Blockade of the GH receptor with B2036 reduced serum-induced DNA synthesis, as measured by thymidine incorporation, by 8 to 33% (mean 20%) in primary meningioma cultures [12].
• These GHR antagonists reduce both the biochemical abnormalities of acromegaly, as well as improve clinical signs and symptomatology.In this article we firstly review available data on dopamine agonists [13].
• OBJECTIVE: The study describes for the first time, a homozygous mutation in the WSXWS-like motif of the human GH receptor (GHR) in a patient with Laron syndrome and describe laboratory data during treatment with GnRHa to suppress puberty and dihydrotestosterone (DHT) [14].
• GHR gene expression is also regulated by factors such as nutritional intake, GH, steroid hormones, and diabetes mellitus [15].

Biological context of GHR

• These results indicate that the D112G mutation in the GH-1 gene causes production of bioinactive GH, which prevents dimerization of GHR and is therefore responsible for the patient's short stature [16].
• Both hGH and bGH stimulated tyrosine phosphorylation of a 95-kDa protein in cells transfected with WT GHR, but bGH was less effective in cells expressing mutant GHR [17].
• We conclude that whereas endocytosis and degradation require the ubiquitin system, they are independent of GHR signal transduction [18].
• The implications of these findings with regard to GH signaling and GHR down-regulation are discussed [19].
• The ubiquitin-proteasome system is required in growth hormone receptor (GHR) endocytosis [18].

Anatomical context of GHR

• By anti-GHR cytoplasmic domain immunoblotting, we observed that the remnant induced in response to phorbol ester or platelet-derived growth factor has a reliable pattern of appearance and disappearance in both mouse preadipocytes endogenously expressing GHR and transfected fibroblasts expressing rabbit GHR [20].
• No proteins showed increased tyrosyl phosphorylation in CHO cells expressing GHR1-294, GHR4P-->A, or GHR delta P [21].
• This modification did not alter the rate and extent of receptor-bound growth hormone internalization as compared with a functional GHR, nor did it change its turnover and transport to the plasma membrane [18].
• Northern blot analysis revealed a 5.5-kb GHR messenger RNA (mRNA) species, but semiquantitative RT-PCR revealed no difference in GHR mRNA expression by normal and OA chondrocytes [22].
• As part of an effort to define the local effects of the placentally expressed members of the GH/Prl family of hormones on the placenta, we have identified an isoform (hGHRd3) of the growth hormone receptor expressed in the placental villi. hGHRd3 mRNA differs from the liver GHR mRNA by the deletion of a 66-base pair segment encoding exon 3 [23].

Associations of GHR with chemical compounds

• In two unrelated families, the same GHR mutation was identified, resulting in the substitution of a highly conserved aspartate residue by histidine at position 152 (D152H) of the exoplasmic domain, within the postulated interface sequence involved in homodimerization [24].
• Deletion and alanine substitution mutagenesis indicated that, similar to other TACE substrates, the spacing of residues in this region, more than their identity, influences GHR cleavage susceptibility [25].
• Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the growth hormone receptor (GHR) signaling domain [26].
• Lactacystin, a specific proteasome inhibitor, did not appreciably change the time course of remnant appearance or clearance but allowed detection of the GHR stub, a receptor fragment slightly smaller than the remnant but containing the C terminus of the remnant (receptor cytoplasmic domain) [20].
• In situ hybridization using the same digoxigenin-labeled oligoprobe localized the GHR mRNA in the granulosa cells of dominant and antral follicles, corpus luteum, corpora albicans and the endothelium of blood vessels [27].

Physical interactions of GHR

• Comparisons with the hGH-hGHR complex reveal how hGH can bind to the two distinctly different receptor binding surfaces [28].
• In 1993, GH receptor (GHR) was first observed to bind to the tyrosine kinase JAK2 [29].
• We found that GHR interacts with SGT [30].
• The crystal structure of human GH bound to human GHR did not resolve this extreme N-terminal region of the receptor but our data indicate that the N-terminal loop undertakes a 180 degrees turn bringing it into close proximity to the hormone-binding domain in a fashion analogous to the prolactin receptor [31].
• For peptides endowed with hGM-CSF binding activity were identified and the postulated homology between the binding sites of hGM-CSFR alpha GHR was confirmed [32].

Enzymatic interactions of GHR

• Once activated, JAK2 tyrosyl-phosphorylates both itself and the cytoplasmic domain of GHR [33].
• We conclude that GH induces activation of STAT3 and STAT5b by two different pathways: one primarily dependent on activation of JAK2 (STAT3) and another that is additionally reliant on the presence of an intact and tyrosine-phosphorylated GHR cytoplasmic domain (STAT5b) [34].
• The disulfide-linked form of the hGHR accounted for a substantial fraction of the receptors that became tyrosine phosphorylated early into hGH treatment [35].

Regulatory relationships of GHR

• In conclusion, hGH 44-191 binds with low affinity to the GHR and at supraphysiologic levels stimulates proliferation of FDC-P1-hGHR cells [36].
• Synthetic tyrosine phosphorylated peptides corresponding to the GH receptor sequence around the three tyrosines inhibited Stat5 DNA-binding activity while their non-phosphorylated counterparts were ineffective [37].
• Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues [38].
• CONCLUSIONS: Most patients with NF1 have localised neurofibromas that express GHR [39].
• One recipient of rhIGF-I developed papilledema, which resolved spontaneously. rhIGF-I therapy did not alter serum IGF-binding protein-3 concentrations. rhIGF-I treatment is effective in stimulating skeletal growth in GH receptor deficiency [40].

Other interactions of GHR

• In this study, we examined the role of JAK2-mediated signal transduction in GHR internalization and down-regulation [18].
• Monocytes specifically bound radiolabeled GH and contained mRNA for the GH receptor and, in some donors, the PRL receptor [41].
• This effect might result from interference of C-terminal nonsense sequence in mutated GHR with STAT5 docking to upstream tyrosine residues [42].
• Objective: The objective was to study the impact of the GHR genotype on the phenotype and growth response in patients with isolated GH deficiency (IGHD) treated with GH [43].
• GH receptors (GHRs) and PRL receptors (PRLRs) were studied in human peripheral blood mononuclear cells (PBMC) using flow cytometry, biotinylated anti-GH receptor monoclonal antibody 10B8, and biotinylated human PRL [44].

Analytical, diagnostic and therapeutic context of GHR

• Binding assay, Northern blot, and reverse transcriptase polymerase chain reaction (RT-PCR) techniques were used for GH receptor (GHR) detection [22].
• Using cell culture model systems, we now explore the effects of GH treatment on inducible GHR proteolysis and GHBP shedding [19].
• Confocal microscopy indicated that the GHR cytoplasmic domain became localized to the nucleus in a fashion dependent on PS1/2 activity [20].
• In transient transfection experiments, anti-GHR(ext-mAb) failed to recognize by immunoprecipitation a previously characterized dimerization interface mutant GHR that is incompetent for signaling [45].
• GHR gene expression was detected in PCR products after Southern blot hybridization using an oligoprobe directed to the intracellular domain sharing no homology to the prolactin receptor [27].

References