Genes for human growth hormone, known as growth hormone 1 (somatotropin; pituitary growth hormone) and growth hormone 2 (placental growth hormone; growth hormone variant), are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. When the receptor is turned on, it causes release of hormones that regulate stress. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and supresses their ability to take up and accumulate circulating lipids. Growth hormone (GH), also known as somatotropin (or as human growth hormone in its human form), is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. A common polymorphism causes the exon to be “skipped” during transcription, and therefore results in a gene product in which exon 3 is spliced (d3-GHR). JAK2 is the primary signal transducer for growth hormone.[8]. It is generated by a metalloprotease-catalyzed cleavage of the plasma membrane-bound receptor form. This mechanism leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation (Figure 1). 159 relations. Schematic structure of the GH receptor. The GH receptor possesses 19 potential ubiquitination sites and can be polyubiquitinated on multiple lysine residues. This signal peptide is cleaved during the secretion process to yield the mature, 191 amino acid form of hGH. GH antibodies are a rare cause of GH resistance. This is probably confined to the few patients with severe gene-deletion GHD where the subject’s immune system has never been exposed to GH and fails to recognize it as self when administered therapeutically. This then acts on virtually every tissue of the body to control metabolism and growth. Growth hormone, peptide hormone secreted by the anterior lobe of the pituitary gland. Diseases associated with GHR include Laron Syndrome and Growth Hormone Insensitivity, Partial.Among its related pathways are Relaxin signaling pathway and PEDF Induced Signaling.Gene Ontology (GO) annotations related to this gene include protein homodimerization activity and protein phosphatase binding. Ubiquitination of the receptor is increased by ligand binding and may play a role in GH receptor internalization. In 2004, a seminal study by Dos Santos and colleagues demonstrated that a common polymorphism in the growth hormone receptor (GHR) may also play a critical role in determining how well a child will grow in response to GH treatment.1. Treatment utilizes recombinant IGF1. For water-soluble proteins, the receptor will be at the plasma membrane of the cell. For clarity, entire assembled receptors or partial structures are not shown. In either case, this binding generates a hormone-receptor complex that moves toward the chromatin in the cell nucleus and binds to a particular segment of the cell’s DNA. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. GHR orthologs have been identified in most mammals. The growth response to GH in children is known to vary depending upon the age and size of the patient, as well as to the dose given. Exons 9 and 10 encode the remaining 346 amino acids of the intracellular domain. Parker, in Encyclopedia of Cell Biology, 2016. hGHR is the paradigm for understanding cytokine recognition and signaling of much of the cytokine superfamily (Figures 1 and 2). Box 1 is one site of association of JAK2 with the GH receptor and is critical for many GH-stimulated cellular functions (Goujon et al., 1994; VanderKuur et al., 1994; Frank et al., 1995). A nearly indistinguishable variant has been described where normal circulating GHBP is found; it is believed that the GH receptor is present but that post-ligand-binding events are abnormal. The protein-coding region of the GHR gene is encoded by exons 2 through 10. Dos Santos et al. When antibodies do occur they effectively block the effects of the GH. GH binding to the two GH receptors is thought to be sequential. Discovery of growth hormone-releasing hormones and receptors in nonmammalian vertebrates Leo T. O. Lee*, Francis K. Y. Siu*, ... chromosomal locations and organization of neighboring genes confirmed that they share the same origins as the mammalian genes. When the dimeric receptor binds GH it undergoes a conformational change which leads to phosphorylation of key tyrosine residues in its cytoplasmic domains and activation of associated tyrosine kinase JAK2. The GHR is a member of the class 1 hematopoietic cytokine family. There are currently no three-dimensional structures for the IL-36α, IL-36β, IL-36γ and TPO cytokines or the TPO receptor. Studies by Graichen et al. Patients with GHIS physically resemble those with IGHD, although some of the facial dysmorphic features (sparse hair, protruding forehead, saddle nose and small chin) tend to be more severe.48 Contrary to IGHD, reduced psychological performance has also been reported. The heterogeneity in the 5′-UTR exon 1 sequences of the GH receptor gene transcripts noted above indicates complex transcriptional control of the GH receptor locus. Excellent reviews of the molecular aspects of the GHR have been published and are cited here.40,64, In addition to the membrane-bound GHR, a soluble form exists that is composed of a portion of the extracellular domain, GHBP. Google Scholar. We use cookies to help provide and enhance our service and tailor content and ads. The 26S proteasome complex is the location where proteolytic degradation of polyubiquitinated proteins occurs. Such observations highlight the critical roles that crystallographic structural studies have played in unmasking unexpected similarities between proteins with highly divergent primary structures and disparate biological functions. OpenStax, Anatomy & Physiology/Creative Commons Attribution 3.0. Ralph Graichen Institute of Molecular and Cell Biology, 117609 Singapore, Republic of Singapore. The growth hormone-binding protein is a location-dependent cytokine receptor transcriptional enhancer. Eight GHR amino acid residues are involved in the salt bridge and the hydrogen bond interactions across the extracellular dimerization domain.39 Of these eight residues, five are important for GH/GHR-mediated signal transduction, namely, Ser 145, His 150, Asp 152, Try 200, and Ser 201, but not Leu 146 or Thr 147. The associated activating cytokines with known three-dimensional structures are shown with their respective receptor. The phosphorylated STATs translocate to the nucleus, where they regulate growth hormone–responsive genes.523-526 In particular, growth hormone indirectly controls growth by regulating production of insulin-like growth factor-1 (IGF-1)—which has direct effects on cell proliferation and hypertrophy.527 Jak2 also activates the mitogen activated protein (MAP) kinase and insulin receptor substrate pathways.528-530 However, the extent to which these pathways contribute to growth hormone action is as yet unknown.520, Patients are considered to have growth hormone insensitivity (GHI) if they do not exhibit appropriate growth and metabolic responses to physiologic levels of growth hormone.521 The phenotype of GHI is variable and ranges from isolated moderate postnatal growth failure to severe postnatal growth failure accompanied by the classic features of Laron syndrome in Ecuadorean patients with GHR deficiency.521,531-535 Features of GHR deficiency include frontal temporal hairline recession, prominent forehead, decreased vertical dimension of face, hypoplastic nasal bridge, shallow orbits, blue sclera, small phallus prior to puberty, crowded permanent teeth, absent third molars, small hands and feet, hypoplastic fingernails, hypomuscularity, delayed age of onset for walking, high-pitched voice, increased total and low-density lipoprotein cholesterol, and fasting hypoglycemia.521,535 All patients with GHI have normal or elevated circulating growth hormone levels, markedly decreased circulating IGF-1 levels, and a delayed bone age.521, Patients homozygous or compound heterozygous for deletion of exons 5 and 6—or homozygous or compound heterozygous for numerous nonsense, missense, frame-shift, and splice-point mutations throughout the GHR gene—have been found to have GHI characterized by severe postnatal growth failure and usually low or absent circulating GHBP levels.521,536-545 Patients homozygous or compound heterozygous for the Arg274Thr or the Gly223Gly splice mutations that result in a truncated receptor that cannot be anchored to the plasma membrane (or that result in the Asp152His missense mutation that interferes with GHR dimerization) have normal circulating GHBP levels.521, Patients heterozygous for mutations that alter the GHR have dimerization complexes that consist of two wild-type receptors, a wild-type receptor and a mutant receptor, and two mutant receptors. This gland is is located at the base of the brain and produces many hormones, including growth hormone. Exon 2 encodes the last 11 bp of the 5′-UTR, an 18-amino-acid signal peptide, and the first 5 amino acids of GH receptor's extracellular domain. By continuing you agree to the use of cookies. These data nicely supported the “cleft” theory pertaining to the interaction of GH Gly 120 with a second target.52 The importance of GH-induced GHR dimerization in humans has been supported by the finding of an adenine-to-guanine mutation in the GH gene that results in the conversion of Asp112 to Gly. After the alternate first exon of the GHR, there are nine coding exons. The ligand-bound receptor will trigger a cascade of secondary messengers inside the cell. This is an illustration of lipid-soluble hormone binding and protein production in a cell. The GHR gene is located on the short arm of chromosome 5 (5p13.1-p12), and 9 of the 13 exons of the gene encode the receptor.517-520 A secretion signal sequence is encoded by exon 2, the N-terminal extracellular ligand binding domain is encoded by exons 3 through 7, the single transmembrane domain is encoded by exon 9, and the C-terminal cytoplasmic domain is encoded by exons 9 and 10.517-520 Growth hormone binding protein (GHBP) is produced by proteolytic cleavage of the extracellular domain of the GHR from the rest of the receptor.521 Approximately 50% of circulating growth hormone is bound to GHBP.521, Binding of growth hormone to its receptor induces receptor dimerization and association with JAK2, a member of the Janus kinase family, which results in self-phosphorylation of the JAK2 and a cascade of phosphorylation of cellular proteins, including Stat1, Stat3, and Stat5.522-526 The most critical of these proteins is STAT5b, which couples GH binding to the activation of gene expression that leads to the intracellular effects of GH, including synthesis of IGF-I, insulin-like growth factor binding protein 3 (IGFBP3), and ALS. Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. Additionally, the extracellular domain of GHR shows substantial flexibility to achieve active conformation in response to GH and will even accommodate GH-GH dimers.74 The interaction of GH with the GHR has been shown to cause rotation of the two GHRs relative to each other that result in repositioning of the intracellular domain of GHR bringing the catalytic domains of the associated JAK2 molecules in position for transphosphorylation to occur (first to the JAK2 molecules, then to receptor tyrosines in the GHR cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins).40,75 This elegant data of the GH/GHR interaction and the animated model of GH-induced GHR rotation developed by Waters and colleagues over the past few years has greatly influenced and stimulated research on the interaction of GH with GHRs and represents a seminal finding in the GH field.40,75. HOW DO WE KNOW ABOUT d3GH RECEPTOR POLYMORPHISM AND RESPONSIVENESS TO GH THERAPY? Intracellular Hormone Receptor: located inside the cell. The GH receptor locus maps to the proximal short arm of human chromosome 5, region p13.1-p12 (Barton et al., 1989). Additional regulatory elements may exist further upstream. Other members of the class I cytokine receptor superfamily include prolactin, leptin, erythropoietin, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), neurotrophic factor (CNTF), thrombopoietin, and interleukins (IL) 2–7, IL-9, IL-11, and IL-12. In liver, GH receptor exon 1 variant 1 (V1) is the most highly expressed form. Exon 10 also codes for a 2 kb 3′-UTR. Exon 8 encodes the final 3 amino acids in the extracellular domain, a 24-amino-acid transmembrane domain, and the first 4 amino acids of the receptor's intracellular domain. Growth hormone receptor mutations (Laron syndrome) — Laron syndrome (MIM #262500), the most common known cause of genetically mediated GHI, is characterized by severe postnatal growth failure . Up to 60% of plasma GH is bound to GHBP, with the fraction bound decreasing at higher plasma GH concentrations. [5] Laron mice (that is mice genetically engineered to carry defective Ghr), have a dramatic reduction in body mass (only reaching 50% of the weight of normal siblings), and also show a ~40% increase in lifespan. NM_001242403NM_001242404NM_001242405NM_001242406NM_001242460NM_001242461NM_001242462, NM_001048147NM_001048178NM_010284NM_001286370, NP_001229332NP_001229333NP_001229334NP_001229335NP_001229389NP_001229391. 2). The condition follows an autosomal recessive pattern of inheritance. A proximal TATA-box is conserved across species, as is a positive-acting C/EBP and glucocorticoid-response element complex site and a negative-acting CCAAT site further upstream. Exon 2 encodes 11 bp of the 5′-UTR and the signal peptide, exons 3 to 7 encode the extracellular domain (246 amino acids), exon 8 encodes the transmembrane domain (24 amino acids), and the cytoplasmic domain is encoded by exons 9 and 10 (350 amino acids) (Fig.
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