growth hormone receptor location

The initial step is “high-affinity” (site 1) binding of GH to one GH receptor. By continuing you agree to the use of cookies. Exon 2 of the GHR gene encodes the secretory signal peptide and the first six amino acids of the mature form of the protein; exons 3 through 7 encode the extracellular domain, exon 8 the transmembrane domain, and exons 9 and 10 the intracellular domain. A metalloprotease tumor necrosis factor (TNF)-α converting enzyme (TACE/ADAM-17) has been reported to act on surface GHR to generate the GHBP.67 The function of the GHBP is not fully understood, but it may modulate GH activity by enhancing its serum half-life or reducing its availability to bind the GHR. Studies by Graichen et al. Box 2 comprises a cluster of approximately 15 hydrophobic and acidic amino acid residues and is located 30 residues distal to box 1. The human growth hormone receptor: secretion from Escherichia coli and disulfide bonding pattern of the extracellular binding domain. 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. In the heterozygous state, this mutation is believed to be the cause of dwarfism in a female child, with the encoded GH analogue binding to GHR in vitro, but not inducing GHR dimerization and JAK2 and STAT5 activation.55, Later studies have dramatically changed the GH-induced dimerization theory. 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. [21][22][23] Human growth hormone (hGH) plays a vital role in growth and development. The extracellular portion of the GHR consists of two fibronectin type III domains, each containing seven β-strands, arranged to form a sandwich of two antiparallel β-sheets.39 Stabilizing the GHR structure is a salt bridge between Arg 39 and Asp 132, and hydrogen bonds between Arg 43 and Glu 169.39 Also, the GHR contains seven cysteine residues in its extracellular domain39; the six in the GH binding domain form three disulfide bonds in the active signaling conformation, and help the receptor to maintain its correct structure.65 Van den Eijnden and coworkers have suggested, after studying the effects of replacing the Cys with Ser and Ala residues, that the middle disulfide bond, Cys83-Cys94, is important for ligand binding, whereas removal of disulfide bond Cys108-Cys122 has little effect on GH-induced intracellular signaling.65 The GHR has a cellular half-life of approximately 1 hour and is internalized and degraded continuously, even in the absence of GH through two known mechanisms: endocytosis and ectodomain cleavage. The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling. The 26S proteasome complex is the location where proteolytic degradation of polyubiquitinated proteins occurs. On ligand binding, couples to, and activates the JAK2/STAT5 pathway. [9][10] Binding of growth hormone to the receptor leads to reorientation of a pre-assembled receptor dimer dimerization (the receptor may however also exist as monomers on the cell surface [11]) and the activation of an intra- and intercellular signal transduction pathway leading to growth. Deletion or mutation of these boxes abrogates both JAK activation and subsequent signal transduction pathways responsible for GH-stimulated cell proliferation (Dinerstein et al., 1995; Tanner et al., 1995). Receptors for peptide hormones tend to be found on the plasma membrane of cells, whereas receptors for lipid-soluble hormones are usually found within the cytoplasm. The growth hormone receptor (GHR), although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. 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. 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. Ralph Graichen Institute of Molecular and Cell Biology, 117609 Singapore, Republic of Singapore. For clarity, entire assembled receptors or partial structures are not shown. Box 1 is 8 amino acid residues in length and is located within 20 residues of the transmembrane domain. In rats, mice, and monkeys, GHBP is generated from the GH receptor at the RNA level, by alternative splicing of the GH receptor precursor RNA. Any factor that disrupts this assembly can block the hormone's function. However, GH receptor expression has been observed in many organ systems, including the gastrointestinal tract, male and female reproductive systems, musculoskeletal system, cardiorespiratory system, hematopoietic and immune systems, central nervous system, the integument, renal and urinary systems, and endocrine system. The receptors for the polypeptide hormones, human growth hormone (hGH)’ and insulin, are located at the cell surface. The associated activating cytokines with known three-dimensional structures are shown with their respective receptor. Genomic structure of the hGH receptor gene. Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. [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. The growth hormone receptor exists as a constitutive dimer, and activation . Heterogeneity of immunoreactivity was found in normal and neoplastic tissue with a variable range of positive cells. The 26 N-terminal amino acids correspond to a signal peptide, which is essential for hormone secretion. A single arginine at residue 43 of the extracellular domain determines the specificity of human GH (hGH) to bind to the hGH receptor (Souza et al., 1995). 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. This gland is is located at the base of the brain and produces many hormones, including growth hormone. 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. Pantel, J., Machinis, K., Sobrier, M.-L., Duquesnoy, P., Goossens, M., Amselem, S. Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution: a novel mechanism accounting for protein diversity between and within species. Binding to the first site forms an inactive intermediate complex. The human GHR gene has been located to chromosome 5p13.1-p12 (Barton et al., 1989). Figure 2. Exons 3–7 encode the majority of the receptor's extracellular domain. The location of steroid and thyroid hormone binding differs slightly: a steroid hormone may bind to its receptor within the cytosol or within the nucleus. In mice and rats, GHBP is encoded by an additional exon of the GHR gene, namely Exon 8A, and is produced by alternative splicing of the GHR precursor mRNA. The cDNA for the human GH receptor encodes a 638 amino acid protein with single extracellular, transmembrane, and cytoplasmic domains. Frank. This cascade culminates with the transcription of target genes, such as the insulin-like growth factors (IGFs), which are responsible for most GH biological effects. 135 : 1292 – 1298. This gene encodes a protein that is a transmembrane receptor for growth hormone. Growth hormone receptor is a protein that in humans is encoded by the GHR gene. The reader is referred to a review paper on GHBPs for further information.68. As stated earlier,52 Kopchick and colleagues have proposed that the reason that GH-Gly120Arg acts as a GHRA is because substitution of Arg for Gly at position 120 blocked or inhibited the “second” GHR from properly interacting with binding Site 2 on the GH molecule. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity. This then acts on virtually every tissue of the body to control metabolism and growth. The untranslated exon 1 is followed by nine protein-coding exons. Only one single mRNA transcript encoding the GHR, sized 4.7 kb, has been identified in human. 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. These receptor proteins are the “eyes” and “ears” of the cells, receiving messages from substances in the bloodstream and then telling the cells what to do. The only available member of this family is pegvisomant (Somavert). Endocrinology. Figure 2. Indeed, the level of GH receptor mRNA can be regulated by both nutritional and hormonal factors, including GH itself. 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. We use cookies to help provide and enhance our service and tailor content and ads. Rather, they have defects in GHR-mediated intracellular signaling—including impaired STAT activation.552 Some patients with GHI were found to have STAT5b mutations.553-557 Unlike patients with GHR mutations, patients with STAT5b mutations also exhibited severe neurocognitive delay, chronic lung disease, and abnormal T-cell function.554 Patients with GHI can now be successfully treated with recombinant IGF1,558 but this does not result in a normal adult height, in contrast to GH deficiency in which GH therapy can achieve normal adult height. 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. Growth hormone receptor is a protein that in humans is encoded by the GHR gene. It is naturally produced by somatotropic cells in the anterior pituitary gland. GHBP acts to increase the half-life of circulating GH by decreasing its rate of clearance and degradation. As stature is a multigenic trait, and also influenced by environmental factors, it is not surprising that, even within a population of GHIS patients that is genetically homogeneous, adult height ranges widely.51 The size of the anterior pituitary is normal.52 Interestingly, sleep disorders are a common feature of adult patients with LS, although this has never been reported in IGHD.48 As one would expect, GHIS patients do not respond to GH therapy. Graichen R 1, Sandstedt J, Goh EL ... (GHBP) exists that is derived from the growth hormone (GH) receptor gene by an alternative mRNA splicing mechanism such that the transmembrane and intracellular domains of the GH receptor are replaced by a hydrophilic carboxyl terminus. The 26S proteasome complex is the location where proteolytic degradation of polyubiquitinated proteins occurs. Growth hormone-releasing hormone is a hormone produced in the hypothalamus. The assembly becomes functionally active only when the second receptor molecule binds at the second binding site on the other side of the hormone. For hGHR and other related cytokine receptors such as the erythropoietin (EPO), prolactin (PRL), and thrombopoietin (TPO) receptors, the hormone-induced model has recently been superseded with the demonstration that these receptors exist largely as inactive dimers in the absence of ligand (Brown et al., 2012; Hercus et al., 2009; Hiwase et al., 2010; Lopez et al., 2010; Wang et al., 2009; Wells and de Vos, 1996). The use of X-ray crystallography has enabled visualization of the three-dimensional structure of the GH receptor extracellular domain and the regions that interact with GH (DeVos et al., 1992). Ghrelin (GHRL; 605353) is a pleiotropic hormone secreted by stomach that promotes food-seeking behavior and positive energy balance. The cytokines IL-36α, IL-36β, and IL-36γ have not been included under the IL-1-like branch due to space limits. However, the actual mass of GH receptor is 100–130 kDa, with the difference in size due to postranslational modifications such as glycosylation and ubiquitination. The GHR gene is used in animals as a nuclear DNA phylogenetic marker. PubMed. Although most if not all of these GH/GHBP interactive studies use a nonglycosylated, bacterially expressed GHBP, and not the membrane-bound GHR, the interaction of one GH with two GHBPs has been extrapolated to the in vivo interaction of GH with the GHR. It was found that the TM domains of these single-pass cytokine receptors play an important role in their constitutive dimerization and the existence of inactive dimers implies that a specific ligand-induced conformational change is required for signal transmission to the associated cytoplasmic JAK2 kinases. Recently, it has been shown that receptor activation induces a separation of the receptor’s JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left-handed crossover arrangement (Brooks et al., 2014). Recent in vivo studies indicate that this mechanism of receptor downregulation may also mediate desensitization to GH in vivo.76 It is interesting to note that the GHR remnant that results from metalloproteolysis is further cleaved within the transmembrane domain by an enzyme termed γ-secretase, leading to release of the intracellular domain into the cytosol and its accumulation in the nucleus. GH receptor expression is highest in the liver, a major target organ of GH action. Growth hormone receptor (GHR) is transmembrane proteins consisting of 620 amino acids. Previous in vitro studies had demonstrated comparable binding kinetics between the full-length and spliced isoforms,2,3 but since the region is highly conserved among mammalian species, Dos Santos et al. SJ, Gilliland. The GHR gene (GHR) consists of 10 exons, and the coding region spans exons 2–9.43 After translation, an 18-amino acid signal sequence is removed. It has no known direct biological effect on cells nor any GH signaling capacity; however, it has been shown to significantly modulate (inhibit) cellular GH action (Lim et al., 1990) via one of two presumed mechanisms: (i) direct sequestration of GH away from the cell membrane-bound GH receptor and (ii) heterodimerization with the full-length, wild-type receptor on the cell surface (Herington, 1994). The consequences of this inducible nuclear localization of the GHR intracellular domain are as yet unknown, but may suggest novel GHR-dependent signaling pathways. The ligand-bound receptor will trigger a cascade of secondary messengers inside the cell. Copyright © 2021 Elsevier B.V. or its licensors or contributors. 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. [32] The model for GHR activation postulates that GH induces GHR dimerization and, consequently, activation and signaling in which most amino acid residues in the two binding interfaces act in an additive fashion.70 In addition, the GHR contains a GH-induced dimerization domain in which Cys 241 undergoes GH-induced intermolecular disulfide bonding, thus bridging together two GHRs. GH binding to the two GH receptors is thought to be sequential. In 2003 a girl was reported with GHIS and compromised immunological function, with a homozygous missense mutation in the STAT5b gene that alters the intracellular mechanisms involved in transmitting the message from the GHR to the nucleus.60 Since then, other mutations in this gene have been reported, causing an association of growth failure and immunodeficiency, likely due to malfunction of T cells that also require an intact Stat5b signaling.61, Peter E. Lobie, David J. Waxman, in Encyclopedia of Hormones, 2003. [12] A common alternate allele of this gene, called GHRd3, lacks exon three and has been well characterized. GHSR is a G protein-coupled receptor found peripherally and in several brain regions that mediates the biologic effects of ghrelin. Mohamadi, Roberto Salvatori, in Handbook of Neuroendocrinology, 2012. Exon 10 also encodes a 2-kb 3′-UTR of the transcript. The protein-coding region of the GHR gene is encoded by exons 2 through 10. U. Dhagat, ... M.W. The growth hormone-binding protein (GHBP) is a soluble, circulating form of the GH receptor (Herington et al., 1986). There are currently no three-dimensional structures for the IL-36α, IL-36β, IL-36γ and TPO cytokines or the TPO receptor. Growth hormone receptors (GHRs) have been found on the cell surfaces of many tissues throughout the body, including liver, muscle, adipose, and kidney, and in early embryonic and fetal tissue. The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling. Distinguish between the location and function of hydrophilic and lipophilic hormone receptors. Although most GHRs reside on the cell surface and in the endoplasmic reticulum, pronounced nuclear localization is noted in many cells.64 Evidence for the importance of the GHR in growth has come from studies on individuals expressing different mutations located throughout the GHR gene that result in the dwarf phenotype and a GH-insensitive state. Growth hormone receptor antagonists. The hormone is produced as a 217 amino acid precursor protein. 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. The first involves binding of the four α-helical bundle hormone to the elbow between the two FnIII domains of one receptor chain, called Site 1, to form a binary complex (Figure 1, far left). Several short but membrane-anchored isoforms of GH receptor have also been described in humans. 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). This finding has led to the theory of a sequential binding mechanism in which GH binds to two GHRs.69 In this model, GH must first bind to one GHR using a high-affinity receptor binding site, which subsequently allows binding of the second receptor. Distinct cytoplasmic regions of the growth hormone receptor are required for activation of JAK2, mitogen-activated protein kinase, and transcription. Each extracellular domain contains seven β strands arranged to form a sandwich of two antiparallel β sheets. CT-1, cardiotrophin-1; CLC, cardiotrophin-like cytokine; CNTF, cillary neurotrophic factor; EPO, erythropoietin; gp130, glycoprotein 130; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GH, growth hormone; IFN, interferon; IL, interleukin; PRL, prolactin; LIF, leukemia inhibitory factor; OSM, oncostatin-M; TLSP, thymic stromal lymphopoietin (PDB IDs are: 2B51, 4GS7, 3BPO, 3BPL, 3DI2, 3TGX, 3SE4, 1FG9, 1AU1, 1RH2, 3S9D, 2GYS, 3CXE, 3QT2, 4JZJ, 1JLI, 3LB6, 3L5H, 1ALU, 1I1R, 1N26, 2KUM, 1EVS, 1EMR, 3E0G, 1F45, 3D87, 4DOH, 1N1F, 1J7V, 3LQM, 3DLQ, 3OG4, 4HSA, 4JPY, 1ICW, 1I16, 4DKC, 3UF2, 4DEP, 2L5X, 2VXT, 4KC3, 3G9V, 1EER, 3D48, 1CD9, 3HHR, 3HHC, 2Z3Q, 1P9M, 1X6D, 1AX8, 3O4O, 3V60, and 1CNT). 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.

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