Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.
The function that stimulates a cell to grow or proliferate. Most growth factors have other actions besides the induction of cell growth or proliferation.
Evidence
1:
Inferred from Physical InteractionBHF-UCL
J. Clin. Endocrinol. Metab. 82, 3813-3817 (1997)[PubMed:9360546]
Previously, we reported the identification of a new human GH receptor (hGHR) messenger RNA species that encodes a smaller hGHR isoform, termed hGHRtr. Its messenger RNA is expressed in several human tissues and predicts a severely truncated GHR protein that lacks 97.5% of the intracellular domain. Because these two hGHR isoforms, which display similar binding affinity, are coexpressed in several tissues, they may reside side by side and, therefore, interrelate. To further characterize the biological properties of hGHRtr in comparison with hGHR, we generated Chinese hamster ovary (CHO) cell lines stably expressing each of these hGHR isoforms. Cross-linking of [125I]hGH to CHO/hGHRtr cells revealed a majored specific complex with apparent Mr of approximately 100 kDa, which would indicate the hGHRtr to be in molecular mass form of about 80 kDa. When compared with CHO/hGHR, CHO/hGHRtr cells secreted higher amounts of soluble GH-binding protein (GHBP). In contrast to CHO/hGHR cells, CHO/hGHRtr cells did not exhibit any GH-induced receptor down-regulation, and internalization was markedly reduced. Analysis of the constitutive turnover of cellular hGHR and soluble GHBP showed that incubation of CHO/hGHR cells with cycloheximide caused parallel disappearance of hGHR and GHBP. This contrasted with the stability of GHRtr, which showed no decline after cycloheximide treatment for up to 4 h, suggesting that the bulk GHRtr and GHBP may be derived from preformed proteins. Thus, in contrast to hGHR, hGHRtr is fixed at the cell membrane; it undergoes minimal internalization, no down-regulation by hGH, no constitutive turnover for as long as 4 h, but increased capacity to generate a soluble GHBP. Because hGHRtr failed to undergo ligand-induced internalization, the source of the continuous, undisturbed GHBP released into the medium may be from an intracellular storage pool. The relative abundance of these two hGHR isoforms, through regulation of splicing, could be of critical importance in modulating the biological effects of GH.
Binding of human (hGH) and bovine (bGH) GH and ovine PRL (oPRL) has been compared in liver membranes from GH-deficient dwarf "little" mice (lit/lit) and their normal-sized littermates (lit/+). Binding of [125I]hGH to lit/lit membranes was dependent on time, temperature, and membrane concentration and was reversible. Scatchard plots of the binding of [125I]hGH to male and female lit/lit and lit/+ membranes were linear, with no significant differences between binding affinities (overall mean +/- SE, 1.42 +/- 0.27 X 10(9) M-1; n = 24). The hormonal specificity of binding was complex, with hGH being displaced by both somatotropic (bGH) and lactogenic (oPRL) competitors, indicating the presence of a mixed population of receptors. This conclusion was supported by the specific binding of both [125I]bGH and [125I]oPRL to membranes from male and female lit/lit and lit/+ mice. No differences in the specific binding of [125I]bGH to any membrane type was observed, indicating that GH receptors were at normal levels in lit/lit mice despite their deficiency of pituitary and serum GH. A sex difference in hGH and oPRL binding was seen only in normal (lit/+) mice. Male and female lit/lit mice exhibited the same degree of binding as normal female mice. These studies have demonstrated that dwarf little mice have normal levels of hepatic GH and PRL receptors, with binding characteristics not different from those of normal mice. Thus, it would appear that the mechanism of regulation of GH receptors by GH itself is different in this animal model of GH deficiency than in the Snell dwarf mouse and the hypophysectomized rat, where GH receptor levels are very low or absent. The failure of lit/lit mice to grow normally despite normal levels of GH receptor raises questions regarding the site and mechanism of the growth defect in the little mouse.
Evidence
2:
Inferred from Physical InteractionBHF-UCL
A putative growth hormone receptor from rabbit liver and the growth hormone binding protein from rabbit serum have the same amino-terminal amino-acid sequence, indicating that the binding protein corresponds to the extracellular hormone-binding domain of the liver receptor. The complete amino-acid sequences derived from complementary DNA clones encoding the putative human and rabbit growth hormone receptors are not similar to other known proteins, demonstrating a new class of transmembrane receptors.
Evidence
3:
Inferred from Physical InteractionBHF-UCL
Binding of human growth hormone (hGH) to its receptor is required for regulation of normal human growth and development. Examination of the 2.8 angstrom crystal structure of the complex between the hormone and the extracellular domain of its receptor (hGHbp) showed that the complex consists of one molecule of growth hormone per two molecules of receptor. The hormone is a four-helix bundle with an unusual topology. The binding protein contains two distinct domains, similar in some respects to immunoglobulin domains. The relative orientation of these domains differs from that found between constant and variable domains in immunoglobulin Fab fragments. Both hGHbp domains contribute residues that participate in hGH binding. In the complex both receptors donate essentially the same residues to interact with the hormone, even though the two binding sites on hGH have no structural similarity. Generally, the hormone-receptor interfaces match those identified by previous mutational analyses. In addition to the hormone-receptor interfaces, there is also a substantial contact surface between the carboxyl-terminal domains of the receptors. The relative extents of the contact areas support a sequential mechanism for dimerization that may be crucial for signal transduction.
The action characteristic of a hormone, any substance formed in very small amounts in one specialized organ or group of cells and carried (sometimes in the bloodstream) to another organ or group of cells in the same organism, upon which it has a specific regulatory action. The term was originally applied to agents with a stimulatory physiological action in vertebrate animals (as opposed to a chalone, which has a depressant action). Usage is now extended to regulatory compounds in lower animals and plants, and to synthetic substances having comparable effects; all bind receptors and trigger some biological process.
The human pituitary hormones, growth hormone (hGH) and prolactin (hPRL), regulate a large variety of physiological processes, among which are growth and differentiation of muscle, bone and cartilage cells, and lactation. These activities are initiated by hormone-receptor binding. The hGH and hPRL receptors (hGHR and hPRLR, respectively) are single-pass transmembrane receptors from class 1 of the haematopoietic receptor superfamily. This classification is based on sequence similarity in their extracellular domains, notably a highly conserved pentapeptide, the so-called 'WSXWS box', the function of which is controversial. All ligands in class 1 activate their respective receptors by clustering mechanisms. In the case of hGH, activation involves receptor homodimerization in a sequential process: the active ternary complex containing one ligand and two receptor molecules is formed by association of a receptor molecule to an intermediate 1:1 complex. hPRL does not bind to the hGH receptor, but hGH binds to both the hGHR and hPRLR, and mutagenesis studies have shown that the receptor-binding sites on hGH overlap. We present here the crystal structure of the 1:1 complex of hGH bound to the extracellular domain of the hPRLR. Comparisons with the hGH-hGHR complex reveal how hGH can bind to the two distinctly different receptor binding surfaces.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
J. Biol. Chem. 271, 32197-32203 (1996)[PubMed:8943276]
Human growth hormone binds two receptor molecules and thereby induces signal transduction through receptor dimerization. At high concentrations, growth hormone acts as an antagonist because of a large difference in affinities at the respective binding sites. This antagonist action can be enhanced further by reducing binding in the low affinity binding site. A growth hormone antagonist mutant Gly-120 --> Arg, has been crystallized with its receptor as a 1:1 complex and the crystal structure determined at 2.9 A resolution. The 1:1 complex is remarkably similar to the native growth hormone-receptor 1:2 complex. A comparison between the two structures reveals only minimal differences in the conformations of the hormone or its receptor in the two complexes, including the angle between the two immunoglobulin-like domains of the receptor. Further, two symmetry-related 1:1 complexes in the crystal form a 2:2 complex with a large solvent inaccessible area between two receptor molecules. In addition, we present here a native human growth hormone-human growth hormone-binding protein 1:2 complex structure at 2.5 A resolution. One important difference between our structure and the previously published crystal structure at 2.8 A is revealed. Trp-104 in the receptor, a key residue in the hormone-receptor interaction, has an altered conformation in the low affinity site enabling a favorable hydrogen bond to be formed with Asp-116 of the hormone.
Evidence
2:
Inferred from Physical InteractionIntAct
Remodeling of the interface between human growth hormone (hGH) and the extracellular domain of its receptor was studied by deleting a critical tryptophan residue (at position 104) in the receptor, creating a large cavity, and selecting a pentamutant of hGH by phage display that fills the cavity and largely restores binding affinity. A 2.1 A resolution x-ray structure of the mutant complex showed that the receptor cavity was filled by selected hydrophobic mutations of hGH. Large structural rearrangements occurred in the interface at sites that were distant from the mutations. Such plasticity may be a means for protein-protein interfaces to adapt to mutations as they coevolve.
The directed movement of the hexose monosaccharide glucose into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore.
Proc. Natl. Acad. Sci. U.S.A. 94, 5125-5130 (1997)[PubMed:9144201]
The results of this study challenge the widely held view that growth hormone (GH) acts only during the postnatal period. RNA phenotyping shows transcripts for the GH receptor and GH-binding protein in mouse preimplantation embryos of all stages from fertilized eggs (day 1) to blastocysts (day 4). An antibody specific to the cytoplasmic region of the GH receptor revealed receptor protein expression, first in two-cell embryos, the stage of activation of the embryonic genome (day 2), and in all subsequent stages. In cleavage-stage embryos this immunoreactivity was localized mainly to the nucleus, but clear evidence of membrane labeling was apparent in blastocysts. GH receptor immunoreactivity was also observed in cumulus cells associated with unfertilized oocytes but not in the unfertilized oocytes. The blastocyst receptor was demonstrated to be functional, exhibiting the classic bell-shaped dose-response curves for GH stimulation of both 3-O-methyl glucose transport and protein synthesis. Maximal stimulation of 40-50% was seen for both responses at less than 1 ng/ml recombinant GH, suggesting a role for maternal GH. However mRNA transcripts for GH were also detected from the morula stage (day 3) by using reverse transcription-PCR, and GH immunoreactivity was seen in blastocysts. These observations raise the possibility of a paracrine/autocrine GH loop regulating embryonic development in its earliest stages.
J. Biol. Chem. 269, 21709-21717 (1994)[PubMed:8063815]
Growth hormone (GH) has recently been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2. In the present study, regions of the GHR required for JAK2 association with GHR were identified. GH-dependent JAK2 association with GHR was detected in Chinese hamster ovary (CHO) cells expressing wild-type GHR (GHR1-638) or GHR truncated at amino acid 454 (GHR1-454) or 380 (GHR1-380). JAK2 did not associate with GHR in cells expressing GHR truncated at amino acid 294 (GHR1-294) or when amino acids 297-311 containing a proline-rich motif were deleted (GHR delta P) or prolines 300, 301, 303, and 305 in the proline-rich motif were mutated to alanines (GHR4P-->A). Cross-linking 125I-human GH to GHR demonstrated that GHR mutants migrated with the appropriate molecular weight, with the exception of GHR4P-->A which migrated as a protein similar in size to GHR1-294. In studies performed in CHO and RIN-5AH cells, the ability of JAK2 to associate with the mutated GHR was found to correlate with GH-dependent activation of JAK2, tyrosyl phosphorylation of GHR (in the case of GHR1-638 and GHR1-454), and the ability of the GHR to copurify with tyrosine kinase activity. In CHO cells expressing mutated GHR, GH-dependent tyrosyl phosphorylation of cellular proteins (p121, p97, p42, and p39) was dependent on the ability to activate JAK2. No proteins showed increased tyrosyl phosphorylation in CHO cells expressing GHR1-294, GHR4P-->A, or GHR delta P. Deletion of the C-terminal half (amino acids 455-638) of the GHR ablated GH-dependent tyrosyl phosphorylation of p97. Taken together, these results provide strong evidence that the N-terminal quarter of the cytoplasmic domain of GHR and within this region, the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2, and that tyrosines in the N-terminal half of the cytoplasmic domain of the GHR are phosphorylated by JAK2. The finding that a specific interaction with the C-terminal half of GHR appears to be necessary for p97 phosphorylation indicates that while JAK2 activation may be necessary for a full biological response to GH, it appears not to be sufficient.
Any process in which STAT proteins (Signal Transducers and Activators of Transcription) and JAK (Janus Activated Kinase) proteins convey a signal to trigger a change in the activity or state of a cell. The JAK-STAT cascade begins with activation of STAT proteins by members of the JAK family of tyrosine kinases, proceeds through dimerization and subsequent nuclear translocation of STAT proteins, and ends with regulation of target gene expression by STAT proteins.
J. Biol. Chem. 269, 21709-21717 (1994)[PubMed:8063815]
Growth hormone (GH) has recently been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2. In the present study, regions of the GHR required for JAK2 association with GHR were identified. GH-dependent JAK2 association with GHR was detected in Chinese hamster ovary (CHO) cells expressing wild-type GHR (GHR1-638) or GHR truncated at amino acid 454 (GHR1-454) or 380 (GHR1-380). JAK2 did not associate with GHR in cells expressing GHR truncated at amino acid 294 (GHR1-294) or when amino acids 297-311 containing a proline-rich motif were deleted (GHR delta P) or prolines 300, 301, 303, and 305 in the proline-rich motif were mutated to alanines (GHR4P-->A). Cross-linking 125I-human GH to GHR demonstrated that GHR mutants migrated with the appropriate molecular weight, with the exception of GHR4P-->A which migrated as a protein similar in size to GHR1-294. In studies performed in CHO and RIN-5AH cells, the ability of JAK2 to associate with the mutated GHR was found to correlate with GH-dependent activation of JAK2, tyrosyl phosphorylation of GHR (in the case of GHR1-638 and GHR1-454), and the ability of the GHR to copurify with tyrosine kinase activity. In CHO cells expressing mutated GHR, GH-dependent tyrosyl phosphorylation of cellular proteins (p121, p97, p42, and p39) was dependent on the ability to activate JAK2. No proteins showed increased tyrosyl phosphorylation in CHO cells expressing GHR1-294, GHR4P-->A, or GHR delta P. Deletion of the C-terminal half (amino acids 455-638) of the GHR ablated GH-dependent tyrosyl phosphorylation of p97. Taken together, these results provide strong evidence that the N-terminal quarter of the cytoplasmic domain of GHR and within this region, the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2, and that tyrosines in the N-terminal half of the cytoplasmic domain of the GHR are phosphorylated by JAK2. The finding that a specific interaction with the C-terminal half of GHR appears to be necessary for p97 phosphorylation indicates that while JAK2 activation may be necessary for a full biological response to GH, it appears not to be sufficient.
Any process that increase the frequency or rate of activation of JAK2 protein. The activation of JAK2 protein is the process of introducing a phosphate group to a tyrosine residue of a JAK2 (Janus Activated Kinase 2) protein, thereby activating it.
J. Biol. Chem. 269, 21709-21717 (1994)[PubMed:8063815]
Growth hormone (GH) has recently been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2. In the present study, regions of the GHR required for JAK2 association with GHR were identified. GH-dependent JAK2 association with GHR was detected in Chinese hamster ovary (CHO) cells expressing wild-type GHR (GHR1-638) or GHR truncated at amino acid 454 (GHR1-454) or 380 (GHR1-380). JAK2 did not associate with GHR in cells expressing GHR truncated at amino acid 294 (GHR1-294) or when amino acids 297-311 containing a proline-rich motif were deleted (GHR delta P) or prolines 300, 301, 303, and 305 in the proline-rich motif were mutated to alanines (GHR4P-->A). Cross-linking 125I-human GH to GHR demonstrated that GHR mutants migrated with the appropriate molecular weight, with the exception of GHR4P-->A which migrated as a protein similar in size to GHR1-294. In studies performed in CHO and RIN-5AH cells, the ability of JAK2 to associate with the mutated GHR was found to correlate with GH-dependent activation of JAK2, tyrosyl phosphorylation of GHR (in the case of GHR1-638 and GHR1-454), and the ability of the GHR to copurify with tyrosine kinase activity. In CHO cells expressing mutated GHR, GH-dependent tyrosyl phosphorylation of cellular proteins (p121, p97, p42, and p39) was dependent on the ability to activate JAK2. No proteins showed increased tyrosyl phosphorylation in CHO cells expressing GHR1-294, GHR4P-->A, or GHR delta P. Deletion of the C-terminal half (amino acids 455-638) of the GHR ablated GH-dependent tyrosyl phosphorylation of p97. Taken together, these results provide strong evidence that the N-terminal quarter of the cytoplasmic domain of GHR and within this region, the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2, and that tyrosines in the N-terminal half of the cytoplasmic domain of the GHR are phosphorylated by JAK2. The finding that a specific interaction with the C-terminal half of GHR appears to be necessary for p97 phosphorylation indicates that while JAK2 activation may be necessary for a full biological response to GH, it appears not to be sufficient.
Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. 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. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
N. Engl. J. Med. 333, 1093-1098 (1995)[PubMed:7565946]
BACKGROUND: Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein. METHODS: We studied 14 children with idiopathic short stature who were selected on the basis of normal GH secretion and low serum concentrations of GH-binding protein. Analysis of single-strand conformation polymorphisms and DNA sequencing were both used to identify mutations in the GH-receptor gene. RESULTS: Mutations in the region of the GH-receptor gene that codes for the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that reduced the affinity of the receptor for GH and a second mutation that may affect a function other than ligand binding. The remaining three children had single mutations in one allele of the gene. One mutation introduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor. CONCLUSIONS: Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene.
GH-induced activation of JAK2, a GH receptor (GHR)-associated tyrosine kinase, leads to tyrosine phosphorylation and activation of STATs (signal transducers and activators of transcription) 1, 3, and 5. The present study investigates the importance of the GHR cytoplasmic domain in the activation of STAT3 and STAT5b. As the perimembranous Box1 region of the GHR cytoplasmic domain is necessary for activation of wild-type (WT) JAK2 by GH, we examined this question using GHR/JAK2 chimeras that have an activatable JAK2 kinase domain replacing the GHR cytoplasmic domain. STAT5b and STAT3, when each was coexpressed in COS-7 cells with WT GHR and WT JAK2, were both strongly tyrosine phosphorylated in response to GH. Coexpression of STAT3 with GHR/ JAK2 chimeras resulted in a strong GH-independent tyrosine phosphorylation of STAT3 that was 40% as active as that seen with WT GHR plus WT JAK2, whereas STAT5b was more minimally phosphorylated (13% of WT GHR plus WT JAK2) when coexpressed with chimeras devoid of the GHR cytoplasmic domain. Transient coexpression of each STAT together with WT JAK2 and GHR COOH-terminal truncation mutants indicated that a GH-induced STAT3-DNA binding complex, but not a STAT5b-DNA binding complex, was detectable when a GHR devoid of 85% of the cytoplasmic domain COOH-terminus (but eliciting significant JAK2 tyrosine phosphorylation) was expressed. In vitro binding experiments using GST/GHR cytoplasmic domain fusions demonstrated that both STATs could interact at a low basal level with GHR regions distal to residue 317. Phosphorylation of tyrosine residues in those distal regions greatly enhanced the receptor's interaction with STAT5b, but not STAT3. 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).
J. Biol. Chem. 269, 21709-21717 (1994)[PubMed:8063815]
Growth hormone (GH) has recently been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2. In the present study, regions of the GHR required for JAK2 association with GHR were identified. GH-dependent JAK2 association with GHR was detected in Chinese hamster ovary (CHO) cells expressing wild-type GHR (GHR1-638) or GHR truncated at amino acid 454 (GHR1-454) or 380 (GHR1-380). JAK2 did not associate with GHR in cells expressing GHR truncated at amino acid 294 (GHR1-294) or when amino acids 297-311 containing a proline-rich motif were deleted (GHR delta P) or prolines 300, 301, 303, and 305 in the proline-rich motif were mutated to alanines (GHR4P-->A). Cross-linking 125I-human GH to GHR demonstrated that GHR mutants migrated with the appropriate molecular weight, with the exception of GHR4P-->A which migrated as a protein similar in size to GHR1-294. In studies performed in CHO and RIN-5AH cells, the ability of JAK2 to associate with the mutated GHR was found to correlate with GH-dependent activation of JAK2, tyrosyl phosphorylation of GHR (in the case of GHR1-638 and GHR1-454), and the ability of the GHR to copurify with tyrosine kinase activity. In CHO cells expressing mutated GHR, GH-dependent tyrosyl phosphorylation of cellular proteins (p121, p97, p42, and p39) was dependent on the ability to activate JAK2. No proteins showed increased tyrosyl phosphorylation in CHO cells expressing GHR1-294, GHR4P-->A, or GHR delta P. Deletion of the C-terminal half (amino acids 455-638) of the GHR ablated GH-dependent tyrosyl phosphorylation of p97. Taken together, these results provide strong evidence that the N-terminal quarter of the cytoplasmic domain of GHR and within this region, the proline-rich motif, is required for association of JAK2 with GHR and GH-dependent activation of JAK2, and that tyrosines in the N-terminal half of the cytoplasmic domain of the GHR are phosphorylated by JAK2. The finding that a specific interaction with the C-terminal half of GHR appears to be necessary for p97 phosphorylation indicates that while JAK2 activation may be necessary for a full biological response to GH, it appears not to be sufficient.
N. Engl. J. Med. 333, 1093-1098 (1995)[PubMed:7565946]
BACKGROUND: Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein. METHODS: We studied 14 children with idiopathic short stature who were selected on the basis of normal GH secretion and low serum concentrations of GH-binding protein. Analysis of single-strand conformation polymorphisms and DNA sequencing were both used to identify mutations in the GH-receptor gene. RESULTS: Mutations in the region of the GH-receptor gene that codes for the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that reduced the affinity of the receptor for GH and a second mutation that may affect a function other than ligand binding. The remaining three children had single mutations in one allele of the gene. One mutation introduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor. CONCLUSIONS: Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene.
J. Clin. Endocrinol. Metab. 76, 1224-1228 (1993)[PubMed:8496314]
The GH1 genes of probands of two families with familial isolated GH deficiency (IGHD) were sequenced. Double stranded sequencing of the polymerase chain reaction (PCR) amplification products from genomic DNA of two affected cousins in a consanguineous Turkish family revealed a G-->A transition in the 20th codon of the GH1 signal peptide. This substitution converts a TGG (Trp) to a TAG (stop) codon and generates a new AluI recognition site. PCR amplification of the GH1 alleles of family members, followed by AluI digestion, revealed that the G-->A transition segregated with the IGHD phenotype. In a Saudi Arabian family, a G-->C transversion was found that alters the first base of the donor splice site of intron IV. This substitution should perturb mRNA splicing, resulting in an altered protein product which should be unstable or bioinactive. This transversion also destroys an HphI site, which was used to assay samples from relatives. Digestion of PCR amplification products with HphI demonstrated cosegregation of the G-->C transversion with IGHD. These results demonstrate that familial IGHD is a heterogeneous disease that perturbs different steps in the expression of the GH1 gene.
J. Biol. Chem. 270, 14685-14692 (1995)[PubMed:7782332]
The identification of JAK2 as a growth hormone (GH) receptor-associated, GH-activated tyrosine kinase has established tyrosyl phosphorylation as a signaling mechanism for GH. In the present study, GH is shown to stimulate tyrosyl phosphorylation of insulin receptor substrate 1 (IRS-1), the principle substrate of the insulin receptor. Tyrosyl phosphorylation of IRS-1 is a critical step in insulin signaling and provides binding sites for proteins with the appropriate Src homology 2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol (PI) 3'-kinase. In 3T3-F442A fibroblasts, GH-dependent tyrosyl phosphorylation of IRS-1 was detected by 1 min and at GH concentrations as low as 5 ng/ml (0.23 nM). Tyrosyl phosphorylation of IRS-1 was transient, with maximal stimulation detected at 30 min and diminished signal detected at 60 min. The ability of GH receptor (GHR) to transduce the signal for IRS-1 tyrosyl phosphorylation is mediated by the intracellular region of GHR between amino acids 295 and 380 by a mechanism not involving the two tyrosines in this region. This region of GHR is required for GH-dependent JAK2 association and activation (VanderKuur, J. A., Wang, X., Zhang, L., Campbell, G. S., Allevato, G., Billestrup, N., Norstedt, G., and Carter-Su, C. (1994) J. Biol. Chem. 269, 21709-21717). When other cytokines that activate JAK2 were tested for the ability to stimulate the tyrosyl phosphorylation of IRS-1, stimulation was detected with interferon-gamma and leukemia inhibitory factor. The correlation between JAK2 tyrosyl phosphorylation and IRS-1 tyrosyl phosphorylation in response to GH, interferon-gamma, and leukemia inhibitory factor and in cells expressing different GHR mutants, provides evidence that IRS-1 may interact with JAK2 or an auxiliary molecule that binds to JAK2. GH is also shown to stimulate binding of IRS-1 to the 85-kDa regulatory subunit of PI 3'-kinase. The ability of GH to stimulate tyrosyl phosphorylation of IRS-1 and its association with PI 3'-kinase provides a biochemical basis for responses shared by insulin and GH including the well characterized insulin-like metabolic effects of GH observed in a variety of cell types.
J. Biol. Chem. 270, 14685-14692 (1995)[PubMed:7782332]
The identification of JAK2 as a growth hormone (GH) receptor-associated, GH-activated tyrosine kinase has established tyrosyl phosphorylation as a signaling mechanism for GH. In the present study, GH is shown to stimulate tyrosyl phosphorylation of insulin receptor substrate 1 (IRS-1), the principle substrate of the insulin receptor. Tyrosyl phosphorylation of IRS-1 is a critical step in insulin signaling and provides binding sites for proteins with the appropriate Src homology 2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol (PI) 3'-kinase. In 3T3-F442A fibroblasts, GH-dependent tyrosyl phosphorylation of IRS-1 was detected by 1 min and at GH concentrations as low as 5 ng/ml (0.23 nM). Tyrosyl phosphorylation of IRS-1 was transient, with maximal stimulation detected at 30 min and diminished signal detected at 60 min. The ability of GH receptor (GHR) to transduce the signal for IRS-1 tyrosyl phosphorylation is mediated by the intracellular region of GHR between amino acids 295 and 380 by a mechanism not involving the two tyrosines in this region. This region of GHR is required for GH-dependent JAK2 association and activation (VanderKuur, J. A., Wang, X., Zhang, L., Campbell, G. S., Allevato, G., Billestrup, N., Norstedt, G., and Carter-Su, C. (1994) J. Biol. Chem. 269, 21709-21717). When other cytokines that activate JAK2 were tested for the ability to stimulate the tyrosyl phosphorylation of IRS-1, stimulation was detected with interferon-gamma and leukemia inhibitory factor. The correlation between JAK2 tyrosyl phosphorylation and IRS-1 tyrosyl phosphorylation in response to GH, interferon-gamma, and leukemia inhibitory factor and in cells expressing different GHR mutants, provides evidence that IRS-1 may interact with JAK2 or an auxiliary molecule that binds to JAK2. GH is also shown to stimulate binding of IRS-1 to the 85-kDa regulatory subunit of PI 3'-kinase. The ability of GH to stimulate tyrosyl phosphorylation of IRS-1 and its association with PI 3'-kinase provides a biochemical basis for responses shared by insulin and GH including the well characterized insulin-like metabolic effects of GH observed in a variety of cell types.
J. Clin. Endocrinol. Metab. 82, 3813-3817 (1997)[PubMed:9360546]
Previously, we reported the identification of a new human GH receptor (hGHR) messenger RNA species that encodes a smaller hGHR isoform, termed hGHRtr. Its messenger RNA is expressed in several human tissues and predicts a severely truncated GHR protein that lacks 97.5% of the intracellular domain. Because these two hGHR isoforms, which display similar binding affinity, are coexpressed in several tissues, they may reside side by side and, therefore, interrelate. To further characterize the biological properties of hGHRtr in comparison with hGHR, we generated Chinese hamster ovary (CHO) cell lines stably expressing each of these hGHR isoforms. Cross-linking of [125I]hGH to CHO/hGHRtr cells revealed a majored specific complex with apparent Mr of approximately 100 kDa, which would indicate the hGHRtr to be in molecular mass form of about 80 kDa. When compared with CHO/hGHR, CHO/hGHRtr cells secreted higher amounts of soluble GH-binding protein (GHBP). In contrast to CHO/hGHR cells, CHO/hGHRtr cells did not exhibit any GH-induced receptor down-regulation, and internalization was markedly reduced. Analysis of the constitutive turnover of cellular hGHR and soluble GHBP showed that incubation of CHO/hGHR cells with cycloheximide caused parallel disappearance of hGHR and GHBP. This contrasted with the stability of GHRtr, which showed no decline after cycloheximide treatment for up to 4 h, suggesting that the bulk GHRtr and GHBP may be derived from preformed proteins. Thus, in contrast to hGHR, hGHRtr is fixed at the cell membrane; it undergoes minimal internalization, no down-regulation by hGH, no constitutive turnover for as long as 4 h, but increased capacity to generate a soluble GHBP. Because hGHRtr failed to undergo ligand-induced internalization, the source of the continuous, undisturbed GHBP released into the medium may be from an intracellular storage pool. The relative abundance of these two hGHR isoforms, through regulation of splicing, could be of critical importance in modulating the biological effects of GH.
Any process that activates or increases the frequency, rate or extent of the introduction of a phosphate group to a tyrosine residue of a Stat3 protein.
GH-induced activation of JAK2, a GH receptor (GHR)-associated tyrosine kinase, leads to tyrosine phosphorylation and activation of STATs (signal transducers and activators of transcription) 1, 3, and 5. The present study investigates the importance of the GHR cytoplasmic domain in the activation of STAT3 and STAT5b. As the perimembranous Box1 region of the GHR cytoplasmic domain is necessary for activation of wild-type (WT) JAK2 by GH, we examined this question using GHR/JAK2 chimeras that have an activatable JAK2 kinase domain replacing the GHR cytoplasmic domain. STAT5b and STAT3, when each was coexpressed in COS-7 cells with WT GHR and WT JAK2, were both strongly tyrosine phosphorylated in response to GH. Coexpression of STAT3 with GHR/ JAK2 chimeras resulted in a strong GH-independent tyrosine phosphorylation of STAT3 that was 40% as active as that seen with WT GHR plus WT JAK2, whereas STAT5b was more minimally phosphorylated (13% of WT GHR plus WT JAK2) when coexpressed with chimeras devoid of the GHR cytoplasmic domain. Transient coexpression of each STAT together with WT JAK2 and GHR COOH-terminal truncation mutants indicated that a GH-induced STAT3-DNA binding complex, but not a STAT5b-DNA binding complex, was detectable when a GHR devoid of 85% of the cytoplasmic domain COOH-terminus (but eliciting significant JAK2 tyrosine phosphorylation) was expressed. In vitro binding experiments using GST/GHR cytoplasmic domain fusions demonstrated that both STATs could interact at a low basal level with GHR regions distal to residue 317. Phosphorylation of tyrosine residues in those distal regions greatly enhanced the receptor's interaction with STAT5b, but not STAT3. 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).
Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. 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. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
Any process that activates or increases the frequency, rate or extent of the introduction of a phosphate group to a tyrosine residue of a Stat5 protein.
GH-induced activation of JAK2, a GH receptor (GHR)-associated tyrosine kinase, leads to tyrosine phosphorylation and activation of STATs (signal transducers and activators of transcription) 1, 3, and 5. The present study investigates the importance of the GHR cytoplasmic domain in the activation of STAT3 and STAT5b. As the perimembranous Box1 region of the GHR cytoplasmic domain is necessary for activation of wild-type (WT) JAK2 by GH, we examined this question using GHR/JAK2 chimeras that have an activatable JAK2 kinase domain replacing the GHR cytoplasmic domain. STAT5b and STAT3, when each was coexpressed in COS-7 cells with WT GHR and WT JAK2, were both strongly tyrosine phosphorylated in response to GH. Coexpression of STAT3 with GHR/ JAK2 chimeras resulted in a strong GH-independent tyrosine phosphorylation of STAT3 that was 40% as active as that seen with WT GHR plus WT JAK2, whereas STAT5b was more minimally phosphorylated (13% of WT GHR plus WT JAK2) when coexpressed with chimeras devoid of the GHR cytoplasmic domain. Transient coexpression of each STAT together with WT JAK2 and GHR COOH-terminal truncation mutants indicated that a GH-induced STAT3-DNA binding complex, but not a STAT5b-DNA binding complex, was detectable when a GHR devoid of 85% of the cytoplasmic domain COOH-terminus (but eliciting significant JAK2 tyrosine phosphorylation) was expressed. In vitro binding experiments using GST/GHR cytoplasmic domain fusions demonstrated that both STATs could interact at a low basal level with GHR regions distal to residue 317. Phosphorylation of tyrosine residues in those distal regions greatly enhanced the receptor's interaction with STAT5b, but not STAT3. 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).
Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. 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. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of stimulus by estradiol, a C18 steroid hormone hydroxylated at C3 and C17 that acts as a potent estrogen.
Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. 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. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
Protein which functions as a hormone, a biochemical substance secreted by specialized cells that affects the metabolism or behavior of other cells which possess functional receptors for the hormone. Hormones may be hydrophilic, like insulin, in which case the receptors are on the cell surface, or lipophilic, like the steroids, where the receptor can be intracellular.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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