The proline-rich region of the GH receptor is essential for JAK2 phosphorylation, activation of cell proliferation, and gene transcription.

Dinerstein, H.; Lago, Francisca; Goujon, Laure; Ferrag, Fatima; Esposito, Nazario; Finidori, J.; Kelly, Paul A.; Postel-Vinay, Marie-Catherine

doi:10.1210/mend.9.12.8614406

Cited by 23 publications

(19 citation statements)

References 14 publications

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“…Both sbGHR1 and sbGHR2 could activate the Spi 2·1 and -casein promoters upon receptor stimulation. It has been reported previously that association of JAK2 to the Box1 motif as well as the presence of the C-terminal portion of the intracellular tail are essential in mediating Spi 2·1 promoter activation by mammalian GHR (Goujon et al 1994, Sotiropoulos et al 1994, Dinerstein et al 1995, Gong et al 1998. Moreover, rat GHR was able to activate the -casein promoter by stimulating the phosphorylation of the signal transducers and activators of transcription-(STAT)1 and STAT5 proteins (Smit et al 1997, Gerland et al 2000.…”

Section: Discussionmentioning

confidence: 98%

The co-existence of two growth hormone receptors in teleost fish and their differential signal transduction, tissue distribution and hormonal regulation of expression in seabream

Jiao

Huang²,

Chan³

et al. 2006

Journal of Molecular Endocrinology

148

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Two genomic contigs of putative growth hormone receptors (GHRs) were identified in fugu and zebrafish genomes by in silico analysis, suggesting the presence of two GHR subtypes in a single teleost species. We have tested this hypothesis by cloning the full-length cDNA sequence of a second GHR subtype from the black seabream in which the first GHR subtype had been previously reported by us. In addition, we had also cloned the sequences of both GHR subtypes from two other fish species, namely the Southern catfish and the Nile tilapia. Phylogenetic analysis of known GHR sequences from various vertebrates revealed that fish GHRs cluster into two distinct clades, viz. GHR1 and GHR2. One clade (GHR1), containing 6 to 7 extracellular cysteine residues, is structurally more akin to the non-teleost GHRs. The other clade (GHR2), containing only 4 to 5 extracellular cysteine residues, is unique to teleosts and is structurally more divergent from the non-teleost GHRs. In addition, we had examined the biological activities of both GHR subtypes from seabream using a number of reporter transcription assays in cultured eukaryotic cells and demonstrated that both of them were able to activate the Spi 2·1 and -casein promoters upon receptor stimulation in a ligand specific manner. In contrast, only GHR1 but not GHR2 in seabream could trigger the c-fos promoter activity, indicating that the two GHR subtypes possess some differences in their signal transduction mechanisms. Also, the expression of GHR2 is significantly higher than GHR1 in many tissues of the seabream including the gonad, kidney, muscle, pituitary and spleen. In vivo hormone treatment data indicated that cortisol upregulated hepatic GHR1 expression in seabream but not GHR2, whereas testosterone decreased hepatic GHR2 expression but not GHR1. On the other hand, hepatic expression of both GHR1 and GHR2 in seabream was decreased by estradiol treatment.

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Section: Discussionmentioning

confidence: 98%

The co-existence of two growth hormone receptors in teleost fish and their differential signal transduction, tissue distribution and hormonal regulation of expression in seabream

Jiao

Huang²,

Chan³

et al. 2006

Journal of Molecular Endocrinology

148

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“…The ICD of sbPRLR comprises 284 amino acids and contains the proline-rich motif (box 1), which shares 100% identity with all PRLRs known so far. This is by far the most highly conserved region within the PRLRs ICD among cytokine receptors and it plays an important role in the signal transduction pathway (Dinerstein et al, 1995;Pezet et al, 1997). The ICD of different PRLR forms varies in size and several isoforms of PRLR which differ from each other in length and composition have been found in the same species (Boutin et al, , 1988Shirota et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Cloning, Characterization, and Tissue Distribution of Prolactin Receptor in the Sea Bream (Sparus aurata)

Santos

Ingleton²,

Cavaco

et al. 2001

General and Comparative Endocrinology

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The prolactin receptor (PRLR) was cloned and its tissue distribution characterized in adults of the protandrous hermaphrodite marine teleost, the sea bream (Sparus aurata). An homologous cDNA probe for sea bream PRLR (sbPRLR) was obtained by RT-PCR using gill mRNA. This probe was used to screen intestine and kidney cDNA libraries from which two overlapping clones (1100 and 2425 bp, respectively) were obtained. These clones had 100% sequence identity in the overlapping region (893 bp) and were used to deduce the complete amino acid sequence of sbPRLR. The receptor spans 2640 bp and encodes a protein of 537 amino acids. Features characteristic of PRLR, two pairs of cysteines, WS box, hydrophobic transmembrane domain, box 1, and box 2, were identified and showed a high degree of sequence identity to PRLRs from other vertebrate species. SbPRLR is 29 and 32% identical to tilapia (Oreochromis niloticus) and goldfish (Carassius auratus) PRLRs, respectively. In the sea bream two PRLR transcripts of 2.8 and 3.2 kb were detected in the intestine, kidney, and gills and a single transcript of 2.8 kb was detected in skin and pituitary by Northern blot. Spermiating gonads (more than 95% male tissue; gonado-somatic index of 0.6) contained, in addition to the 2.8-kb transcript, three more transcripts of 1.9, 1.3, and 1.1 kb. RT-PCR, which is a far more sensitive method than Northern blot, detected PRLR mRNA in gills, intestine, brain, pituitary, kidney, liver, gonads, spleen, head-kidney, heart, muscle, and bone. Immunohistochemistry using specific polyclonal antibodies raised against an oligopeptide from the extracellular domain of sbPRLR detected PRLR in several epithelial tissues of juvenile sea bream, including the anterior gut, renal tubule, choroid membrane of the third ventricle, saccus vasculosus, branchial chloride cells, and branchial cartilage.

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“…Membrane protein (300 µg) was incubated with 125 I-hGH (1·5 10 5 c.p.m.) as described in Dinerstein et al (1995). Bound and free hormones were separated by centrifugation at 17 000 g for 15 min, and the radioactivity in the pellet was counted.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…Cells were incubated for 24 h with serum-free medium containing 20 nM hGH and 250 mM dexamethasone or 250 mM dexamethasone alone. Cells were lyzed as described previously (Dinerstein et al 1995) and whole cell extracts were used for determination of luciferase and -galactosidase activities. Luciferase activity was normalized to -galactosidase activity.…”

Section: Transcription Assaysmentioning

confidence: 99%

The D152H mutation found in growth hormone insensitivity syndrome impairs expression and function of human growth hormone receptor but is silent in rat receptor

Esposito¹,

Wojcik²,

Chomilier³

et al. 1998

Journal of Molecular Endocrinology

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In two patients with growth hormone (GH) insensitivity syndrome (Laron syndrome), in whom the GH receptor is able to bind the hormone, the D152H mutation was identified, and lack of dimerization was proposed to explain GH resistance in these patients. To examine further the consequences of the substitution of conserved aspartate 152 on the function of the GH receptor (GHR), we reproduced the mutation in vitro on the full length GH receptor cDNA from man and rat. Effects of the mutation on expression and activity of the GHR were analyzed in 293 cells transfected with wild-type and mutant GHR cDNAs. Mutant human receptor protein was expressed at a lower level than wild-type receptor and its activity was reduced: GH-dependent signal transducer and activator of transcription 5 (Stat5)-mediated transactivation of a reporter gene was lower in 293 cells transfected with mutant GHR cDNA than in transfected cells expressing a comparable level of wild-type GHR. The membrane-bound form of the mutant and of the wild-type human GHR were able to homodimerize, as suggested by the size of the complexes detected in cross-linking experiments with 125 I-human (h) GH, and also by the activity in the functional test. With the soluble GHR resulting from proteolysis of the wild-type membrane form, no dimeric complexes could be detected. However, when a soluble receptor lacking the transmembrane and cytoplasmic domains of the receptor was expressed, wild-type and not mutant GH binding protein (GHBP) was able to form dimers in the presence of hGH. The amino acid substitution has no effect on either expression or function of the rat receptor. Structural modeling of D152H soluble human and rat GHR (GHBP) supports the species-specific functional consequences of the mutation. Evaluation of the functional importance of the mutation strongly suggests that impairment in expression and activity of the mutant receptor, rather than complete lack of dimerization, explains the GH resistance of the patients.

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The proline-rich region of the GH receptor is essential for JAK2 phosphorylation, activation of cell proliferation, and gene transcription.

Cited by 23 publications

References 14 publications

The co-existence of two growth hormone receptors in teleost fish and their differential signal transduction, tissue distribution and hormonal regulation of expression in seabream

The co-existence of two growth hormone receptors in teleost fish and their differential signal transduction, tissue distribution and hormonal regulation of expression in seabream

Cloning, Characterization, and Tissue Distribution of Prolactin Receptor in the Sea Bream (Sparus aurata)

The D152H mutation found in growth hormone insensitivity syndrome impairs expression and function of human growth hormone receptor but is silent in rat receptor

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