Expression of two isoforms of the human growth hormone receptor in normal liver and hepatocarcinoma

Esposito, Nazario; Paterlini, P.; Kelly, Paul A.; Postel-Vinay, Marie-Catherine; Finidori, J.

doi:10.1016/0303-7207(94)90064-7

Cited by 35 publications

(22 citation statements)

References 18 publications

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“…The variable expression of hGHR isoforms indicated an influence on splicing, but it was difficult to correlate the appearance of the splicing patterns with any known parameters. Esposito et al (7) suggested that the exclusion of exon 3 was random in nature, but we found it difficult to comprehend that an exon would be alternatively spliced in an uncontrolled fashion.…”

Section: Discussioncontrasting

confidence: 39%

“…It was originally reported that hGHRd3 expression was limited to placental villi and amnion (4,6), whereas hGHRwt was found only in chorion and decidua (4). However, both isoforms were observed in normal adult hepatic tissue and in fetal and cancerous liver samples, indicating isoform expression was not tissue-specific or developmentally regulated (7). Likewise, both isoforms were expressed in 19 different tissues obtained from autopsied individuals (8).…”

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confidence: 95%

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Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Stallings-Mann

Ludwiczak

Klinger

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Two isoforms of the human growth hormone receptor (hGHR), which differ in the presence (hGHRwt) or absence (hGHRd3) of exon 3, are expressed in the placenta. Specifically, three expression patterns are observed: only hGHRwt, only hGHRd3, or an approximately 1:1 combination of both isoforms. We investigated several potential regulatory mechanisms which might account for the expression of the hGHR isoforms. The frequency of hGHRd3 expression did not change when placentas from differing stages of gestation were examined, suggesting splicing was not developmentally regulated. However, when hGHR isoform expression patterns were examined in each component of a given placenta, it was evident that alternative splicing of exon 3 is individualspecific. Surprisingly, the individual-specific regulation of hGHR isoforms appears to be the result of a polymorphism in the hGHR gene. We analyzed hGHRwt and hGHRd3 expression in Hutterite pedigrees, and our results are consistent with a simple Mendelian inheritance of two differing alleles in which exon 3 is spliced in an "all-or-none" fashion. We conclude the alternative splicing of exon 3 in hGHR transcripts is the result of an unusual polymorphism which significantly alters splicing of the hGHR transcript and that the relatively high frequency ("10O%) of homozygous hGHRd3 expression suggests the possibility it may play a role in polygenic determined events.In humans, chorionic somatomammotropin (hCS) and growth hormone (hGH) are encoded by a family of genes clustered on chromosome 17 (1). At least two forms of each hormone are encoded by separate genes for both hCS (hCS-A and hCS-B) and hGH (hGH-N and hGH-V). hGH-N, which is expressed only in the anterior lobe of the pituitary, is best known for its effects on the growth of skeletal and soft tissues and for its metabolic actions. The remaining proteins are expressed exclusively in the placenta. Their precise function remains obscure, and the picture is further complicated by the presence of alternatively spliced mRNAs that can give rise to additional isoforms.The synthesis and secretion of hCS, hGH-V, and their multiple isoforms in the placenta raises an important question as to whether a single receptor mediates the activity of these proteins or if different receptors exist. A receptor for hGH (hGHR) has been cloned (2) and shown to belong to the cytokine receptor family (3). A second, alternatively

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Section: Discussioncontrasting

confidence: 39%

mentioning

confidence: 95%

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Stallings-Mann

Ludwiczak

Klinger

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…Whereas no meaningful differences in the biological properties between the two isoforms have been discovered until now (10,11,20), a change in the conformation of the receptor complex due to different combinations of its monomeric constituents may influence downstream signaling after binding of the ligand (12). The missing 22 amino acids in the extracellular part of the E3(2 )GHR isoform that are encoded by exon 3 do not harbor any significant motifs for phosphorylation or glycosylation as found by searching the PROSITE database (http://www.ebi.ac.uk/ ppsearch/).…”

Section: Discussionmentioning

confidence: 99%

“…As far as ligand specificity, ligand affinity and the general ability to shed GHBP are concerned (11,19,20), the typical biological properties of E3(2 )GHR do not differ from the full-length GHR. However, the possibility that the missing amino acids affect signal transduction properties of the receptor cannot be ruled out and remains to be examined (21).…”

Section: Introductionmentioning

confidence: 99%

Association between the GH receptor/exon 3 genotype and the level of exon 3-positive GH-binding protein in human serum

Seidel

Glasow²,

Schütt³

et al. 2003

European Journal of Endocrinology

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Objective: The human GH-binding protein (GHBP) is derived from the GH receptor (GHR) through proteolytic cleavage of its extracellular domain. Two isoforms of the GHBP exist, differing in the retention or exclusion of exon 3: E3(+)GHBP and E3(2 )GHBP. Our study aimed to answer the questions whether the level of E3(+)GHBP in the serum correlates with the GHR exon 3 expression and whether or not the E3 genotype matches the mRNA expression pattern. Methods: Since exon 3 retention/deletion can be detected at the protein level using epitope-specific antibodies, we were able to quantify the two isoforms by means of specific immunoassays in a total of 37 individuals. Additionally, these persons were also genotyped for exon 3 by genomic PCR and tested for GHR exon 3 mRNA expression by RT-PCR. Results: We found a significant correlation between GHR exon 3 genotype and the ratio of E3(+)GHBP and E3(2 )GHBP in the serum. Moreover, the genotype matched exactly the mRNA expression in fibroblasts and/or blood leukocytes in all samples investigated. The levels of E3(+)GHBP are more strongly correlated with body mass index, proinsulin and C-peptide than the levels of the E3(2 ) isoform. Conclusions: Our results show that the GHR exon 3 genotype is in accord with the type of GHBP isoforms found in the serum. Our data thus support the idea that the presence of exon 3-retaining and -excluding GHR/GHBP isoforms results from a genomic deletion rather than from alternative splicing.

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“…Among these proteins, Grb10 is a recently identified adaptor that was reported to associate with insulin receptor (19) as well as with other tyrosine kinase receptors (20 -23). We show in the Huh-7 hepatoma cell line which expresses both Grb10 (24) and GHR (25,26), that GH stimulation induces the association of the receptor with Grb10. In order to better characterize the interactions between Grb10 and the activated GHR complex, as well as to test the potential role of this new adaptor protein in GHR signaling, we used 293 cells co-transfected with GHR and Grb10 cDNA.…”

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confidence: 99%

Grb10 Identified as a Potential Regulator of Growth Hormone (GH) Signaling by Cloning of GH Receptor Target Proteins

Moutoussamy

Renaudie

Lago

et al. 1998

Journal of Biological Chemistry

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The cloning of receptor targets procedure, used so far to identify proteins associated with tyrosine kinase receptors was modified to clone SH2 proteins able to bind to the growth hormone receptor (GHR). The cytoplasmic region of GHR, a member of the cytokine receptor superfamily does not contain tyrosine kinase activity. It was thus phosphorylated in bacteria by the Elk tyrosine kinase and radiolabeled to screen a mouse expression library. With this probe, we identified Shc and the p85 subunit of phosphatidylinositol 3-kinase as direct targets of the receptor. The other proteins identified, Csk, Shb, Grb4, and Grb10 are new potential transducers for cytokine receptors. We show in Huh-7 hepatoma cells that Grb10 and GHR associate under GH stimulation. Co-transfections in 293 cells further show that Grb10 interacts with both the GHR and Jak2. Functional tests demonstrate that Grb10 inhibits transcription of two reporter genes containing, respectively, the serum response element of c-fos and the GH response element 2 of the Spi2.1 gene, whereas it has no effect on a reporter gene containing only Stat5 binding elements. Our results suggest that Grb10 is a new target for a member of the cytokine receptor family that down-regulates some GH signaling pathways downstream of Jak2 and independently of Stat5.

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Expression of two isoforms of the human growth hormone receptor in normal liver and hepatocarcinoma

Cited by 35 publications

References 18 publications

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Association between the GH receptor/exon 3 genotype and the level of exon 3-positive GH-binding protein in human serum

Grb10 Identified as a Potential Regulator of Growth Hormone (GH) Signaling by Cloning of GH Receptor Target Proteins

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