<i>O</i>‐Glycosylated 24 kDa human growth hormone has a mucin‐like biantennary disialylated tetrasaccharide attached at Thr‐60

Bustamante, Juan J.; Gonzalez, Leticia; Carroll, Christopher A.; Weintraub, Susan T.; Aguilar, Roberto M.; Muñoz, José Manuel Perea; Martinez, Andrew O.; Haro, Luis S.

doi:10.1002/pmic.200800989

Cited by 18 publications

(15 citation statements)

References 86 publications

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“…Small hGH isoforms (5-kDa and 17-kDa) are produced by fragmentation of the 22-kDa hGH and a slightly smaller alternatively spliced 20-kDa hGH is also produced [4][5][6][7][8]10]. Other molecular variants of hGH include the 24-kDa and 12-kDa glycosylated hGHs [11][12][13], deamidated hGHs [14] and phosphorylated hGHs [15,16]. In addition, large hGH isoforms such as a 35-kDa hGH, 45-kDa hGH dimers and higher oligomers of hGH have been reported [4][5][6][7][8]10].…”

Section: Introductionmentioning

confidence: 99%

Human growth hormone: 45-kDa isoform with extraordinarily stable interchain disulfide links has attenuated receptor-binding and cell-proliferative activities

Bustamante

Grigorian

Muñoz

et al. 2010

Growth Hormone & IGF Research

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Background Human growth hormone (hGH) is a complex mixture of molecular isoforms. Gaps in our knowledge exist regarding the structures and biological significances of the uncharacterized hGH molecular variants. Mercaptoethanol-resistant 45-kDa human growth hormone (MER-45kDa hGH) is an extraordinarily stable disulfide-linked hGH homodimer whose biological significance is unknown. Objectives To elucidate the pharmacokinetic abilities of dimeric MER-45-kDa hGH to bind to GH and prolactin (PRL) receptors and to elucidate its abilities to stimulate cell-proliferation in lactogen-induced and somatogen-induced in vitro cell proliferation bioassays. Design The binding of MER-45-kDa hGH to GH and PRL receptors was tested in radioreceptorassays (RRAs). Competitive displacements of [125I]-bovine GH from bovine liver membranes, [125I]-ovine PRL from lactating rabbit mammary gland membranes and [125I]-hGH from human IM-9 lymphocytes by unlabelled GHs, PRLs or dimeric MER-45-kDa hGH were evaluated. The abilities of dimeric MER-45-kDa hGH to stimulate proliferation of lactogen-responsive Nb2 lymphoma cells and to stimulate proliferation of somatogen-responsive T47-D human breast cancer cells was assessed by incubation of cells with GHs or PRLs and subsequently measuring growth using the MTS cell proliferation assay. Results Dimeric MER-45-kDa hGH, compared to monomeric hGH, had reduced binding affinities to both GH and prolactin receptors. In a bovine liver GH radioreceptorassay its ED50 (197.5 pM) was 40.8% that of monomeric hGH. In a human IM-9 lymphocyte hGH RRA its ED50 (2.96 nM) was 26.2% that of monomeric hGH. In a lactating rabbit mammary gland prolactin RRA its ED50 (3.56 nM) was 16.8% that of a monomeric hGH. Dimeric MER-45-kDa hGH, compared to monomeric hGH, had a diminished capacity to stimulate proliferation of cells in vitro. In a dose-response relationship assessing proliferation of Nb2 lymphoma cells its ED50 (191 pM) was 18.0% that of monomeric hGH. While monomeric hGH stimulated a 2.2-fold proliferation of T47-D human breast cancer cells above vehicle control, dimeric MER-45-kDa hGH was unable to stimulate the cells to proliferate and slightly inhibited their proliferation to 77.6% that of control. Conclusions The topological arrangement of monomeric hGHs to form an unusually stable disulfide-linked dimer markedly diminishes hGH’s binding affinities to both GH and PRL receptors and also drastically attenuates its ability to stimulate proliferation of cells in vitro.

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Section: Introductionmentioning

confidence: 99%

Human growth hormone: 45-kDa isoform with extraordinarily stable interchain disulfide links has attenuated receptor-binding and cell-proliferative activities

Bustamante

Grigorian

Muñoz

et al. 2010

Growth Hormone & IGF Research

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“…However, the growth hormone molecule has been shown to have O-glycoslylation with carbohydrate moieties including galactose, so it is possible that the B4GALT7 variant could affect growth hormone biosynthesis or biological action. 38 Discordance of abnormal bone density assessed by DEXA scan in the male and female siblings suggests possible sex-associated or agedependent mechanisms of bone density regulation, effect of genetic modifiers, or unidentified environmental differences.…”

Section: Discussionmentioning

confidence: 99%

Phenotype and response to growth hormone therapy in siblings with B4GALT7 deficiency

Sandler-Wilson

Wambach

Marshall

et al. 2019

Bone

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B4GALT7 encodes beta-1,4-galactosyltransferase which links glycosaminoglycans to proteoglycans in connective tissues. Rare, biallelic variants in B4GALT7 have been associated with spondylodysplastic Ehlers-Danlos and Larsen of Reunion Island syndromes. Thirty patients with B4GALT7-related disorders have been reported to date with phenotypic variability. Using whole exome sequencing, we identified male and female siblings with biallelic, pathogenic B4GALT7 variants and phenotypic features of spondylodysplastic Ehlers-Danlos syndrome as well as previously unreported skeletal characteristics. We also provide detailed radiological characterization and describe the siblings' responses to growth hormone treatment. Our report extends the phenotypic spectrum of B4GALT7-associated spondylodysplastic Ehlers-Danlos syndrome and reports results of growth hormone treatment for patients with this rare disorder.

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“…Protein glycosylation plays an important role in protein structure, signal transduction, cell-cell interactions, and hormone action [45; 46; 47]. Addition and editing of carbohydrate units to proteins occurs in the endoplasmic reticulum and Golgi apparatus.…”

Section: Discussionmentioning

confidence: 99%

GPER1 Stimulation Alters Posttranslational Modification of RGSz1 and Induces Desensitization of 5-HT<sub>1A</sub> Receptor Signaling in the Rat Hypothalamus

McAllister¹,

Mi²,

Mure

et al. 2014

Neuroendocrinology

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Hyperactivity of the hypothalamic-pituitary-adrenal axis is a consistent biological characteristic of depression, and response normalization coincides with clinical responsiveness to antidepressant medications. Desensitization of serotonin 1A receptor (5-HT_1AR) signaling in the hypothalamic paraventricular nucleus of the hypothalamus (PVN) follows selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and contributes to the antidepressant response. Estradiol alone produces a partial desensitization of 5-HT_1AR signaling and synergizes with SSRIs to result in a complete and more rapid desensitization than with SSRIs alone as measured by a decrease in the oxytocin and adrenocorticotrophic hormone (ACTH) responses to 5-HT_1AR stimulation. G protein-coupled estrogen receptor 1 (GPER1) is necessary for estradiol-induced desensitization of 5-HT_1AR signaling, although the underlying mechanisms are still unclear. We now find that stimulation of GPER1 with the selective agonist G-1 and nonselective stimulation of estrogen receptors dramatically alter isoform expression of a key component of the 5-HT_1AR signaling pathway, RGSz1, a GTPase-activating protein selective for Gαz, the Gα subunit necessary for 5-HT_1AR-mediated hormone release. RGSz1 isoforms are differentially glycosylated, SUMOylated, and phosphorylated, and differentially distributed in subcellular organelles. High-molecular-weight RGSz1 is SUMOylated and glycosylated, localized to the detergent-resistant microdomain (DRM) of the cell membrane, and increased by estradiol and G-1 treatment. Because activated Gαz also localizes to the DRM, increased DRM-localized RGSz1 by estradiol and G-1 could reduce Gαz activity, functionally uncoupling 5-HT_1AR signaling. Peripheral G-1 treatment produced a partial reduction in oxytocin and ACTH responses to 5-HT_1AR stimulation similar to direct injections into the PVN. Together, these results identify GPER1 and RGSz1 as novel targets for the treatment of depression.

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O‐Glycosylated 24 kDa human growth hormone has a mucin‐like biantennary disialylated tetrasaccharide attached at Thr‐60

Cited by 18 publications

References 86 publications

Human growth hormone: 45-kDa isoform with extraordinarily stable interchain disulfide links has attenuated receptor-binding and cell-proliferative activities

Human growth hormone: 45-kDa isoform with extraordinarily stable interchain disulfide links has attenuated receptor-binding and cell-proliferative activities

Phenotype and response to growth hormone therapy in siblings with B4GALT7 deficiency

GPER1 Stimulation Alters Posttranslational Modification of RGSz1 and Induces Desensitization of 5-HT<sub>1A</sub> Receptor Signaling in the Rat Hypothalamus

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