Mechanism of signaling by growth hormone receptor

Argetsinger, Lawrence S.; Carter‐Su, Christin

doi:10.1152/physrev.1996.76.4.1089

Cited by 252 publications

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“…In the case of the GHR, JAK2 is the proximal effector, and once activated, it phosphorylates selected tyrosines in the receptor cytoplasmic domain, providing docking sites for SH2-domain containing signaling proteins and adaptors. Several important pathways are activated by this process, including the STAT5a/b, the ERK, and Akt pathways (3).…”

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confidence: 99%

Increased Site 1 Affinity Improves Biopotency of Porcine Growth Hormone

Wan

McDevitt

Shen

et al. 2004

Journal of Biological Chemistry

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Based on phage display optimization studies with human growth hormone (GH), it is thought that the biopotency of GH cannot be increased. This is proposed to be a result of the affinity of the first receptor for hormone far exceeding that which is required to trap the hormone long enough to allow diffusion of the second receptor to form the ternary complex, which initiates signaling. We report here that despite similar site 1 kinetics to the hGH/hGH receptor interaction, the potency of porcine GH for its receptor can be increased up to 5-fold by substituting hGH residues involved in site 1 binding into pGH. Based on extensive mutations and BIAcore studies, we show that the higher potency and site 1 affinity of hGH for the pGHR is primarily a result of a decreased off-rate associated with residues in the extended loop between helices 1 and 2 that interact with the two key tryptophans Trp 104 and Trp 169 in the receptor binding hot spot. Our mutagenic analysis has also identified a second determinant (Lys 165 ), which in addition to His 169 , restricts the ability of non-primate hormones to activate hGH receptor. The increased biopotency of GH that we observe can be explained by a model for GH receptor activation where subunit alignment is critical for effective signaling.The growth hormone receptor (GHR) 1 was the first class 1 cytokine receptor to be characterized, and the interaction between the human receptor and its ligand has been particularly well characterized (1, 2). The GHR has served as a paradigm for the ligand-induced dimerization mechanism that is believed to result in the activation of paired Janus kinases bound to the membrane proximal box 1 sequence of the receptor by a process of transphosphorylation. In the case of the GHR, JAK2 is the proximal effector, and once activated, it phosphorylates selected tyrosines in the receptor cytoplasmic domain, providing docking sites for SH2-domain containing signaling proteins and adaptors. Several important pathways are activated by this process, including the STAT5a/b, the ERK, and Akt pathways (3).In a series of elegant investigations, a Genentech group demonstrated that the 4-helix bundle hormone possesses two non-identical binding surfaces, but binds to similar receptor binding sites in an ordered sequence, with the initial binding site possessing a higher affinity (site 1). Site 2 binding is stabilized by a further inter-receptor interaction involving the "dimerization domain" in the lower of the two cytokine homology modules (4 -6). Both site 1 and site 2 interactions are critically dependent on a key tryptophan contributed by the upper cytokine module (Trp 104 ), with a second precisely oriented tryptophan (Trp 169 ) from the lower module also contributing critically to site 1 binding (2, 7). These tryptophans form the center of a hydrophobic binding surface (hot spot), which is the basis for the hormone-receptor interaction, with surrounding residues packing around these tryptophans to ensure high affinity interactions with the relevant hormone residu...

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confidence: 99%

Increased Site 1 Affinity Improves Biopotency of Porcine Growth Hormone

Wan

McDevitt

Shen

et al. 2004

Journal of Biological Chemistry

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“…Since both the human and rhesus receptors are glycosylated at several sites (Leung et al 1987, Martini et al 1997, it is likely that carbohydrate groups are added to the baboon GHR at the conserved asparagine residues. The formation of two extracellular domain disulphide bridges occurs in the GHRs of all species studied to date, and is also a feature of the class I division of the cytokine/GH/prolactin receptor superfamily (Argetsinger & Carter-Su 1996). Another characteristic of class I receptors is the presence of a WSXWS (where X is any amino acid) motif in the proximal region of the extracellular domain (Baumgartner et al 1994, Argetsinger & Carter-Su 1996.…”

Section: Discussionmentioning

confidence: 99%

“…The characteristic features of the GHR are all well conserved in the three primates: the 18 amino acid signal peptide, the seven cysteine residues, five potential N-glycosylation sites and YGEFS motif of the extracellular domain, and the proline-rich Box 1 region of the cytoplasmic tail (Fig. 3) (Argetsinger & Carter-Su 1996).…”

Section: Cloning Of Ghr Cdnas From Baboon Livermentioning

confidence: 99%

The baboon: a model for the study of primate growth hormone receptor gene expression during development

Zogopoulos

Nathanielsz

Hendy

et al. 1999

Journal of Molecular Endocrinology

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In subprimates, significant onset of growth hormone receptor (GHR) expression occurs only after birth whereas, in the human, GHR mRNA and protein are widely manifest from the first trimester of fetal life. Thus, it is likely that subprimates are not the best models for studying regulation of human GHR gene transcription, especially during early stages in development. Here we have explored the potential of the baboon as a more appropriate model. Baboon GHR cDNAs were cloned from postnatal liver by reverse transcription (RT)-PCR, using human GHRspecific primers. The encoded baboon GHR precursor protein has an identical signal peptide sequence to that of human and rhesus monkey GHRs, and the mature baboon GHR is also 620 amino acids long, with 95% and 98·5% amino acid identity to the human and rhesus monkey receptors respectively. Previous studies in the human have identified eight 5 untranslated region (5 UTR) variants of the GHR mRNA (V1 to V8, numbered according to their relative abundance). We cloned the baboon V1, V3 and V4 homologues by RT-PCR: these variants have a high degree (>92%) of sequence identity with their human counterparts and also diverge at an identical point, 12 nucleotides upstream of the start of translation. The expression pattern of these three GHR mRNA isoforms in baboon liver during development was characterized. Strong expression of baboon V1 and V4 was evident by 49 days of postnatal life (n=5, 49 days and adult (18·6-19·6 kg)); very low levels of V1, but not V4, were observed in younger animals (n=2, 6 and 30 days). In contrast, V3 5 UTR variant mRNA was present in all fetal (n=4, 141-155 days gestation) and postnatal (n=7, 6-19·6 days and adult (18·6 kg)) hepatic specimens examined. Analysis of postnatal kidney and lung (n=2, 19 and 19·6 kg) revealed that V3 transcripts are present in these tissues, but not V1 and V4. Together, these data demonstrate that, as in the human, baboon V1 and V4 expression is developmentally regulated and tissue specific, while the V3 isoform is more widely expressed. Therefore, it is likely that the regulatory regions of the baboon and human GHR genes are well conserved. Our findings suggest that the baboon is an appropriate animal model in which to define the mechanisms regulating GHR gene transcription during primate development.

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“…Circulating GH is largely complexed with binding proteins (GHBP) that regulate levels of free and bound GH, prolong GH half-life and modulate GH bioactivity through competition with receptors of GH (GHR) for the ligand (Baumann 1995). GH signaling is propagated by the sequential binding of a single free GH molecule to two identical membrane-bound GHR molecules whose dimerization activates intracellular signaling cascades of tyrosine kinases, ultimately leading to the regulation of gene expression or protein activity (Argetsinger and Carter-Su 1996).…”

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confidence: 99%

Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice

Coschigano

2006

AGE

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Since generation of the growth hormone receptor/binding protein (GHR/BP) gene-disrupted mouse nearly 10 years ago, use of this mouse model has become widespread in the elucidation of the physiological roles of GH and insulin-like growth factor-1 (IGF-1). In particular, it serves as a useful model to study mechanisms of aging. This review highlights the evidence demonstrating that the loss of GH signaling leads to lifespan extension in mice, and presents the multiple characteristics of this mouse line that suggest the life extension is due to alteration of the aging process.

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Mechanism of signaling by growth hormone receptor

Cited by 252 publications

References 0 publications

Increased Site 1 Affinity Improves Biopotency of Porcine Growth Hormone

Increased Site 1 Affinity Improves Biopotency of Porcine Growth Hormone

The baboon: a model for the study of primate growth hormone receptor gene expression during development

Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice

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