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REVIEW ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 2  |  Page : 61-68

Growth hormone and its receptor: A molecular insight


Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Dammam, Kingdom of Saudi Arabia

Date of Web Publication13-Sep-2012

Correspondence Address:
Yahia A Kaabi
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Dammam, Dammam-Al-Khobar Cornish Road, P.O. Box 76447, Al-Khobar 31952
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-0521.100942

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  Abstract 

Growth hormone (GH) is a peptide hormone necessary for normal postnatal growth as well as human metabolism. It works via its widely expressed receptor (GHR), which is a dimer of transmembrane glycoproteins, belonging to cytokines type I receptor family. Signaling via GHR is initiated by conformational changes triggered upon GH association. GHR is recognized as an important therapeutic target for treatment of many pathologic conditions, including growth disorders and cancer by designing highly specific and efficient GHR agonists or antagonists. However, engineering of such molecules requires deep understanding of the structure and function of both GH and GHR protein molecules. This work reviews the current status of knowledge covering the molecular structure of both GH and GHR and their molecular interactions, in addition to different GH agonists or antagonists developed to regulate GH action.

Keywords: Growth hormone, growth hormone receptor, growth hormone receptor antagonist


How to cite this article:
Kaabi YA. Growth hormone and its receptor: A molecular insight. Saudi J Health Sci 2012;1:61-8

How to cite this URL:
Kaabi YA. Growth hormone and its receptor: A molecular insight. Saudi J Health Sci [serial online] 2012 [cited 2019 Jul 21];1:61-8. Available from: http://www.saudijhealthsci.org/text.asp?2012/1/2/61/100942


  Introduction Top


Human growth hormone (GH) is a 191-amino acid peptide hormone secreted from somatotrophs of the anterior pituitary under stimulation of GH-releasing hormone (GHRH). GH considered to be the central endocrine postnatal growth regulator and the only hormone to date with known dose-dependent stimulation of longitudinal growth. [1] GH also regulates carbohydrate, protein, and lipid metabolism. [2] It exerts its metabolic activity via the widely expressed growth hormone receptor (GHR), but predominantly in liver. GH binding to the GHR stimulates the release of the insulin-like growth factor-1 (IGF-1) that mediates most of the GH metabolic activities; however, a direct action of the GH has been also confirmed experimentally. [3] Defects in GH gene causes GH deficiency (GHD) characterized by severe growth retardation and dwarfism while defects in GHR gene causes GH insensitivity syndrome (GHIS) or Laron syndrome with similar manifestations to GHD, reviewed in. [4] Inappropriate overproduction of GH from the anterior pituitary, usually due to pituitary adenomas, resulted in overgrowth conditions with high mortality rate known as gigantism and acromegaly. Apart from anterior pituitary endocrine GH secretion, autocrine/paracrine mode secretion has been reported in several human tissues, including mammary, central nervous system, immune and lung cells with a predicted proliferative function. [5] Autocrine GH has been linked to several human malignancies, especially mammary carcinoma. [6] Therefore, GHR has been suggested as an important target for the treatment of several GH-derived disease conditions by designing efficient GHR agonists or antagonists. However, designing of such molecules requires extensive knowledge about the structure and function of the GH and GHR molecules. This work will revisit the GH and GHR gene and protein structure and revise the molecular mechanism of GH-GHR interaction as well as current models for GHR activation. In addition, this review also discusses the available GH agonists or antagonists and their application in treatment of either GH deficiency or GH excess disease conditions.


  GH Gene and Protein Structure Top


The gene encoding GH consists of a cluster of 5 related genes: GH-N (growth hormone normal gene or GH1), GH-V (growth hormone variant gene or GH2), and 3 other placental lactogens [chorionic somatomammotropins (CSs)], spanning approximately 47 kb in the long arm of chromosome 17. [7] Only the GH-N gene is transcribed in the anterior pituitary, whereas the GH-V and CSs are known to be expressed in the placenta. The GH-N gene transcription is trans regulated by the pituitary-specific transcription factor (Pit-1/GHF-1). [8] GH-N possesses 5 exons and 4 introns covering about 3 kb and its mRNA transcript is cleaved by alternative splicing into 2 mature mRNA codes for 2 peptides with 20 and 22 kDa. [9] The 22 kDa peptide (191 amino acid) is regarded as hGH and it is the most predominant GH isoform present in the circulation. A third GH isoform (17.48kDa) arises from the deletion of exon3 and, lacking amino acids 32-71, has also been reported. [10] Other variants from the GH-N gene as a result of alternative splicing may also exist. [11]

The X-ray crystallography of the GH in complex with the GHR by de Vos and colleagues shed light on the GH 3D structure. [12] The major structural feature of the hGH is the 4 α-helix bundle organized in an unusual up-up-down-down topology characteristic of the hematopoietic factors family of peptides. The N-terminal and C-terminal helices (helices 1 and 4 containing 26 and 30 residues, respectively) are longer than the other helices (helices 2 and 3 containing 21 and 23 residues) and each are connected by 3 more mini-helices. The core of the 4 α-helix bundle is mostly made of hydrophobic amino acids, which aid in stabilizing the structure. The 3D structure is also stabilized by 2 disulfide bonds between cysteines; C53-165 and C182-189 in addition to several hydrogen bonds between various amino acids residues [Figure 1]. [12]
Figure 1: Structure of the growth hormone (GH). The structure of GH was elucidated after being crystallized in complex with its receptor. It is composed of 4 a-helices (shown as cylinders) arranged in an up-up-down-down topology. Three mini-helices also exist, 2 of them located in the α1-α2 loop and 1 mini-helix in α2-α3 loop. The structure is also stabilized by 2 disulfide bonds (shown as dotted lines)

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  GHR Gene and Protein Structure Top


A cDNA for GHR was first cloned in 1987 from human and rabbit livers. [13] The GHR gene is located on the short arm of chromosome 5, spanning at least 87 kb and comprising 9 coding exons in addition to several noncoding exons in the 5´ untranslated region. [14] Exon2 encodes the peptide signal sequence, exons3-7 encode the extracellular domain and the remaining exons encode the transmembrane and the cytoplasmic domain. [14]

GHR is a transmembrane glycoprotein that belongs to the type I cytokine receptor family, which also includes erythropoietin, prolactin, leptin, thrombopoietin, and several interleukin receptors. [15] The full-length GHR consists of 620 amino acids with a predicted molecular weight of 70 kDa, although on gel electrophoresis it runs heavier with 109 kDa due to added carbohydrate groups to the extracellular domain. The GHR consists of an N-terminal extracellular domain (246 amino acids), a single pass transmembrane domain (24 amino acids), and a long C-terminal intracellular domain (350 amino acids). [13] The extracellular domain of the GHR contains 2 fibronectin type III (FNIII) subdomains [Figure 2]. The first FNIII domain spans amino acids 1-123 and the second 128-238 amino acids. A linker of 4 amino acid residues (124-127) joins the 2 domains together. Each domain contains 7 antiparallel β-strands forming a β-sandwich similar in topology to immunoglobulins. [15] Peptide mapping studies showed that the GHR extracellular domain contains 7 cysteine residues. Six of them are involved in the formation of disulphide bonds between cysteines; C38-48, C83-94, and C108-122. [12],[16] The GHR extracellular domain contains a well-conserved tryptophan, serine, amino acid, tryptophan, serine (WSXWS)-like motif located near the C-terminus of the extracellular domain required for normal ligand-binding affinity. The WSXWS motif present in all members of the type I cytokines receptor and is replaced by tyrosine, glycine, glutamate, phenylalanine, serine (YGEFS) motif in case of GHR. [15] Mutational studies of asparagine (N) into glutamate (D) has shown that GHR extracellular domain contains 5 N-glycosylation sites necessary for maintaining high-affinity binding with GH at positions 28, 97, 138, 143, and 182. [17]
Figure 2: Structure of the growth hormone receptor (GHR). Different domains of the GHR are shown in this figure. In the extracellular domain, the 2 FNIII subdomains in addition to the YGEFS motif are shown. In the cytoplasmic tail, Box 1 and 2 motifs, necessary for association of Jak2, and the ubiquitination motif (UbE motif), necessary for GHR internalization, are shown. The figure also shows the multiple tyrosine residues (Y) that are readily phosphorylated by Jak2 during receptor activation and 5 N-glycosylation sites (in red)

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The transmembrane domain of the GHR consists of 24 hydrophobic amino acid residues. In common with other members of type I cytokine receptors, the membrane proximal of the intracellular domain of human GHR contains a proline-rich motif ( 280 ILPPVPVP 287 ) known as Box1, which is important for Janus tyrosine kinase 2 association. Another cytoplasmic motif is Box2, spanning 15 amino acids and located ~23 amino acid downstream Box1 motif. [18] It begins with a cluster of hydrophobic residues and ends with 1 or 2 positively charged amino acids. [19] The cytoplasmic domain also contains an ubiquitination motif or (UbE motif) ( 322 DSWVEFIELD 331 ) necessary for receptor internalization. [20]

GHR variants

An important variant of the GHR is the growth hormone-binding protein (GHBP) that corresponds to the GHR extracellular domain. [21] The GHBP is a 55 kDa protein, which was first described in the mid-1980s by 2 separate groups. [22],[23] It is normally circulated in the plasma, and under physiologic conditions about half of the plasma hGH are bound to the GHBP. [24] The exact function of the circulating GHBP is still unclear. However, the GHBP is believed to act as a GH reservoir, prolonging the GH half-life, and as a modulator for GH activity by competing with the native GHR to the GH. [25]

In rodents (rat and mouse), the soluble GHBP present in the plasma is derived from the GHR gene by alternative splicing of the GHR mRNA transcripts encoding the GHR extracellular domain with a hydrophilic tail. [26],[27] In human and rabbit, the GHBP is thought to be as a result of proteolytic cleavage of the full-length membrane bound GHR or truncated GHR. [28] Shedding of the GHBP from the cell membrane has been found to be promoted by treating cells with sulfhydryl alkylating reagents, such as N-ethylmaleimide. [29] Complete blockage of the GHR shedding by the metalloprotease inhibitors suggests that the GHR proteolytic cleavage is probably due to the action of metalloproteases, particularly TNFa-converting enzyme. [30]

In addition to the extracellular generation of the GHBP, studies have shown that it can be produced intracellularly and prominently in the nucleus. [31] This endogenous GHBP expression has been found to have the ability to enhance the STAT5-mediated transcription. [32]

GHR as well as other members of the cytokines receptor family, is expressed in short isoforms. Two different GHR mRNA transcripts were firstly identified from the human placenta as a result of retention or exclusion of exon3 from the GHR mRNA transcript due to alternative splicing. [33] This resulted in 2 isoforms of the human GHR: full-length isoform (GHRfl) and a short isoform lacking the exon3 (GHRd3). Deletion of the exon3 causes an in-frame deletion of 22 amino acid from the GHR extracellular domain that did not alter the GH binding. [34] Recently, the GHRd3 polymorphism has been linked to some pathologic conditions involving type 2 diabetes mellitus, [35] high insulin secretion during puberty, [36] and polycystic ovary syndrome. [37]

A shorter isoform of the GHR, known as truncated GHR (GHRtr), was also determined from several human tissues, including liver, stomach, and mammary gland. [38] This receptor variant is due to deletion of 26 bp in the exon9 that introduces a stop codon at amino acid position 280 leading to the truncation of about 97.5% of the cytoplasmic domain of the receptor. [38] Unlike GHRfl, GHRtr is found to be fixed to the cell membrane and undergoes only minimal internalization with a high tendency to generate the soluble form of the receptor GHBP. [39] GHRtr isoforms also found to act as negative regulators of the GHR signaling capabilities and found to be responsible for a form of genetic short stature. [28],[40]


  Molecular Basis of GH/GHR2 Interaction Top


The interaction between the GH and GHR has been intensively studied using mutational and structural methods. The hGH possesses 2 receptor-binding sites (site-1 and site-2), present on either side of the molecule, therefore it can bind 2 GHR molecules. Interestingly, both receptor molecules utilize the same amino acids to interact with the GH, given that the 2 binding sites on the GH have no structural similarities [Figure 3]. The initial step in the GH-GHR2 interaction is binding of the GH via site-1 to a GHR to form a high affinity 1:1 complex. The binding interface on the GH is defined as a part of the α-helix 1 and most of α-helix 4 and most of the binding energy is provided by 8 amino acid (K41, L45, P61, R64, K172, T175, F17, and R178) clustered at the center of the binding interface. [41] On the GHR, the binding amino acids are located mainly in a cysteine-rich region, which forms a patch of 4 loops connecting the β-strands between the 2 FNIII subdomains. [42] Alanine mutagenesis studies have shown that a subset of 11 amino acids in the GHR functional epitope (W104 W169, I103, I105 I106, I165, R43, E44, D126, E127, and D164) are necessary for ligand binding. [43] Among these amino acids, the hydrophobic amino acid side chain W104 and W169 have more contact with the ligand and their alanine substitution was shown virtually to abolish binding. [42] Once the GH has bound with the first GHR via site-1, it is thought that site-2 then becomes exposed and able to bind the second GHR receptor via low affinity, causing a conformational change necessary for signaling. Important amino acid residues present in GH site-2 include F1, I4, R8, D116, and G120. [44] Of these amino acids G120, present in α-helix 3, is particularly important for receptor binding. Mutation in this single amino acid residue to a charged residue, either G120R or G120K, produces a GH analogue molecule that is able to bind to the receptor via site-1 but not site-2, thus it cannot dimerize and agonize the receptor. [45]
Figure 3: The molecular interaction of growth hormone (GH) and growth hormone receptor (GHR). GH binds to 2 GHR molecules via 2 binding sites present on either side of the GH molecule. First, it binds via site I (part of the a-helix 1 and most of a-helix 4) to the first GHR molecule to form a high-affinity 1:1 complex. Important amino acids on GHR involved in the binding include the hydrophobic tryptophans 104 and 169 and negatively charged amino acids aspartic acid 126 (D126) and glutamic acid 127 (E127). The GH then binds to the second GHR molecule with low affinity via site-2 (most of a-helix 3 and several N-terminal amino acids) causing a conformational change necessary for signaling

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  Models for GHR Activation Top


Hormone-induced dimerization model

The ability of the GH to dimerize 2 GHR molecules in solution was confirmed by X-ray crystallography. [12] Subsequently, Fuh et al. have shown that some bivalent monoclonal antibodies are able to activate GHR on the proliferation assay while the monovalent Fab fragments cannot. [45] This observation has led to the introduction of the early model of GHR action based on ligand-induced receptor dimerization [Figure 4]a. It suggests that the GH binds to 2 GHR monomers sequentially. First, the GH binds with high affinity to a GHR monomer via site-1, followed by binding of the GH site-2 to a second GHR, and this binding causes a conformational change in the GHR extracellular domain and initiation of the signaling. This model was also supported by the ability of G120R GH analogue with site-2 mutated GH to disrupt the GH action and act as a GHR receptor antagonist. [45]
Figure 4: Models for growth hormone receptor (GHR) activation. (a) The early model for GHR activation is based on GH-induced receptor dimerization. The GH first binds to 1 receptor molecule via site-1; this binding attracts the second molecule binding via site-2 causing dimerization and initiation of the signaling. However, the GHR is now proved to exist as a homodimer on the cell membrane, suggesting the existence of a ligand-induced conformational change model. (b) The GH binds the receptor dimer and causes a rotation in the GHR domains enough to trigger the signaling

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Hormone-induced conformational change model

Recent studies have shown that the GHR, as well as other type I cytokine receptors, such as erythropoietin receptor, exists as a preformed dimer on the cell membrane in the absence of the GH. [46],[47] Therefore, the activation of the GHR must be mediated by conformational changes rather than receptor dimerization on the GH binding [Figure 4]b. Brown and his colleagues have investigated a new model for GHR activation that involves a rotation in the transmembrane domains and juxtamembrane region of the individual GHR molecule upon GH binding. [46] The study is based on a comparison of the already published crystal structures of unliganded GHR against the GH:GHR 1:1 and 1:2 complex crystal structures and they predict that a rotation might occur as a result of asymmetric binding of the GHR dimer to the binding sites present on the GH. Consistent with the subunit rotation model, using atomistic molecular dynamics simulation recently it has been found that removal of the GH from the GH:GHR2 complex resulted in a 30°-64° anticlockwise rotation in the 2 receptor subunits relative to each other. [48] In another study, Pang et al. suggested 2 essential rotations in the GHR molecules upon GH binding for receptor activation; one is a scissor-like rotation that separates intracellular domains from each other to make a room for the Janus kinase molecules and a second self-rotation allow proper orientation of these molecules for transphosphorylation. [49] Other conformational changes may also play an important role in GHR activation.


  Cytoplasmic Signaling Cascade Top


As a member of cytokine receptors family, GHR is devoid of intrinsic kinase activity and instead it recruits and activates several cytoplasmic tyrosine kinases for signaling. [50] Among the different nonreceptor tyrosine kinases, Janus kinase 2 (Jak2) is the predominant tyrosine kinase utilized by the GHR. [51] In a nonsignaling state, Jak2 is weakly associated with the cytoplasmic proline-rich motif (Box1) of the GHR. Upon the GH binding, the conformational change in the GHR brings the Jak2 molecules into close proximity and they transphosphorylate and activate each other. Activation of Jak2 results in phosphorylation of several tyrosine residues present on the cytoplasmic domain of the GHR that act as a docking site for several signaling molecules and transcription factors possessing a Src homology2 (SH2) domain, most importantly signal transducers and activators of transcription proteins (STATs). [18] STAT5a and b were found to be the major contributors in the GH signaling via Jak/STAT pathway. [52] STAT5a and b are encoded by 2 independent genes exhibiting up to 90% homology in their coding sequence with STAT5b being 12 amino acid shorter. The 2 forms of STAT5 were found to have both distinct and overlapped function with respect to their role in GH signaling. [53]

Jak2 phosphorylates STAT molecules at conserved tyrosine residues. The phosphorylated STATs then dissociate from the receptor as homo- or heterodimers and translocate into the nucleus where they bind a specific sequence of the promoter to activate the GH-sensitive genes transcription. [54] STAT1 homo- or heterodimers bind to the Sis-inducible element (SIE) on the c-fos promoter while STAT3 and 5 bind to the lactogene hormone response elements (LHRE) on the βcasein gene promoter. [55]

In addition to the Jak-STAT pathway, GH signaling can also occur through other elements, such as the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3´-Kinase (PI3K) pathway [Figure 5]. [56] MAPKs, which are a family of proline-directed serine/threonine protein kinases, mediate signaling for a variety of extracellular stimuli. [51] Members of the MAPK family found to be activated by the GH include the following: the extracellular signal-regulated kinases (ERKs) known as p44/42, [57] the c-jun N-terminal kinases (JNK) [58] and p38 MAPK. [59]
Figure 5: Intracellular pathways involved in growth hormone signaling. The activated Jak2 upon GH binding activates several intracellular substrates, most importantly signal transducer and activator of transcriptions 1, 3, and 5 (STATs), but it also activates other signaling pathways, such as mitogen-activated protein kinases (MAPKs) and phosphoinositol 3kinase (PI3K)

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The role of the PI3K pathway in GH intracellular signaling has also been suggested. For example, inhibition of the PI3K pathway in rat adipocytes attenuated the lipogenic effect of the GH. [60] Activation of the PI3K signaling pathway was also found to regulate the p44/42 MAPK full activation by the GH. [61] In a recent study performed on macrophages, it has been shown that the Jak2 inhibition causes a significant inhibition of the GH-induced PI3K phosphorylation, suggesting that the Jak2 is an upstream regulator of PI3K. [62]


  Modulation of The GHR Activity Top


GHR agonists

A regimen for GH replacement therapy involved daily injections of the hormone, which is inconvenient for many patients. Several approaches have been developed to produce a long-acting GH and avoid this inconvenience. One approach is based on introducing a mutation in the GH-binding sites to enhance the GH biopotency. For example, substitution of certain amino acid residues present on porcine GH (pGH) site-1 by those present in human GH increased the activity up to 5-fold higher than the normal pGH. [63]

Covalent attachment of a polyethylene glycol to the GH (GH-PEG) molecules has also been shown to increase the hormone half-life by reducing the rate of the GH clearance by the kidney with less susceptibility to intravascular proteolysis. [64] Pegylated GH is well tolerated within the body and provides a promising therapy that can be administered weekly instead of daily doses as a treatment for GHD patients. [65]

Sustained release of the GH formulation strategy for a prolonged GH effect is an alternative strategy. This approach is based on encapsulation of the recombinant GH in biodegradable polymers or microspheres to ensure sustained release of the GH in GHD patients. Among the most studied examples are Nutropin Depot [66] and Biosphere. [67]

Another approach for the production of long-acting GHR agonist is based on ligand-receptor fusion proteins. Wilkinson et al. have recently developed a chimera of the recombinant GH linked to a GHBP molecule via a flexible linker that is able to act as a long-acting agonist. In vivo studies showed that this fusion molecule has a reduced clearance rate up to 300-fold slower than the GH and with half-life 100-fold longer than the GH. [68]

GHR antagonists

In addition to the GHR receptor agonists, GHR antagonists have also been developed. They are all based on introduction of mutation into the native GH amino acids that increases its binding affinity via site-1 and at the same time reduces site-2 binding, resulting in a molecule that can bind GHR but is unable to initiate the necessary conformational change. The first observations suggesting that mutagenesis in the GH amino acid sequence can negatively affect the GH signaling was credited to Chen et al. who found that substitutions of E117 to L, G119 to R, and A122 to D, in site-2 of bovine GH were able to bind to the receptors but cause no receptor activation in mice. [69] This was followed by several studies indicating the importance of the glycine at position 120 of the GH site-2 for GH biologic activity. Based on the previous studies, glycine 120 substitution to lysine (G120K) resulted in a GH analogue that was able to bind GHR with high affinity via site-1, but unable to bind the second receptor and therefore block the signaling. [45] It has also been shown previously that altering a cluster of several amino acids on the hGH to that of placental lactogen enhanced the binding via site-1. [70] These altered site-1 amino acids were combined with the G120K mutation and resulted in a mutated GH molecule with a potent antagonistic activity, known as B2036. Pegylation of the B2036 molecule (B2036-PEG), commercially known as pegvisomant, has increased its half-life from 30min to 7 hours, reduced its immunogenicity and provides a promising GHR antagonist. [71],[72] Although the long-term effectiveness of pegvisomant needs to be assessed, it has been successfully used along with somatostatin analogues to treat acromegaly. [73],[74]

In the last 2 decades, multiple publications have reported the association between the GH and development of neoplasia in human and animal models. For example, patients with acromegaly have a high incidence for colorectal cancers. [75] Upregulation of the GHR has been also reported in many cancerous tissues, including prostate, breast, and colorectal tissues. [76],[77] Polymorphisms in either GH- or GHR-encoding gene has been shown to alter the risk for breast cancer. [78],[79] In addition, several human malignancies, such as human mammary carcinoma and endometrial adenocarcinoma, are known to secrete high levels of GH, suggesting an autocrine-paracrine role for the GH/IGF-1 axis in human malignancies. [80] Autocrine GH secretion in these tissues is responsible for increased proliferation and differentiation, oncogenic transformation, metastasis, decreased apoptosis, and drug resistance. [81],[82]

Treatment of cancer by GH/IGF-I axis blockade has been suggested and tested. Somatostatin analogues (SSA) in conjunction with anticancer chemotherapy has been shown to benefit some patients with breast and prostate cancers in terms of progression reduction and symptoms improvement. [83] However, there was insufficient evidence suggesting routine endorsement of these agents in clinical trials. Pegvisomant, although there are no encouraging human studies, has been shown to reduce tumor growth by up to 40% in tumor xenografted mice [84] and recently, it has been shown that GHR antagonist pegvisomant inhibits GH-induced chemoresistance by enhancing apoptosis in breast cancer cell lines. [85] Therefore, pegvisomant represents a potential treatment option that should be considered in combat against GH-expressing tumors.





GH is a multifunctional peptide hormone needed for normal growth, hepatic metabolism, and immune function. In the past 20 years, structural studies of GH in complex with GHR extracellular domains has revealed that GH is a bundle of 4 α-helices stabilized by 2 disulfide and several hydrogen bonds while GHR extracellular domain is formed of 2 FNIII subdomains each with 7 antiparallel β-strands. During cellular signaling, the GH binds 2 GHR molecules between FNIII subdomains and causes the conformational changes to turn on the receptor. Two models of GHR activation have been proposed to date: GH-induced dimerization model and GH-induced conformational change model. The former model suggests that the GH binds to 2 GHR monomers sequentially causing receptor dimerization and initiation of signaling. In the second model, the GH binds to a preformed GHR dimer causing conformational changes necessary for signaling, including rotations in the GHR subdomains. These conformational changes bring the Jak2 molecules present on the cytoplasmic domain of the GHR into close proximity when they activate each other. Activation of Jak2 leads to activation of several signaling molecules and transcription factors possessing an Src homology2 (SH2) domain, especially STAT5a and b.

In conclusion, GH and its receptor are important molecules involved in many pathophysiologic conditions, most importantly, growth disorders and cancer. They interact with each other, as many cytokines, in a unique GH:GHR2 manner where the ligand causes a conformational change and signaling. Exogenous manipulation GHR activity by activating (agonists) or deactivating (antagonists) molecules possess a great therapeutic potential. For instant, pegylated GH and GH-GHBP fusion molecules are promising tools for prolonged GH activity in treatment of GHD. On the other hand, the GHR antagonist pegvisomant (GH with mutated site-2) has been introduced successfully in treatment of acromegaly and potentially other proliferative conditions, such as breast cancer.

 
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