Human GH Receptor-IGF-1 Receptor Interaction: Implications for GH Signaling

Published on Nov 1, 2014in Molecular Endocrinology3.628
· DOI :10.1210/me.2014-1174
Yujun Gan6
Estimated H-index: 6
(UAB: University of Alabama at Birmingham),
Ashiya Buckels2
Estimated H-index: 2
(UAB: University of Alabama at Birmingham)
+ 5 AuthorsStuart J. Frank45
Estimated H-index: 45
(UAB: University of Alabama at Birmingham)
GH signaling yields multiple anabolic and metabolic effects. GH binds the transmembrane GH receptor (GHR) to activate the intracellular GHR-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signals, including signal transducer and activator of transcription 5 (STAT5) activation and IGF-1 gene expression. Some GH effects are partly mediated by GH-induced IGF-1 via IGF-1 receptor (IGF-1R), a tyrosine kinase receptor. We previously demonstrated in non-human cells that GH causes formation of a GHR-JAK2-IGF-1R complex and that presence of IGF-1R (even without IGF-1 binding) augments proximal GH signaling. In this study, we use human LNCaP prostate cancer cells as a model system to further study the IGF-1R's role in GH signaling. GH promoted JAK2 and GHR tyrosine phosphorylation and STAT5 activation in LNCaP cells. By coimmunoprecipitation and a new split luciferase complementation assay, we find that GH augments GHR/IGF-1R complex formation, which is inhibited by a Fab of an antagonistic anti-GHR monoclonal antibody. Short hairpin RNA-mediated IGF-1R silencing in LNCaP cells reduced GH-induced GHR, JAK2, and STAT5 phosphorylation. Similarly, a soluble IGF-1R extracellular domain fragment (sol IGF-1R) interacts with GHR in response to GH and blunts GH signaling. Sol IGF-1R also markedly inhibits GH-induced IGF-1 gene expression in both LNCaP cells and mouse primary osteoblast cells. On the basis of these and other findings, we propose a model in which IGF-1R augments GH signaling by allowing a putative IGF-1R-associated molecule that regulates GH signaling to access the activated GHR/JAK2 complex and envision sol IGF-1R as a dominant-negative inhibitor of this IGF-1R-mediated augmentation. Physiological implications of this new model are discussed.
  • References (69)
  • Citations (16)
📖 Papers frequently viewed together
25 Citations
12 Citations
1 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Ying Liu (UAB: University of Alabama at Birmingham)H-Index: 4
#2Philip A. Berry (UAB: University of Alabama at Birmingham)H-Index: 2
Last. Stuart J. FrankH-Index: 45
view all 10 authors...
The transmembrane GH receptor (GHR) exists at least in part as a preformed homodimer on the cell surface. Structural and biochemical studies suggest that GH binds GHR in a 1:2 stoichiometry to effect acute GHR conformational changes that trigger the activation of the receptor-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signaling. Despite information about GHR-GHR association derived from elegant fluorescence resonance energy transfer/bioluminescence resonance energy transfe...
9 CitationsSource
#1Marcia Hiriart (UNAM: National Autonomous University of Mexico)H-Index: 22
#2Carmen Sanchez-Soto (UNAM: National Autonomous University of Mexico)H-Index: 7
Last. Deyanira Fuentes-SilvaH-Index: 5
view all 13 authors...
It has been generally assumed that insulin circulates freely in blood. However it can also interact with plasma proteins. Insulin receptors are located in the membrane of target cells and consist of an alpha and beta subunits with a tyrosine kinase cytoplasmic domain. The ectodomain, called soluble insulin receptor (SIR) has been found elevated in patients with diabetes mellitus. We explored if insulin binds to SIRs in circulation under physiological conditions and hypothesize that this SIR may ...
6 CitationsSource
#1Yujun Gan (UAB: University of Alabama at Birmingham)H-Index: 6
#2Andrew J. Paterson (UAB: University of Alabama at Birmingham)H-Index: 32
Last. Stuart J. Frank (UAB: University of Alabama at Birmingham)H-Index: 45
view all 5 authors...
GH signals through the GH receptor (GHR), a cytokine receptor linked to Janus kinase 2 (JAK2). GH activates signal transducer and activator of transcription 5 (STAT5), causing expression of genes including IGF-I. IGF-I binds IGF-I receptor (IGF-IR), a heterotetrameric (α2-β2) tyrosine kinase growth factor receptor similar to insulin receptor (IR). In addition to this GH -> GHR -> IGF-I -> IGF-IR pathway, GH induces a complex including GHR, JAK2, and IGF-IR and deletion of floxed IGF-1R in primar...
6 CitationsSource
#1Yujun Gan (UAB: University of Alabama at Birmingham)H-Index: 6
#2Yue Zhang (UAB: University of Alabama at Birmingham)H-Index: 12
Last. Stuart J. Frank (UAB: University of Alabama at Birmingham)H-Index: 45
view all 10 authors...
GH is a potent anabolic and metabolic factor that binds its cell surface receptor (GHR), activating the GHR-associated tyrosine kinase, Janus kinase 2, which phosphorylates and activates the latent transcription factor, signal transducer and activator of transcription 5 (STAT5). Some GH actions are mediated by the elaboration of IGF-1, which exerts effects by binding and activating the heterotetrameric tyrosine kinase growth factor receptor, IGF-1R. In addition to this GH-GHR-IGF-1-IGF-1R scheme...
11 CitationsSource
#1YingJie Wu (NYU: New York University)H-Index: 4
#2Hui Sun (NYU: New York University)H-Index: 15
Last. Shoshana Yakar (NYU: New York University)H-Index: 51
view all 12 authors...
States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT ...
21 CitationsSource
#1Jie Xu (UAB: University of Alabama at Birmingham)H-Index: 1
#2Dongmei Sun (UAB: University of Alabama at Birmingham)H-Index: 1
Last. Stuart J. Frank (UAB: University of Alabama at Birmingham)H-Index: 45
view all 11 authors...
GH and prolactin (PRL) are structurally related hormones that exert important effects in disparate target tissues. Their receptors (GHR and PRLR) reside in the cytokine receptor superfamily and share signaling pathways. In humans, GH binds both GHR and PRLR, whereas PRL binds only PRLR. Both hormones and their receptors may be relevant in certain human and rodent cancers, including breast cancer. GH and PRL promote signaling in human T47D breast cancer cells that express both GHR and PRLR. Furth...
19 CitationsSource
#1John G. MentingH-Index: 13
#2Jonathan WhittakerH-Index: 20
Last. Michael C. Lawrence (University of Melbourne)H-Index: 38
view all 17 authors...
The three-dimensional structure of the insulin–insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein; here is the first glimpse of the interaction between insulin and its primary binding site on the insulin receptor, a view based on four crystal structures of insulin bound to truncated insulin receptor complexes.
201 CitationsSource
The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response, l...
129 CitationsSource
#1Luqin DengH-Index: 10
#2Jing JiangH-Index: 29
Last. Stuart J. Frank (UAB: University of Alabama at Birmingham)H-Index: 45
view all 3 authors...
GH receptor (GHR) mediates important somatogenic and metabolic effects of GH. A thorough understanding of GH action requires intimate knowledge of GHR activation mechanisms, as well as determinants of GH-induced receptor down-regulation. We previously demonstrated that a GHR mutant in which all intracellular tyrosine residues were changed to phenylalanine was defective in its ability to activate signal transducer and activator of transcription (STAT)5 and deficient in GH-induced down-regulation,...
10 CitationsSource
#1Fanxin Ma (St. Joseph's Hospital and Medical Center)H-Index: 4
#2Zhe Wei (St. Joseph's Hospital and Medical Center)H-Index: 1
Last. Yao Huang (St. Joseph's Hospital and Medical Center)H-Index: 15
view all 8 authors...
25 CitationsSource
Cited By16
#1Ashiya Buckels (UAB: University of Alabama at Birmingham)H-Index: 2
#2Yue Zhang (UAB: University of Alabama at Birmingham)H-Index: 12
Last. Stuart J. Frank (UAB: University of Alabama at Birmingham)H-Index: 45
view all 7 authors...
Abstract Melanoma is the most aggressive skin cancer. Its aggressiveness is most commonly attributed to ERK pathway mutations leading to constitutive signaling. Though initial tumor regression results from targeting this pathway, resistance often emerges. Interestingly, interrogation of the NCI-60 database indicates high growth hormone receptor (GHR) expression in melanoma cell lines. To further characterize melanoma, we tested responsiveness to human growth hormone (GH). GH treatment resulted i...
1 CitationsSource
The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement of IGF signaling in the pathogenesis of cancer, endocrine disorders including acromegaly, diabetes and thyroid eye disease, skin diseases such as acne and psoriasis, and the frailty that accompanies aging. We di...
4 CitationsSource
#1Yue Zhang (UAB: University of Alabama at Birmingham)H-Index: 12
#2Sajina Gc (UAB: University of Alabama at Birmingham)
Last. Stuart J. Frank (UAB: University of Alabama at Birmingham)H-Index: 45
view all 8 authors...
Abstract Human growth hormone (GH) binds and activates GH receptor (GHR) and prolactin (PRL) receptor (PRLR). LNCaP human prostate cancer cells express only GHR. A soluble fragment of IGF-1 receptor (IGF-1R) extracellular domain (sol IGF-1R) interacts with GHR and blocks GH signaling. We now explore sol IGF-1R's specificity for inhibiting GH signaling via GHR vs. PRLR and test GHR and PRLR extracellular domain inhibition determinants. Although T47D human breast cancer cells express GHR and PRLR,...
#1Xinyi Tan (SPU: Shenyang Pharmaceutical University)H-Index: 3
#2Yan Zhang (Shenyang University)H-Index: 5
Last. Xing Tang (SPU: Shenyang Pharmaceutical University)H-Index: 28
view all 10 authors...
Poor permeation across intestinal mucous barriers often limits the oral delivery of prospective therapeutic proteins and peptides (TPPs). In order to address this issue, cell penetrating peptide (CPP) together with PEG modified and pore-enlarged mesostructured silica nanoparticle (NP) were constructed to form the mucus-penetrating electrostatic particle-complexes, CPP/TPP/NP. Alone, CPP and TPP often present with poor stability, and their traditional electrostatic complex shows reduced pharmacod...
#1Vera Chesnokova (Cedars-Sinai Medical Center)H-Index: 23
#2Svetlana Zonis (Cedars-Sinai Medical Center)H-Index: 12
Last. Shlomo Melmed (Cedars-Sinai Medical Center)H-Index: 92
view all 5 authors...
: DNA damage occurs as a result of environmental insults and aging and, if unrepaired, may lead to chromosomal instability and tumorigenesis. Because GH suppresses ataxia-telangiectasia mutated kinase phosphorylation, decreases DNA repair, and increases DNA damage accumulation, we elucidated whether GH effects on DNA damage are mediated through induced IGF-1. In nontumorous human colon cells, GH, but not IGF-1, increased DNA damage. Stably disrupted IGF-1 receptor (IGF-1R) by lentivirus-expressi...
#1Man Lu (University of Auckland)H-Index: 1
#2Jack U. Flanagan (University of Auckland)H-Index: 19
Last. Jo K. Perry (University of Auckland)H-Index: 21
view all 5 authors...
Human growth hormone (GH) is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems. GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites. In adults, hypersecretion of GH causes acromegaly, and strategies that block the release of GH or that inhibit GH receptor (GHR) activation are the primary forms of medical therapy for this disease. Overproduc...
2 CitationsSource
#1Vera ChesnokovaH-Index: 23
#2Svetlana ZonisH-Index: 12
Last. Shlomo MelmedH-Index: 92
view all 11 authors...
: Growth hormone (GH) decreases with age, and GH therapy has been advocated by some to sustain lean muscle mass and vigor in aging patients and advocated by athletes to enhance performance. Environmental insults and aging lead to DNA damage, which - if unrepaired - results in chromosomal instability and tumorigenesis. We show that GH suppresses epithelial DNA damage repair and blocks ataxia telangiectasia mutated (ATM) kinase autophosphorylation with decreased activity. Decreased phosphorylation...
2 CitationsSource
#1Gherardo MazziottiH-Index: 42
#2Stefano Frara (UniSR: Vita-Salute San Raffaele University)H-Index: 9
Last. Andrea Giustina (UniSR: Vita-Salute San Raffaele University)H-Index: 61
view all 3 authors...
: Neuroendocrinology of bone is a new area of research based on the evidence that pituitary hormones may directly modulate bone remodeling and metabolism. Skeletal fragility associated with high risk of fractures is a common complication of several pituitary diseases such as hypopituitarism, Cushing disease, acromegaly, and hyperprolactinemia. As in other forms of secondary osteoporosis, pituitary diseases generally affect bone quality more than bone quantity, and fractures may occur even in the...
18 CitationsSource
#1Jingren XuH-Index: 2
#2Canjun ZhuH-Index: 5
Last. Gang Shu (SCAU: South China Agricultural University)H-Index: 17
view all 17 authors...
Abstract Objective Growth hormone stimulates growth by increasing insulin-like growth factor 1 expression and secretion. In the presence of insufficient nutrients, GH increases, whereas IGF-1 expression becomes severely suppressed, leading to GH resistance. This study aimed to explore the effect of arginine (Arg) on GH resistance during malnutrition and to describe its underlying mechanism. Methods C57BL/6 J mice were injected intraperitoneally with Arg for 1 h or subjected to caloric restrictio...
1 CitationsSource
#1Maulida Mazaya (UOU: University of Ulsan)H-Index: 1
#2Hung-Cuong Trinh (UOU: University of Ulsan)H-Index: 3
Last. Yung-Keun Kwon (UOU: University of Ulsan)H-Index: 7
view all 3 authors...
Background Identification of novel gene-gene relations is a crucial issue to understand system-level biological phenomena. To this end, many methods based on a correlation analysis of gene expressions or structural analysis of molecular interaction networks have been proposed. They have a limitation in identifying more complicated gene-gene dynamical relations, though.
1 CitationsSource