Post-Receptor Inhibitors of the GHR-JAK2-STAT Pathway in the Growth Hormone Signal Transduction

Wójcik, M.; Krawczyńska, Agata; Antushevich, Hanna; Herman, Andrzej Przemysław

doi:10.3390/ijms19071843

Cited by 26 publications

(26 citation statements)

References 134 publications

(164 reference statements)

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“… targeted knockin mutations to the box 1 sequence of GHR in mice, which inhibited JAK2 activation by GH in vivo , and found that the activation of hepatic ERK via Src did not decrease. Src family kinase is reported to associate constitutively with GHR, and acts in parallel to JAK2/STAT5, which activates RAS and then ERK1/2 . The GHR/JAK2/STAT pathway has the most pronounced role in the somatotropic axis signal transduction.…”

Section: Discussionmentioning

confidence: 99%

“…Growth hormone, a peptide hormone produced in the anterior pituitary gland, induces cell division, regeneration and growth . It first binds to preformed growth hormone (GH) receptor (GHR) dimers and then causes a conformational change, further activating the GHR, JAK2 (Janus Kinase 2) and STAT5 signaling pathway and inducing the synthesis of insulin‐like growth factor I (IGF‐I) in liver . The effect of the GH/IGF‐1 system on cancer progression recently has been the focus of much interest.…”

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confidence: 99%

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Growth hormone receptor promotes breast cancer progression via the BRAF/MEK/ERK signaling pathway

Zhu

et al. 2020

FEBS Open Bio

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Growth hormone receptor (GHR), a member of the class I cytokine receptor family, plays key roles in cancer progression. Recently, GHR has been reported to be associated with breast cancer development, but the molecular mechanism of GHR in this malignancy is not fully understood. To investigate this issue, we stably inhibited GHR in breast cancer cell lines, which were observed to reduce cell proliferation, tumor growth and induction of apoptosis, and arrest the cell‐cycle arrest at the G1–S phase transition. In addition, GHR silencing suppressed the protein levels of B‐Raf proto‐oncogene, serine/threonine kinase (BRAF), Mitogen‐activated protein kinase kinase (MEK) and Extracellular regulated protein kinases (ERK). These findings suggest that GHR may mediate breast cell progression and apoptosis through control of the cell cycle via the BRAF/MEK/ERK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Growth hormone receptor promotes breast cancer progression via the BRAF/MEK/ERK signaling pathway

Zhu

et al. 2020

FEBS Open Bio

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“…Both GH and IGF1 are involved in somatotropic axis (GH-GHR-IGF1). IGF1 is a very potent growth factor that stimulates growth in all cell types playing a critical role in pre-and postnatal growth [34]. Therefore, further exploration of changes in GH and IGF1 proteins caused by GHR-AS-EST might provide insights into the biological significance of GHR-AS-EST and details on its regulatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…For signaling, GH needs to bind to a GHR dimer, which modifies the position of the GHR extracellular domains and activates JAK2-STAT signaling [17,34]. GHBP inhibits the binding of GH to GHR by forming a GH-GHBP complex [20].…”

Section: Ghr-as-est Blocks Signal Transmission From Gh To Ghr and Fromentioning

confidence: 99%

Identiﬁcation of a novel antisense RNA that regulates growth hormone receptor expression in chickens

et al. 2019

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Natural antisense transcripts (NATs) are widely present in mammalian genomes and act as pivotal regulator molecules of gene expression. However, studies on NATs in the chicken are relatively rare. We identiﬁed a novel antisense transcript in the chicken, designated GHR-AS-EST , transcribed from the growth hormone receptor ( GHR ) locus, which encodes a well-known regulatory molecule of muscle development and fat deposition. GHR-AS-EST is predominantly expressed in the chicken liver and muscle tissues. GHR-AS-EST sequence conservation among vertebrates is weak. GHR-AS-EST forms an RNA–RNA duplex with GHBP to increase its stability, and regulates the expression of GHR sense transcripts at both the mRNA and protein levels. Further, GHR-AS-EST promotes cell proliferation by stimulating the expression of signaling factors in the JAK2/STAT pathway, and contributes to fat deposition via downregulating the expression of signaling factors in the JAK2/SOCS pathway in LMH hepatocellular carcinoma cells. We expect that the discovery of a NAT for a regulatory gene associated with cell proliferation and lipolysis will further our understanding of the molecular regulation of both muscle development and fat deposition.

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“…As is logical, so that vascular homeostasis is fulfilled correctly, negative regulation mechanisms must exist to prevent an excess of intracellular signaling by GH after its interaction with its membrane receptor. The negative regulation of GH signaling is mainly performed by intracellular protein tyrosine phosphatases 1B and H1, suppressors of cytokine signaling (SOCS, 1, 2 and 3), sirtuin 1, protein inhibitors of activated STAT (1, 3 and 4), cytokine-inducible SH2-containing protein (CIS), and Src homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP) [82] (Figure 1). Given the different systems that act on the negative regulation of GH signaling pathways, there must be a perfect balance between them to prevent a pathological situation from occurring.…”

Section: Figurementioning

confidence: 99%

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial

Caicedo¹,

Devesa²,

Álvarez³

et al. 2019

Preprint

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Despite the important role that the GH/IGF-I axis plays in vascular homeostasis, these kind of growth factors barely appear in articles addressing the neovascularization process. Currently, the vascular endothelium has turned to be considered as an authentic gland of internal secretion due to the wide variety of released factors and functions with local effect, including the paracrine/autocrine production of GH or IGF-I, for which the endothelium has specific receptors. In this comprehensive review, it will be described the evidence involving these proangiogenic hormones in arteriogenesis dealing with the arterial occlusion and making of them a potential therapy. It will be analyzed all those elements triggering the local and systemic production of GH/IGF-I and their possible role both in physiological and pathological conditions. The whole evidence will be combined with important data from the GHAS trial, in which GH or placebo were administrated to patients suffering from critical limb ischemia with no option for revascularization. We postulate that GH, alone or in combination, should be considered as a promising therapeutic agent for helping in the approach of the ischemic disease.A normal embryonic development needs the formation of blood vessels [21]; after birth there is also the need of the formation of new blood vessels while growing, but also in some physiological processes such as the menstrual cycle in women and the development of the mammary gland during pregnancy [22], but apart from these situations, adult neovascularization rarely takes place and when it happens it is associated with pathological affectations, such as wounds, muscle injuries, fractures or hypoxia/ischemia. The question now would be: how does neovascularization occur in adults and what is the role of the GH / IGF-I system in it?As it seems logical, hypoxia is a very important stimulus for the growth of new blood vessels [23], triggering this growth through hypoxia-inducible factors (HIF) that act on the expression of proangiogenic factors, but also that of anti-angiogenic factors to achieve the perfect number and size of the vessels necessary to compensate for the lack of oxygen supply and to regenerate the tissue [23]. This is a clear and well-established fact for angiogenesis. However, when a progressive narrowing of the vascular lumen appears, preexisting collaterals will have to growth to compensate the lack of distal flow which is triggered in a totally different way. With independence of that, the stimulation of endothelial nitric oxide synthase (eNOS) that leads to the production of nitric oxide (NO) from the vascular endothelium seems to be the key mediator for both kind of reparative processes. NO is a potent vasodilator, therefore increasing blood supply to the zone affected by hypoxia/ischemia. This implies changes in the vascular tone, vasorelaxation and vasopermeability, which are affected in arteries suffering an atherosclerotic damage. Interestingly, GH activates the NO pathway [14,24] throughout direct mechanisms tha...

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Post-Receptor Inhibitors of the GHR-JAK2-STAT Pathway in the Growth Hormone Signal Transduction

Cited by 26 publications

References 134 publications

Growth hormone receptor promotes breast cancer progression via the BRAF/MEK/ERK signaling pathway

Growth hormone receptor promotes breast cancer progression via the BRAF/MEK/ERK signaling pathway

Identiﬁcation of a novel antisense RNA that regulates growth hormone receptor expression in chickens

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial

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