The basic route of the nuclear translocation porcine growth hormone (GH)-growth hormone receptor (GHR) complex (pGH/GHR) in porcine hepatocytes

Lan, Hangzhen; Liu, Huilin; Khan, Muhammad Akram; Zheng, Xin; Yang, Yilin; Zhang, Hui; Yao, Ning

doi:10.1016/j.ygcen.2018.05.002

Cited by 20 publications

(23 citation statements)

References 31 publications

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“…Internalized GH and GHR were in the form of GH‐GHR dimers, which has been reported in other species extensively (Hainan et al, ; Lobie et al, ; Mertani et al, ; Roupas & Herington, ; Sachse, Van, Strous, & Klumperman, ). There are multiple pathways of endocytosis into cells, such as caveolin‐dependent, clathrin‐dependent, and caveolin‐ and clathrin‐independent manners (Doherty & McMahon, ).…”

Section: Resultssupporting

confidence: 69%

Zinc ions increase GH signaling ability through regulation of available plasma membrane‐localized GHR

Hui

Luo

et al. 2019

Journal Cellular Physiology

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It is well known that zinc ion (Zn 2+ ) can regulate the biological activity of growth hormone (GH). However, until now, the mechanism by which Zn 2+ regulates GH biological activity remains unclear. In the current study, we first performed molecular docking between Zn 2+ and porcine GH (pGH) using computational biology. We then explored the effect of Zn 2+ on the GH signaling ability in the cell model expressing porcine growth hormone receptor (GHR). It was found that the phosphorylation levels of Janus kinase 2, signal transducers and activators of transcription 5/3/1, and GHR increased significantly under Zn 2+ treatment, indicating that Zn 2+ can enhance the signaling ability of GH/GHR. On this basis, we further explored how Zn 2+ regulates the biological activity of GH/GHR. The results showed that downregulation and turnover of GHR changed under Zn 2+ /pGH treatment. Zn 2+ enhanced the membrane residence time of pGH/GHR and delayed GHR downregulation. Further investigation showed that the internalization dynamic of pGH/GHR was changed by Zn 2+ , which prolonged the residence time of pGH/GHR in the cell membrane. These factors acted together to upregulate the signaling of GH/GHR. This study lays a foundation for further exploration of the biological effects of Zn 2+ on GH. K E Y W O R D S GHR downregulation, growth hormone receptor, porcine growth hormone, signal transduction, Zn 2+ SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Li R, Hui J, Luo G, et al. Zinc ions increase GH signaling ability through regulation of available plasma membrane-localized GHR. J Cell Physiol.

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Section: Resultssupporting

confidence: 69%

Zinc ions increase GH signaling ability through regulation of available plasma membrane‐localized GHR

Hui

Luo

et al. 2019

Journal Cellular Physiology

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“…It seems clear that sorting into NAE occurs very early as NAEs co-localise with the early endosomal marker EEA1, a Rab5 effector protein [71,72]. Similarly to EGFR, GHR co-localises with early endosomal markers such as EEA1, Rab5 and Rab4 in NAE [73]. It is yet unknown whether an endosomal Rab-conversion or maturation step is involved between EE and NAE [74,75].…”

Section: Implications Of Nae For Endosomal Sortingmentioning

confidence: 99%

The NAE Pathway: Autobahn to the Nucleus for Cell Surface Receptors

Shah

Chaumet

Royle

et al. 2019

Cells

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Various growth factors and full-length cell surface receptors such as EGFR are translocated from the cell surface to the nucleoplasm, baffling cell biologists to the mechanisms and functions of this process. Elevated levels of nuclear EGFR correlate with poor prognosis in various cancers. In recent years, nuclear EGFR has been implicated in regulating gene transcription, cell proliferation and DNA damage repair. Different models have been proposed to explain how the receptors are transported into the nucleus. However, a clear consensus has yet to be reached. Recently, we described the nuclear envelope associated endosomes (NAE) pathway, which delivers EGFR from the cell surface to the nucleus. This pathway involves transport, docking and fusion of NAEs with the outer membrane of the nuclear envelope. EGFR is then presumed to be transported through the nuclear pore complex, extracted from membranes and solubilised. The SUN1/2 nuclear envelope proteins, Importin-beta, nuclear pore complex proteins and the Sec61 translocon have been implicated in the process. While this framework can explain the cell surface to nucleus traffic of EGFR and other cell surface receptors, it raises several questions that we consider in this review, together with implications for health and disease.

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“…3,16 Waters et al found that the binding domain of importin α/β on GHR is located in GHBP (the ECD of growth hormone receptor, ECD-GHR), and GHBP undergoes significant conformational change after GH binding (this is a prerequisite for GHR to trigger intracellular signal transduction). 3,16 Based on this, we speculate that 22-kD GHinduced conformational change can correctly expose the binding domain of importinα/β on GHR (but the conformational change induced by 20-kD GH cannot correctly expose the binding domain of importinα/β on GHR). This is because that 20-kD GH lacks 15 amino acid (residues 32-46) compared to 22-kD GH, which leads to that the inconsistency of the conformational changes of GHR induced by 20-kD GH or 22-kD GH.…”

Section: Discussionmentioning

confidence: 99%

“…GH is a peptide hormone synthesized and secreted by the anterior pituitary gland 3 . It can accelerate the degradation of fat, promote the proliferation of bone cells, and regulate the metabolism of carbohydrate.…”

Section: Discussionmentioning

confidence: 99%

22‐kD growth hormone‐induced nuclear GHR/STAT5/CyclinD1 signaling pathway plays an important role in promoting mesenchymal stem cell proliferation

Zheng

et al. 2021

BioFactors

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Growth hormone (GH) exhibited the important biological activities in the mesenchymal stem cell (MSCs). However, the cellular behavior and properties of GH/GHR in MSCs remain unclear. A series of experiments (such as confocal laser scanning microscope [CLSM] and Western-blot) were performed to systematically investigate the cellular behavior of GH/GHR in MSCs, and the results showed that GH/GHR not only internalized into the cytoplasm, but also transported into the cell nuclei of MSCs. Furthermore, we studied the molecular mechanism by which GH/GHR internalized into cell, and the results indicated that clathrin plays more important role in the process of GHR internalization. More importantly, it can be found that nuclear-targeted GHR has the important biological functions in MSCs, which could promote MSCs proliferation. We further revealed the molecular mechanism by which nuclear-localized GHR regulates MSCs proliferation, and found that nucleartargeted GHR enhanced the phosphorylation of STAT5, and the activated STAT5 initiates the transcription of CyclinD1, after which, the complex of CyclinD1 and CDK4 further phosphorylates Rb, and the activated Rb releases E2F1, the released E2F1 ultimately realizes the biological function of GH promoting cell proliferation. In short, in the current study，we used MSCs as a model to study the cellular behavior and properties of GH/GHR, and found that GH/GHR can internalize into cell cytoplasm and transport into the cell nuclei. Further work showed that nuclear GHR could drive cell proliferation via GHR/STAT5/CyclinD1 signaling pathway. The current research has laid an important foundation for further study on the regulatory effect of GH on MSCs.

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The basic route of the nuclear translocation porcine growth hormone (GH)-growth hormone receptor (GHR) complex (pGH/GHR) in porcine hepatocytes

Cited by 20 publications

References 31 publications

Zinc ions increase GH signaling ability through regulation of available plasma membrane‐localized GHR

Zinc ions increase GH signaling ability through regulation of available plasma membrane‐localized GHR

The NAE Pathway: Autobahn to the Nucleus for Cell Surface Receptors

22‐kD growth hormone‐induced nuclear GHR/STAT5/CyclinD1 signaling pathway plays an important role in promoting mesenchymal stem cell proliferation

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