scholarly journals ADAM10 and ADAM17 in Liver Regeneration and Fibrosis: Regulation of EGFR, c-Met and TNF RI Signalling

2021 ◽  
Author(s):  
Olga Zbodakova ◽  
Karel Chalupsky ◽  
Lenka Sarnova ◽  
Petr Kasparek ◽  
Marketa Jirouskova ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Signalling Pathways ◽  
Substrate Specificities ◽  
Akt Phosphorylation ◽  
Receptor Signalling ◽  
Cellular Context ◽  
Per Se ◽  
Deficient Mice ◽  
Combined Deficiency ◽  
Severe Fibrosis

Abstract ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in impaired EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl4 intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development and results in decreased shedding of TNF RI, while ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.

scholarly journals ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Olga Zbodakova ◽  
Karel Chalupsky ◽  
Lenka Sarnova ◽  
Petr Kasparek ◽  
Marketa Jirouskova ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Signalling Pathways ◽  
Substrate Specificities ◽  
Akt Phosphorylation ◽  
Receptor Signalling ◽  
Cellular Context ◽  
Per Se ◽  
Deficient Mice ◽  
Combined Deficiency ◽  
Severe Fibrosis

AbstractADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in inhibited EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl4 intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development. Furthermore, we show that while ablation of ADAM17 resulted in decreased shedding of TNF RI, ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.

124. Regulation of SOCS3 expression by prostaglandin, prolactin and growth hormone: challenging the Jak/STAT signalling dogma

2005 ◽  
Vol 17 (9) ◽  
pp. 74
Author(s):  
J. L. Barclay ◽  
T. Wonisch ◽  
S. T. Anderson ◽  
M. J. Waters ◽  
J. D. Curlewis
Keyword(s):  
Fold Increase ◽  
Signalling Pathways ◽  
Akt Inhibitor ◽  
Akt Phosphorylation ◽  
Jak2 Inhibitor ◽  
Receptor Signalling ◽  
Socs3 Expression ◽  
Cellular Responsiveness ◽  
Responsive Element ◽  
Socs3 Mrna

SOCS3 is an inhibitor of various cytokine-receptor signalling pathways and is therefore involved in suppression of cellular responsiveness to these critical regulators. SOCS3 expression is thought to be regulated by a STAT responsive element (SRE). However, our research suggests the involvement of other signalling pathways. In T-47D breast cancer cells, we found that PGE2 induces a 3–5 fold increase in SOCS3 mRNA, as determined by real-time PCR. This effect was not due to phosphorylation of STATs, or inhibited by the Jak2 inhibitor, AG490, but was inhibited by the PI3Kinase inhibitor, LY294002, Akt Inhibitor IV and partially inhibited by the PKA inhibitor, H89. It was not affected by inhibitors of MEK, PDK1, mTOR or p38-MAPK. We concurrently examined PRL-induced SOCS3 expression, and found that although STAT1 and 5 phosphorylation was increased, SOCS3 expression was again inhibited by Akt Inhibitor IV and H89 but unaffected by AG-490. To explore this further, we used a model of GH signalling, BaF3 cells stably expressing GH receptor. GH induced a 15–20 fold increase in SOCS3 mRNA, which was accompanied by increased STAT5 phosphorylation. However the SOCS3 response was not inhibited by AG-490 or H89, but was diminished by Akt Inhibitor IV. Analysis of the SOCS3 promoter revealed a FOXO binding site. When we mutated this site in a mouse SOCS3 promoter–luciferase construct, basal and GH-induced promoter activity was significantly increased. These results are consistent with FOXO acting as a repressor, which is inactivated by Akt. We propose that in T-47D cells, SOCS3 expression involves cross-talk between PI3K/Akt and cAMP/PKA, whereas in BaF3 cells, expression is enhanced by Akt phosphorylation and subsequent FOXO inactivation. These findings contrast with the accepted Jak/STAT regulation of SOCS3 expression. This work is supported by the Australian Research Council.

Impaired liver regeneration in GBA2-deficient mice

2010 ◽  
Vol 48 (01) ◽  
Author(s):  
ER Almajan ◽  
R Sandhoff ◽  
MC Gonzales ◽  
R Büttner ◽  
S Weber ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Impaired Liver ◽  
Deficient Mice

Lyn kinase plays important roles in erythroid expansion, maturation and erythropoietin receptor signalling by regulating inhibitory signalling pathways that control survival

2014 ◽  
Vol 459 (3) ◽  
pp. 455-466 ◽  
Author(s):  
Neli S. Slavova-Azmanova ◽  
Nicole Kucera ◽  
Alison Louw ◽  
Jiulia Satiaputra ◽  
Adley Handoko ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Development ◽  
Erythropoietin Receptor ◽  
Erythroid Cell ◽  
Signalling Pathways ◽  
Erythroid Cells ◽  
Src Family Kinase ◽  
Receptor Signalling ◽  
Lyn Kinase ◽  
Control Survival

In erythroid cells both positive viability signals and feedback inhibitory signalling require the Src family kinase Lyn, influencing cell survival and their ability to differentiate. This illustrates that Lyn is critical for normal erythropoiesis and erythroid cell development.

Mesoderm-inducing properties of INT-2 and kFGF: two oncogene-encoded growth factors related to FGF

Development ◽  
1989 ◽  
Vol 106 (1) ◽  
pp. 79-83 ◽  
Author(s):  
G.D. Paterno ◽  
L.L. Gillespie ◽  
M.S. Dixon ◽  
J.M. Slack ◽  
J.K. Heath
Keyword(s):  
Growth Factors ◽  
Embryonic Development ◽  
Xenopus Laevis ◽  
Dna Synthesis ◽  
Signalling Pathways ◽  
Control Mechanisms ◽  
Animal Pole ◽  
Receptor Signalling ◽  
Mammalian Embryogenesis ◽  
Mesoderm Formation

Many theories of neoplasia suggest that oncogenic transformations result from aberrations in the control mechanisms which normally regulate growth and differentiation during embryonic development. It has recently become clear that many proto-oncogenes are differentially expressed during embryonic development and may thus be important embryonic regulatory molecules. We report here that the products of two transforming oncogenes int-2 and hst/ks (now called kfgf) can, with different potencies, induce mesoderm formation in isolated Xenopus laevis animal pole explants and stimulate DNA synthesis in mammalian fibroblasts. The results suggest that these proteins may function as mesoderm inducers in mammalian embryogenesis and that similar receptor/signalling pathways may be utilized for developmental and oncogenic processes. Finally, we have shown that the Xenopus assay system used in this study provides a powerful screen for protein factors that are active in development.

scholarly journals Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice

Gut ◽  
2020 ◽  
pp. gutjnl-2019-320230
Author(s):  
Anne Abot ◽  
Eve Wemelle ◽  
Claire Laurens ◽  
Adrien Paquot ◽  
Nicolas Pomie ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Enteric Neurons ◽  
Signalling Pathways ◽  
Bioactive Lipids ◽  
Mu Opioid Receptors ◽  
Mu Opioid ◽  
Receptor Signalling ◽  
Pathological Conditions

ObjectiveThe enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes.DesignWe measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human.ResultsWe found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic.ConclusionsUsing a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.

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