scholarly journals Annexin A2 Regulates AKT Upon H2O2-Dependent Signaling Activation in Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 492 ◽  
Author(s):  
Stéphanie Castaldo ◽  
Tom Ajime ◽  
Gisela Serrão ◽  
Fábio Anastácio ◽  
Joana Rosa ◽  
...  
Keyword(s):  
Regulatory Protein ◽  
Growth Factor Receptor ◽  
Annexin A2 ◽  
Dependent Manner ◽  
Oncogenic Signaling ◽  
Akt Phosphorylation ◽  
Oncogenic Ras ◽  
Signaling Activation ◽  
And Function ◽  
Phosphatase And Tensin Homologue

Hydrogen peroxide (H2O2) is a main second messenger in oncogenic signaling networks including the Ras and the growth factor receptor pathways. This is achieved predominantly through the oxidation of redox-sensitive cysteine (Cys) residues in proteins resulting in changes to their structure and function. We previously identified annexin A2 (ANXA2) as a redox regulatory protein that plays an important cellular role during oxidative stress and also promoting tumorigenesis. Here we investigated the role of ANXA2 in the regulation of H2O2-dependent signaling that drives tumor progression. We show that depletion of ANXA2 leads to the enhanced activation of AKT following either EGF/EGFR stimulation or oncogenic Ras transformation. The phosphatase and tensin homologue (PTEN) protein negatively regulates the PI3K/AKT pathway. We demonstrate that ANXA2 via its reactive Cys-8 residue, binds to PTEN and that the co-expression of PTEN and ANXA2, but not ANXA2 Cys-8-Ala mutant, inhibits AKT phosphorylation on Ser 473. These results indicate that ANXA2 is important for PTEN regulation within the PI3K/AKT signaling cascade. Furthermore, we also reveal that ANXA2 inversely regulates the expression of the peroxidase, peroxiredoxin 2, in a reactive oxygen species dependent manner.

scholarly journals PDGFRα: Expression and Function during Mitral Valve Morphogenesis

2021 ◽  
Vol 8 (3) ◽  
pp. 28
Author(s):  
Kelsey Moore ◽  
Diana Fulmer ◽  
Lilong Guo ◽  
Natalie Koren ◽  
Janiece Glover ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Primary Cilia ◽  
Growth Factor Receptor ◽  
Akt Phosphorylation ◽  
Valve Development ◽  
Biochemical Assays ◽  
Factor Receptor Alpha ◽  
Mesenchymal Transformation ◽  
And Function

Mitral valve prolapse (MVP) is a common form of valve disease and can lead to serious secondary complications. The recent identification of MVP causal mutations in primary cilia-related genes has prompted the investigation of cilia-mediated mechanisms of disease inception. Here, we investigate the role of platelet-derived growth factor receptor-alpha (PDGFRα), a receptor known to be present on the primary cilium, during valve development using genetically modified mice, biochemical assays, and high-resolution microscopy. While PDGFRα is expressed throughout the ciliated valve interstitium early in development, its expression becomes restricted on the valve endocardium by birth and through adulthood. Conditional ablation of Pdgfra with Nfatc1-enhancer Cre led to significantly enlarged and hypercellular anterior leaflets with disrupted endothelial adhesions, activated ERK1/2, and a dysregulated extracellular matrix. In vitro culture experiments confirmed a role in suppressing ERK1/2 activation while promoting AKT phosphorylation. These data suggest that PDGFRα functions to suppress mesenchymal transformation and disease phenotypes by stabilizing the valve endocardium through an AKT/ERK pathway.

H2O2-induced transactivation of EGF receptor requires Src and mediates ERK1/2, but not Akt, activation in renal cells

2004 ◽  
Vol 286 (5) ◽  
pp. F858-F865 ◽  
Author(s):  
Shougang Zhougang ◽  
Rick G. Schnellmann
Keyword(s):  
Oxidative Stress ◽  
Egf Receptor ◽  
Primary Cultures ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Dependent Manner ◽  
Egfr Transactivation ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Renal Proximal Tubular Cells

Although oxidative stress activates epidermal growth factor receptor (EGFR), ERK1/2, and Akt in a number of cell types, the mechanisms by which oxidative stress activates these kinases are not well defined in renal epithelial cells. Exposure of primary cultures of rabbit renal proximal tubular cells to hydrogen peroxide (H2O2) stimulated Src, EGFR, ERK1/2, and Akt activation in a time-dependent manner as determined by the phosphorylation of each protein. The Src inhibitor PP1 completely blocked EGFR, ERK1/2, and Akt phosphorylation following H2O2 exposure. In contrast, blockade of the EGFR by AG1478 inhibited phosphorylation of ERK1/2 but not Src or Akt phosphorylation following H2O2 exposure. Exogenous EGF stimulated EGFR, ERK1/2, and Akt activation and the EGFR inhibitor blocked phorphorylation of ERK1/2 and Akt. The presence of PP1, but not AG1478, significantly accelerated H2O2-induced cell death. These results suggest that Src mediates H2O2-induced EGFR transactivation. H2O2- and EGF-induced ERK1/2 activation is mediated by EGFR, whereas Akt is activated by Src independent of EGFR following H2O2 exposure. Src-mediated EGFR transactivation contributes to a survival response following oxidative injury.

scholarly journals Liraglutide Preserves CD34 + Stem Cells from Dysfunction Induced by High Glucose Exposure

2021 ◽  
Author(s):  
Annalisa Sforza ◽  
Vera Vigorelli ◽  
Erica Rurali ◽  
Elisa Gambini ◽  
Martina Arici ◽  
...  
Keyword(s):  
High Glucose ◽  
Intracellular Signaling ◽  
Receptor Protein ◽  
Intracellular Camp ◽  
Protective Effects ◽  
Hematopoietic Stem ◽  
Akt Phosphorylation ◽  
Glucagon Like Peptide 1 ◽  
Signaling Activation ◽  
And Function

Abstract Background: Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34+ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34+ HSPC function.Methods: In cord blood (CB)-derived CD34+ HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and by Western Blot respectively. CD34+ HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34+ HSPC were evaluated. Results: CD34+ HSPCs express GLP-1R at transcriptional and protein level. LIRA treatment prevented and rescued HSPC proliferation and CXCR4/SDF-1α axis activity from HG-induced impairment. LIRA stimulation promoted intracellular cAMP accumulation as well as ERK1/2 and AKT signaling activation. The selective GLP-1R antagonist exendin (9-39) abrogated LIRA-dependent ERK1/2 and AKT phosphorylation along with the related protective effects. Conclusion: We provided the first evidence that CD34+ HSPC express GLP-1R and that LIRA can favorably impact on cell dysfunction due to HG exposure. These findings open new perspectives on the favorable CV effects of GLP-1 RAs in T2DM patients.

scholarly journals 20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

2009 ◽  
Vol 297 (3) ◽  
pp. F662-F670 ◽  
Author(s):  
Talha Akbulut ◽  
Kevin R. Regner ◽  
Richard J. Roman ◽  
Ellis D. Avner ◽  
John R. Falck ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Dienoic Acid ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Renal Epithelial Cells ◽  
Akt Phosphorylation ◽  
Src Inhibitor ◽  
Epidermal Growth

20-Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE) and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK1 renal epithelial cells. 20-HETE (20 μM) increased phosphorylation of Raf-1 (2.5 ± 0.2-fold), MEK1/2 (6.3 ± 1.6-fold), and ERK1/2 (5.8 ± 0.3-fold) compared with vehicle-treated cells. Similarly, the 20-HETE analogs also strongly activated ERK1/2 in a Raf-1- and MEK1/2-dependent manner. Moreover, 5,14-20-HEDE increased Akt phosphorylation by 2.2 ± 0.3-fold. 20-HETE and 5,14-20-HEDE also promoted activation (Y1086) of epidermal growth factor receptor (EGFR; Y1086) by 1.9 ± 0.2- and 2.5 ± 0.2-fold, respectively. These effects were completely blocked by the EGFR inhibitor EKB-569 (0.1 μM). Moreover, EKB-569 (0.1 μM), as well as a c-Src inhibitor, SKI-606 (0.05 μM), completely abolished the 20-HETE-mediated activation of the Raf/MEK/ERK and PI3K-Akt pathways. Blockade of PKC with bisindolylmaleimide I had no effect on 20-HETE-induced ERK1/2 activation. This study demonstrated that 20-HETE activated the Raf/MEK/ERK and Akt pathways in renal epithelial cells secondary to the activation of c-Src and EGFR.

ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases

2002 ◽  
Vol 283 (6) ◽  
pp. H2322-H2330 ◽  
Author(s):  
Thomas Krieg ◽  
Qining Qin ◽  
Elizabeth C. McIntosh ◽  
Michael V. Cohen ◽  
James M. Downey
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Pi3 Kinase ◽  
Dependent Manner ◽  
Src Tyrosine Kinase ◽  
Akt Phosphorylation ◽  
Downstream Target

Adenosine and acetylcholine (ACh) trigger preconditioning through different signaling pathways. We tested whether either could activate myocardial phosphatidylinositol 3-kinase (PI3-kinase), a putative signaling protein in ischemic preconditioning. We used phosphorylation of Akt, a downstream target of PI3-kinase, as a reporter. Exposure of isolated rabbit hearts to ACh increased Akt phosphorylation 2.62 ± 0.33 fold ( P = 0.001), whereas adenosine caused a significantly smaller increase (1.52 ± 0.08 fold). ACh-induced activation of Akt was abolished by the tyrosine kinase blocker genistein indicating at least one tyrosine kinase between the muscarinic receptor and Akt. ACh-induced Akt activation was blocked by the Src tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo[3,4- d]pyrimidine (PP2) and by 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG-1478), an epidermal growth factor receptor (EGFR) inhibitor, suggesting phosphorylation of a receptor tyrosine kinase in an Src tyrosine kinase-dependent manner. ACh caused tyrosine phosphorylation of the EGFR, which could be blocked by PP2, thus supporting this receptor hypothesis. AG-1478 failed to block the cardioprotection of ACh, however, suggesting that other receptor tyrosine kinases might be involved. Therefore, Gi protein-coupled receptors can activate PI3-kinase/Akt through transactivation of receptor tyrosine kinases in an Src tyrosine kinase-dependent manner.

SIRPα signaling regulates podocyte structure and function

2013 ◽  
Vol 305 (6) ◽  
pp. F861-F870 ◽  
Author(s):  
Satoshi Takahashi ◽  
Mai Tomioka ◽  
Keiju Hiromura ◽  
Toru Sakairi ◽  
Hiroko Hamatani ◽  
...  
Keyword(s):  
Microscopic Examination ◽  
Transmembrane Protein ◽  
Regulatory Protein ◽  
Structure And Function ◽  
Mutant Mice ◽  
Dependent Manner ◽  
Wild Type ◽  
Cytoplasmic Region ◽  
Filtration Barrier ◽  
And Function

Signal-regulatory protein-α (SIRPα) is a transmembrane protein that contains tyrosine phosphorylation sites in its cytoplasmic region; two tyrosine phosphatases, SHP-1 and SHP-2, bind to these sites in a phosphorylation-dependent manner and transduce multiple intracellular signals. Recently, SIRPα was identified as one of the major tyrosine-phosphorylated proteins in the glomeruli and found to be expressed in podocytes. In the present study, we examined the role of SIRPα expression in podocytes using knockin mice (C57BL/6 background) expressing mutant SIRPα that lacks a cytoplasmic region (SIRPα-mutant mice). Light microscopic examination revealed no apparent morphological abnormalities in the kidneys of the SIRPα-mutant mice. On the other hand, electron microscopic examination revealed abnormal podocytes with irregular major processes and wider and flattened foot processes in the SIRPα-mutant mice compared with their wild-type counterparts. Significantly impaired renal functions and slight albuminuria were demonstrated in the SIRPα-mutant mice. In addition, adriamycin injection induced massive albuminuria together with focal glomerulosclerosis in the SIRPα-mutant mice, while their wild-type counterparts were resistant to adriamycin-induced nephropathy. These data demonstrate that SIRPα is involved in the regulation of podocyte structure and function as a filtration barrier under both physiological and pathological conditions.

scholarly journals The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

2020 ◽  
Author(s):  
Enrico Castroflorio ◽  
Joery den Hoed ◽  
Daria Svistunova ◽  
Mattéa J. Finelli ◽  
Alberto Cebrian-Serrano ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Regulatory Protein ◽  
Molecular Function ◽  
Neuronal Connectivity ◽  
Nuclear Receptor Coactivator ◽  
Lysm Domain ◽  
Behavioural Assessment ◽  
And Function ◽  
The Brain

Abstract Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment. Graphic abstract

scholarly journals Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα12

2006 ◽  
Vol 26 (1) ◽  
pp. 50-62 ◽  
Author(s):  
Rashmi N. Kumar ◽  
Ji Hee Ha ◽  
Rangasudhagar Radhakrishnan ◽  
Danny N. Dhanasekaran
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Dominant Negative Mutant ◽  
Dependent Manner ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT The GTPase-deficient, activated mutant of Gα12 (Gα12Q229L, or Gα12QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells. Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor α (PDGFRα) in Gα12-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004). In the present study, we report that Gα12QL stimulates the functional expression of PDGFRα and demonstrate that the expression of PDGFRα by Gα12QL is dependent on the small GTPase Rho. Our results indicate that it is cell type independent as the transient expression of Gα12QL or the activation of Gα12-coupled receptors stimulates the expression of PDGFRα in NIH 3T3 as well as in human astrocytoma 1321N1 cells. Furthermore, we demonstrate the presence of an autocrine loop involving PDGF-A and PDGFRα in Gα12QL-transformed cells. Analysis of the functional consequences of the Gα12-PDGFRα signaling axis indicates that Gα12 stimulates the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway through PDGFR. In addition, we show that Gα12QL stimulates the phosphorylation of forkhead transcription factor FKHRL1 via AKT in a PDGFRα- and PI3K-dependent manner. Since AKT promotes cell growth by blocking the transcription of antiproliferative genes through the inhibitory phosphorylation of forkhead transcription factors, our results describe for the first time a PDGFRα-dependent signaling pathway involving PI3K-AKT-FKHRL1, regulated by Gα12QL in promoting cell growth. Consistent with this view, we demonstrate that the expression of a dominant negative mutant of PDGFRα attenuated Gα12-mediated neoplastic transformation of NIH 3T3 cells.

scholarly journals Low-Dose Radiation Activates Akt and Nrf2 in the Kidney of Diabetic Mice: A Potential Mechanism to Prevent Diabetic Nephropathy

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Xiao Xing ◽  
Chi Zhang ◽  
Minglong Shao ◽  
Qingyue Tong ◽  
Guirong Zhang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Low Dose ◽  
X Rays ◽  
Diabetic Mice ◽  
Low Dose Radiation ◽  
Single Exposure ◽  
Akt Phosphorylation ◽  
And Function ◽  
Nrf2 Expression ◽  
Dose Radiation

Repetitive exposure of diabetic mice to low-dose radiation (LDR) at 25 mGy could significantly attenuate diabetes-induced renal inflammation, oxidative damage, remodeling, and dysfunction, for which, however, the underlying mechanism remained unknown. The present study explored the effects of LDR on the expression and function of Akt and Nrf2 in the kidney of diabetic mice. C57BL/6J mice were used to induce type 1 diabetes with multiple low-dose streptozotocin. Diabetic and age-matched control mice were irradiated with whole body X-rays at either single 25 mGy and 75 mGy or accumulated 75 mGy (25 mGy daily for 3 days) and then sacrificed at 1–12 h for examining renal Akt phosphorylation and Nrf2 expression and function. We found that 75 mGy of X-rays can stimulate Akt signaling pathway and upregulate Nrf2 expression and function in diabetic kidneys; single exposure of 25 mGy did not, but three exposures to 25 mGy of X-rays could offer a similar effect as single exposure to 75 mGy on the stimulation of Akt phosphorylation and the upregulation of Nrf2 expression and transcription function. These results suggest that single 75 mGy or multiple 25 mGy of X-rays can stimulate Akt phosphorylation and upregulate Nrf2 expression and function, which may explain the prevention of LDR against the diabetic nephropathy mentioned above.

Effect of gallic acid on the reproduction of adolescent male Brandt’s vole (Lasiopodomys brandtii)

2021 ◽  
Author(s):  
Xin Dai ◽  
Xiao-Feng Sun ◽  
Ai-Qin Wang ◽  
Wanhong Wei ◽  
Sheng-Mei Yang
Keyword(s):  
Gallic Acid ◽  
Low Dose ◽  
Regulatory Protein ◽  
Antioxidant Properties ◽  
Adolescent Male ◽  
Seminiferous Tubules ◽  
High Dose ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Lasiopodomys Brandtii

Gallic acid (GA), a phenol that is present in various plants, potentially contains antioxidant properties. This study aimed to investigate the effects of GA on the reproduction of adolescent male Brandt’s voles (Lasiopodomys brandtii (Radde, 1861)). Antioxidant levels and apoptosis in the testis, as well as reproductive physiology, were evaluated in adolescent males treated with GA. The results showed that a low dose of GA enhanced relative epididymis weight and the sperm density in the epididymis, increased the mRNA levels of steroidogenic acute regulatory protein in the testis, and reduced the percentages of abnormal and dead sperm. In addition, a low dose of GA significantly increased the levels of superoxide dismutase, catalase, and glutathione peroxidase, and decreased the level of malondialdehyde in the testis, as well as the mRNA and protein levels of the apoptosis related gene, caspase-3. However, a high dose of GA sharply reduced the average diameter of the seminiferous tubules compared to a low dose. Collectively, these findings demonstrate that GA treatment during puberty affects the reproductive responses of male Brandt’s voles in a dose-dependent manner by regulating antioxidant levels and apoptosis.

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