Redox-Linked Signal Transduction Pathways for Protein Tyrosine Kinase Activation

Nakashima, Izumi; Kato, Masashi; Akhand, Anwarul A.; Suzuki, Haruhiko; Takeda, Kazuhisa; Hossain, Khaled; Kawamoto, Y.

doi:10.1089/15230860260196326

Cited by 121 publications

(71 citation statements)

References 94 publications

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“…However, ligand-independent EGFR activation occurs in nonhepatic cells in response to acute oxidative stress, 31 possibly through oxidation and inactivation of protein tyrosine phosphatases. 45 Similar mechanisms probably underlie EGFR activation in S-CYP cells. Overactivation of the ErbB family of tyrosine kinase receptors has been implicated in the pathogenesis of human cancer.…”

Section: Discussionmentioning

confidence: 99%

CYP2E1 overexpression alters hepatocyte death from menadione and fatty acids by activation of ERK1/2 signaling

et al. 2004

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Chronic oxidative stress induced by overexpression of the cytochrome P450 isoform 2E1 (CYP2E1) has been implicated in hepatocyte injury and death. However, the mechanism by which CYP2E1 overexpression may promote cell death is unknown. Acute oxidative stress activates mitogen-activated protein kinases (MAPK), suggesting that chronic oxidant generation by CYP2E1 may regulate cellular responses through these signaling pathways. The effect of CYP2E1 overexpression on MAPK activation and their function in altering death responses of CYP2E1-overexpressing hepatocytes were investigated. Chronic CYP2E1 overexpression led to increased extracellular signal-regulated kinase 1/2 (ERK1/2) activation constitutively and in response to oxidant stress from the superoxide generator menadione. CYP2E1-overexpressing cells were resistant to menadione toxicity through an ERK1/2-dependent mechanism. Similar to menadione, the polyunsaturated fatty acid (PUFA) arachidonic acid (AA) induced an increased activation of ERK1/2 in hepatocytes that overexpressed CYP2E1. However, CYP2E1-overexpressing cells were sensitized to necrotic death from AA and the PUFA ␥-linolenic acid, but not from saturated or monounsaturated fatty acids. Death from PUFA resulted from oxidative stress and was blocked by inhibition of ERK1/2, but not p38 MAPK or activator protein-1 signaling. CYP2E1 expression induced ERK1/2 activation through increased epidermal growth factor receptor (EGFR)/c-Raf signaling. Inhibition of EGFR signaling reversed CYP2E1-induced resistance to menadione and sensitization to AA toxicity. In conclusion, chronic CYP2E1 overexpression leads to sustained ERK1/2 activation mediated by EGFR/c-Raf signaling. This adaptive response in hepatocytes exposed to chronic oxidative stress confers differential effects on cellular survival, protecting against menadione-induced apoptosis, but sensitizing to necrotic death from PUFA. (HEPATOLOGY 2004;39:444 -455.)

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Section: Discussionmentioning

confidence: 99%

CYP2E1 overexpression alters hepatocyte death from menadione and fatty acids by activation of ERK1/2 signaling

et al. 2004

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“…Down-regulation of Nox4 with siRNA prevents ROS generation, Src and PDK-1 tyrosine phosphorylation/activation, and fibronectin expression. Interestingly, it has been documented that Src can be directly oxidized by ROS at specific cysteine residues and that this modification enhances kinase activity (43,51). Therefore, it is tempting to speculate that the most proximal event physically tethering Nox4 activation by Ang II to the rest of the signaling cascade is a redox-dependent posttranslational modification of Src induced by Nox4-derived ROS.…”

Section: Discussionmentioning

confidence: 99%

“…Src has been shown to be activated by G-protein-coupled receptors, includingAngIIreceptors,inaROSdependent manner (48 -50). Furthermore, it has been proposed that ROS can directly target Src via an oxidative modification of specific cysteine residues, leading to activation of the tyrosine kinase (43,51). Therefore, ROS are potential proximal mediators of Ang II-induced Src and PDK-1 activation.…”

Section: Involvement Of Src In Ang Ii-induced Pdk-1 Tyrosinementioning

confidence: 99%

Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II

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Griendling

et al. 2008

Journal of Biological Chemistry

123

133

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Activation of glomerular mesangial cells (MCs) by angiotensin II (Ang II) leads to hypertrophy and extracellular matrix accumulation. Here, we demonstrate that, in MCs, Ang II induces an increase in PDK-1 (3-phosphoinositide-dependent protein kinase-1) kinase activity that required its phosphorylation on tyrosine 9 and 373/376. Introduction into the cells of PDK-1, mutated on these tyrosine residues or kinase-inactive, attenuates Ang II-induced hypertrophy and fibronectin accumulation. Ang II-mediated PDK-1 activation and tyrosine phosphorylation (total and on residues 9 and 373/376) are inhibited in cells transfected with small interfering RNA for Src, indicating that Src is upstream of PDK-1. In cells expressing oxidationresistant Src mutant C487A, Ang II-induced hypertrophy and fibronectin expression are prevented, suggesting that the pathway is redox-sensitive. Ang II also up-regulates Nox4 protein, and siNox4 abrogates the Ang II-induced increase in intracellular reactive oxygen species (ROS) generation. Small interfering RNA for Nox4 also inhibits Ang II-induced activation of Src and PDK-1 tyrosine phosphorylation (total and on residues 9 and 373/376), demonstrating that Nox4 functions upstream of Src and PDK-1. Importantly, inhibition of Nox4, Src, or PDK-1 prevents the stimulatory effect of Ang II on fibronectin accumulation and cell hypertrophy. This work provides the first evidence that Nox4-derived ROS are responsible for Ang II-induced PDK-1 tyrosine phosphorylation and activation through stimulation of Src. Importantly, this pathway contributes to Ang IIinduced MC hypertrophy and fibronectin accumulation. These data shed light on molecular processes underlying the oxidative signaling cascade engaged by Ang II and identify potential targets for intervention to prevent renal hypertrophy and fibrosis.Cellular hypertrophy and extracellular matrix accumulation in glomeruli contributes to the pathogenesis of glomerulosclerosis in fibrotic renal diseases (1-5). The octapeptide hormone angiotensin II (Ang II) 2 is the dominant renin-angiotensin system effector (5-7) and is implicated in the pathogenesis of fibrosis of the glomerular microvascular bed. Up-regulation of the renin-angiotensin system plays a key role in the initiation and the progression of glomerular injury via induction of hypertrophy and extracellular matrix expansion in glomerular mesangial cells (MCs) (6 -13).Ang II-induced oxidative stress has emerged as a critical pathogenic factor in the development of renal and vascular diseases (13-16). NAD(P)H oxidases of the Nox family are major sources of reactive oxygen species (ROS) in many nonphagocytic cells, including renal cells (17-21). The Nox proteins correspond to homologues of gp91 phox (or Nox2), the catalytic moiety found in phagocytes (17,18). Seven members of the Nox family have been identified in the human genome: Nox1 to -5 and the dual oxidases Duox1 and -2 (17, 18, 22). The isoform Nox4 (NAD(P)H oxidase 4) is abundant in the vascular system and kidney cortex (16, 17, 19 -22). We ...

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“…platelet-derived growth factor receptor (PDGFR) and c-Ret have all been reported to undergo direct oxidation (Nakashima et al, 2002). In addition to this and as documented by Kemble et al (2009) there is evidence to suggest that FGFR1 is negatively redox regulated while report that VEGFR undergoes oxidative activation.…”

Section: Rtks Such As the Insulin Receptor (Ir) Epidermal Growth Facmentioning

confidence: 85%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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Access to the full text of the published version may require a subscription. and ideas for this work, and who supported and believed in me throughout -I am grateful to have had the opportunity to learn from the best. I must also give a huge thank you to Kate Cotter, who made me feel at home from day one, and who has continued to be a tireless source of energy and assistance. RightsI was fortunate to interact with a vibrant, dynamic group in the Cotter Lab and I owe a huge thanks to every single member, past-Claire, Ruth, Carolyn, Chris, Ashley, To all the friends that I have made in U.C.C. and beyond during this process, as well as those friends lucky enough not to be involved but who still got to listen to all that whingeing-thank you! Lastly, I am most indebted to those closest to me. My mam -who is always ready to listen, comfort and reassure, and as a result probably knows more than she ever wanted to about cells and reactive oxygen species! My dad, a real scientist, who never stops teaching and never stops learning, and is still the person I turn to with my "homework" questions! I am so grateful to you both for your wisdom, encouragement and patience; truly I could not have achieved this without you. ToSinead and Dara, for all the much needed distractions and laughs, and for even being interested! And to John, for being there throughout, for the joy and the inspiration. To everyone still waiting for good news or the right medicine 'Happy is he who gets to know the reasons for things.' -Virgil DeclarationThis thesis has not been submitted in whole or in part to this or any other university for any degree and is, unless otherwise stated, the original work of the author. pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to iii NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study.The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalli...

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Redox-Linked Signal Transduction Pathways for Protein Tyrosine Kinase Activation

Cited by 121 publications

References 94 publications

CYP2E1 overexpression alters hepatocyte death from menadione and fatty acids by activation of ERK1/2 signaling

CYP2E1 overexpression alters hepatocyte death from menadione and fatty acids by activation of ERK1/2 signaling

Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

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