Low molecular weight protein tyrosine phosphatase (LMW-PTP) and its possible physiological functions of redox signaling in the eye lens

Xing, Kuiyi; Raza, Ashraf; Löfgren, Stefan; Fernando, M. Rohan; Ho, Ye Shih; Lou, Marjorie F.

doi:10.1016/j.bbapap.2007.03.001

Cited by 23 publications

(32 citation statements)

References 30 publications

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“…Our results showed that knocking down TXNIP expression blunted VEGF-induced S-glutathionylation of LMW-PTP resulting in its hyperactivation and inhibition of VEGFR2. In support, LMW-PTP activity has been shown to be regulated by the glutathione reducing system and cellular redox state (9,53). involvement of PTP1B or SHP1 in TXNIP-mediated regulation of VEGFR2 activation (40), future work is warranted to examine whether S-glutathionylation can play a role in modulating other phosphatases similar to LMW-PTP.…”

mentioning

confidence: 97%

Thioredoxin-Interacting Protein Expression Is Required for VEGF-Mediated Angiogenic Signal in Endothelial Cells

Abdelsaid

Matragoon

El-Remessy

2013

Antioxidants & Redox Signaling

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Aims: Thioredoxin-interacting protein (TXNIP) contributes to cellular redox-state homeostasis via binding and inhibiting thioredoxin (TRX). Increasing evidence suggests that cellular redox homeostasis regulates vascular endothelial growth factor (VEGF)-mediated signaling. This study aims to examine the redox-dependant role of TXNIP in regulating VEGF-mediated S-glutathionylation and angiogenic signaling. TXNIP-knockout mice (TKO) or wild-type (WT) treated with the reduced glutathione (GSH)-precursor, N-acetyl cysteine (WT-NAC, 500 mg/kg) were compared to WT using hypoxia-induced neovascularization model. Results: In response to hypoxia, retinas from TKO and WT-NAC mice showed significant decreases in reparative revascularization and pathological neovascularization with similar VEGF expression compared with WT. VEGF failed to stimulate vascular sprouting from aortic rings of TKO compared to WT mice. TKO mice or WT+NAC experienced reductive stress as indicated by twofold increase in TRX reductase activity and fourfold increase in reduced-GSH levels compared with WT. In human microvascular endothelial (HME) cells, VEGF stimulated co-precipitation between vascular endothelial growth factor receptor 2 (VEGFR2) with low molecular weight protein tyrosine phosphatase (LMW-PTP). Silencing TXNIP expression blunted VEGF-induced oxidation of GSH and S-glutathionylation of the LMW-PTP in HME cells. These effects were associated with impaired VEGFR2 phosphorylation that culminated in inhibiting cell migration and tube formation. Overexpression of TXNIP restored VEGFR2 phosphorylation and cell migration in TKO-endothelial cells. Innovation: TXNIP expression is required for VEGF-mediated VEGFR2 activation and angiogenic response in vivo and in vitro. TXNIP expression regulates VEGFR-2 phosphorylation via S-glutathionylation of LMW-PTP in endothelial cells. Conclusion: Our results provide novel mechanistic insight into modulating TXNIP expression as a potential therapeutic target in diseases characterized by aberrant angiogenesis.

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confidence: 97%

Thioredoxin-Interacting Protein Expression Is Required for VEGF-Mediated Angiogenic Signal in Endothelial Cells

Abdelsaid

Matragoon

El-Remessy

2013

Antioxidants & Redox Signaling

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“…In parallel, VEGF induced the immediate yet reversible thiol oxidation of LMW-PTP (1-5 minutes), which was restored to normal levels after 15 minutes. The activity of LMW-PTP is dually regulated, whereby the two active cysteines (C13 and C18) that are located in the catalytic pocket must be reduced to allow enzyme phosphorylation and activity (Chiarugi, 2001;Chiarugi et al, 2001;Xing et al, 2007). In agreement, VEGF-induced phosphorylation of LMW-PTP was detected only after 15-30 minutes, a time frame where thiols of LMW-PTP are not oxidized.…”

Section: Discussionmentioning

confidence: 81%

“…LMW-PTP shares the CX5R motif with other protein tyrosine phosphatases (PTPs), which render them vulnerable targets for cellular redox changes (Okamoto et al, 2001;Shackelford et al, 2005;Shelton and Mieyal, 2008). Furthermore, a unique property of LMW-PTP is that it has two cysteines that are located in the catalytic pocket; both cysteines must be reduced for enzyme phosphorylation and activity (Chiarugi, 2001;Chiarugi et al, 2001;Xing et al, 2007). Therefore, the activity of LMW-PTP is tightly linked to redox-changes and can be a molecular switch for the regulation of cell migration and angiogenesis (Giannoni et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

S-Glutathionylation of LMW-PTP regulates VEGF-mediated FAK activation and endothelial cell migration

Abdelsaid

El-Remessy

2012

Journal of Cell Science

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SummaryAlthough promising, the ability to regulate angiogenesis through delivery of VEGF remains an unrealized goal. We have shown previously that physiological levels of peroxynitrite (1 mM) are required for a VEGF-mediated angiogenic response, yet the redox-regulated mechanisms that govern the VEGF signal remain unexplored. We assessed the impact of VEGF and peroxynitrite on modifying redox-state, the level of reduced-glutathione (GSH) and S-glutathionylation on regulation of the low molecular weight protein tyrosine phosphatase (LMW-PTP) and focal adhesion kinase (FAK), which are key mediators of VEGF-mediated cell migration. Stimulation of human microvascular endothelial (HME) cells with VEGF (20 ng/ml) or peroxynitrite (1 mM) caused an immediate and reversible negative-shift in the cellular redox-state and thiol oxidation of LMW-PTP, which culminated in cell migration. VEGF causes reversible S-glutathionylation of LMW-PTP, which inhibits its phosphorylation and activity, and causes the transient activation of FAK. Modulating the redox-state using decomposing peroxynitrite (FeTPPS, 2.5 mM) or the GSH-precursor [N-acetylcysteine (NAC), 1 mM] caused a positive-shift of the redoxstate and prevented VEGF-mediated S-glutathionylation and oxidative inhibition of LMW-PTP. NAC and FeTPPS prevented the activation of FAK, its association with LMW-PTP and cell migration. Inhibiting LMW-PTP expression markedly enhanced FAK activation and cell migration. Although mild oxidative stress achieved by combining VEGF with 0.1-0.2 mM peroxynitrite augmented cell migration, an acute shift to oxidative stress achieved by combining VEGF with 0.5 mM peroxynitrite induced and sustained FAK activation, and LMW-PTP Sglutathionylation, resulting in LMW-PTP inactivation and inhibited cell migration. In conclusion, our findings demonstrate that a balanced redox-state is required for VEGF to facilitate reversible S-glutathionylation of LMW-PTP, FAK activation and endothelial cell migration. Shifting the redox-state to reductive stress or oxidative stress inhibited the VEGF-mediated angiogenic response.

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“…27 TTase is also known to be a multifunctional enzyme with a role in many biochemical processes, including protein dethiolation, 29 reduction of ribonucleotide reductase, 28,30 reactivation of key glycolytic and oxidation defense enzymes, 31 reducing oxidized ascorbate with its dehydroascorbate reductase activity, 32,33 and participation in the regulation of signal transduction. 34,35 Trx is a small 12-kDa protein, with two highly conserved vicinal cysteine residues (WCGPC) at the active site that can reduce protein-protein disulfides. 36 Oxidized Trx is then reduced by thioredoxin reductase (TR) with electrons donated from NADPH.…”

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confidence: 99%

Ultraviolet Radiation–Induced Cataract in Mice: The Effect of Age and the Potential Biochemical Mechanism

Zhang

Löfgren

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To study the effect of age on the morphologic and biochemical alterations induced by in vivo exposure of ultraviolet radiation (UV).METHODS. Young and old C57BL/6 mice were exposed to broadband UVBþUVA and euthanized after 2 days. Another batch of UV-exposed young mice was monitored for changes after 1, 2, 4, and 8 days. Age-matched nonexposed mice served as controls. Lens changes were documented in vivo by slit-lamp biomicroscopy and dark field microscopy photographs ex vivo. Lens homogenates were analyzed for glutathione (GSH) level, and the activities of thioredoxin (Trx), thioltransferase (TTase), and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Glutathionylated lens proteins (PSSGs) were detected by immunoblotting using GSH antibody. Western blot analysis was also done for the expression levels of TTase and Trx.RESULTS. Both age groups developed epithelial and superficial anterior subcapsular cataract at 2 days postexposure. The lens GSH level and G3PD activity were decreased, and PSSGs were elevated in both age groups, but more prominent in the older mice. TTase and Trx activity and protein expression were elevated only in the young mice. Interestingly, lens TTase and Trx in the young mice showed a transient increase, peaking at 2 days after UV exposure and returning to baseline at day 8, corroborated by lens transparency.CONCLUSIONS. The lenses of old mice were more susceptible to UV radiation-induced cataract. The upregulated TTase and Trx likely provided oxidation damage repair in the young mice. (Invest Ophthalmol Vis Sci. 2012;53:7276-7285)

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Low molecular weight protein tyrosine phosphatase (LMW-PTP) and its possible physiological functions of redox signaling in the eye lens

Cited by 23 publications

References 30 publications

Thioredoxin-Interacting Protein Expression Is Required for VEGF-Mediated Angiogenic Signal in Endothelial Cells

Thioredoxin-Interacting Protein Expression Is Required for VEGF-Mediated Angiogenic Signal in Endothelial Cells

S-Glutathionylation of LMW-PTP regulates VEGF-mediated FAK activation and endothelial cell migration

Ultraviolet Radiation–Induced Cataract in Mice: The Effect of Age and the Potential Biochemical Mechanism

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