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

Abdelsaid, Mohammed; El-Remessy, Azza B.

doi:10.1242/jcs.103481

Cited by 55 publications

(37 citation statements)

References 50 publications

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“…For example, S-glutathionylation of the low-molecular-weight protein tyrosine phosphatase negatively regulates angiogenesis through inhibition of vascular endothelial growth factor (VEGF)-regulated FAK activation. 39 GSH is known to play other roles in regulating angiogenesis. It has been shown to prohibit ischemia-induced lung angiogenesis by sequestering of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Kassaar¹,

McMahon

Thompson³

et al. 2014

Blood

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Key Points• The x-ray crystal structure of the N2 domain from HRG at 1.93Å resolution is presented.• The structure reveals an S-glutathionyl adduct at Cys185, which has implications for angiogenic regulation.Histidine-rich glycoprotein (HRG) is a plasma protein consisting of 6 distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of 2 N-terminal domains (N1 and N2), 2 proline-rich regions (PRR1 and PRR2) that flank a histidine-rich region (HRR), and a C-terminal domain. To date, structural information of HRG has largely come from sequence analysis and spectroscopic studies. It is thought that an HRG fragment containing the HRR, released via plasmin-mediated cleavage, acts as a negative regulator of angiogenesis in vivo. However, its release also requires cleavage of a disulphide bond suggesting that its activity is mediated by a redox process. Here, we present a 1.93Å resolution crystal structure of the N2 domain of serum-purified rabbit HRG. The structure confirms that the N2 domain, which along with the N1 domain, forms an important molecular interaction site on HRG, possesses a cystatin-like fold composed of a 5-stranded antiparallel b-sheet wrapped around a 5-turn a-helix. A native N-linked glycosylation site was identified at Asn184. Moreover, the structure reveals the presence of an S-glutathionyl adduct at Cys185, which has implications for the redox-mediated release of the antiangiogenic cleavage product from HRG. (Blood. 2014;123(12):1948-1955 Introduction Histidine-rich glycoprotein (HRG) is a plasma protein that regulates angiogenesis, coagulation, and immune function in vertebrates. Human HRG has an approximate mass of 70 kDa and is present in plasma at low micromolar concentrations (ca ;1.5 mM). The protein is arranged into 6 domains: 2 N-terminal domains (N1 and N2), a central histidine-rich region (HRR) flanked by 2 proline rich regions (PRR1 and PRR2), and a C-terminal domain (C). The N1, N2, and C domains are highly conserved between species, as is an arrangement of 6 disulfide bridges (Figure 1). In plasma, HRG binds to and regulates the function of a diverse variety of targets that include fibrinogen, plasminogen, thrombospondin, immunoglobulin G (IgG), complement factors, and heparin as well as cell-surface molecules such as Fcg receptors and heparan sulfate.1-9 HRG binds divalent metal cations within the HRR. 10 In particular, Zn 21 is known to bind this region and can modulate HRG activity by altering the protein's affinity for other targets. 11HRG is heavily glycosylated; the human protein has 6 putative N-linked glycosylation sites.11 The histidine-and proline-rich regions are predicted to be intrinsically disordered but N1, N2, and the C-terminal domains are likely to have ordered structures. The N1 and N2 domains share a high degree of sequence similarity to members of the cystatin superfamily of cysteine protease inhibitors.12 Type 1 cystatins (also known as stefins) are characterized b...

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Section: Discussionmentioning

confidence: 99%

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Kassaar¹,

McMahon

Thompson³

et al. 2014

Blood

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“…ROS-dependent inactivation of some of these phosphatases would facilitate VEGF signal transduction. There are already some examples supporting this working model, such as the inhibition of SHP1 [160], LMW-PTP [161], PTP1B, and DEP1 [162]. …”

Section: Redox Signaling In Angiogenesismentioning

confidence: 94%

The Importance of NADPH Oxidases and Redox Signaling in Angiogenesis

Prieto-Bermejo

Hernández‐Hernández

2017

Antioxidants

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Eukaryotic cells have to cope with the constant generation of reactive oxygen species (ROS). Although the excessive production of ROS might be deleterious for cell biology, there is a plethora of evidence showing that moderate levels of ROS are important for the control of cell signaling and gene expression. The family of the nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidases or Nox) has evolved to produce ROS in response to different signals; therefore, they fulfil a central role in the control of redox signaling. The role of NADPH oxidases in vascular physiology has been a field of intense study over the last two decades. In this review we will briefly analyze how ROS can regulate signaling and gene expression. We will address the implication of NADPH oxidases and redox signaling in angiogenesis, and finally, the therapeutic possibilities derived from this knowledge will be discussed.

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“…Low molecular weight (LMW)-PTP (HCPTPA) was found as an interacting protein with the kinase domain of VEGFR2 [73]. LMW-PTP regulates VEGF-induced phosphorylation of focal adhesion kinase and its activity is inhibited by GSH adducts [74]. PTP1B-/- mice demonstrated enhanced in vivo angiogenesis and cardiac function after coronary artery ligation [75].…”

Section: Molecular Mechanism and Protein Targetsmentioning

confidence: 99%

Redox regulation of ischemic limb neovascularization – What we have learned from animal studies

2017

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Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.

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

Cited by 55 publications

References 50 publications

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

The Importance of NADPH Oxidases and Redox Signaling in Angiogenesis

Redox regulation of ischemic limb neovascularization – What we have learned from animal studies

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