The Lipoxin A4 Receptor Is Coupled to SHP-2 Activation

Mitchell, Derick; O'Meara, Sarah J.; Gaffney, Andrew; Crean, John; Kinsella, B. Thérèse; Godson, Catherine

doi:10.1074/jbc.m611004200

Cited by 39 publications

(6 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, we also speculate that this lipid analogue could be able to inhibit SHP-2, because, as reported previously, LXs inhibit mesangial cell proliferation via SHP-2 inhibition (Wu et al, 2005). In addition, it has been shown that ALX is coupled to activation and recruitment of SHP-2 (Mitchell et al, 2007). Further experiments are required to confirm this hypothesis and whether other phosphatases could be involved, such as PTEN (phosphatase and tensin homologue), as this phosphatase can negatively modulate VEGF-induced angiogenic effects, including cell survival, proliferation and migration (Huang and Kontos, 2002).…”

Section: Atl-1 Inhibits Multiple Steps Of Angiogenesissupporting

confidence: 75%

ATL‐1, an analogue of aspirin‐triggered lipoxin A₄, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

Cezar-de-Mello

Vieira

Nascimento-Silva

et al. 2008

British J Pharmacology

View full text Add to dashboard Cite

Background and purpose: Vascular endothelial growth factor (VEGF) is the most important proangiogenic protein. We have demonstrated that ATL-1, a synthetic analogue of aspirin-triggered lipoxin A 4 , inhibits VEGF-induced endothelial cell (EC) migration. In the present study, we investigated the effects of ATL-1 in several other actions stimulated by VEGF. Methods: Human umbilical vein ECs were treated with ATL-1 for 30 min before stimulation with VEGF. Cell proliferation was measured by thymidine incorporation. Adherent cells were determined by fluorescence intensity using a Multilabel counter. Expression and activity of matrix metalloproteinases (MMP) were analysed by western blot and zymography. Key results: ATL-1 inhibited EC adhesion to fibronectin via interaction with its specific receptor. Furthermore, VEGF-induced MMP-9 activity and expression were reduced by pretreatment with ATL-1. Because the transcription factor NF-kB has been implicated in VEGF-mediated MMP expression and EC proliferation, we postulated that ATL-1 might modulate the NF-kB pathway and, indeed, ATL-1 inhibited NF-kB nuclear translocation. Pretreatment of EC with ATL-1 strongly decreased VEGFdependent phosphorylation of phosphainositide 3-kinase (PI3-K) and extracellular signal-regulated kinase-2 (ERK-2), two signalling kinases involved in EC proliferation. Inhibition of VEGF-induced EC proliferation by ATL-1 was antagonized by sodium orthovanadate, suggesting that this inhibitory activity was mediated by a protein tyrosine phosphatase. This was confirmed by showing that ATL-1 inhibition of VEGF receptor-2 (VEGFR-2) phosphorylation correlates with SHP-1 association with VEGFR-2. Conclusions and implications:The synthetic 15-epi-lipoxin analogue, ATL-1, is a highly potent molecule exerting its effects on multiple steps of the VEGF-induced angiogenesis.

show abstract

Section: Atl-1 Inhibits Multiple Steps Of Angiogenesissupporting

confidence: 75%

ATL‐1, an analogue of aspirin‐triggered lipoxin A₄, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

Cezar-de-Mello

Vieira

Nascimento-Silva

et al. 2008

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…The in vivo agonist and anti-inflammatory and pro-resolving actions of this eicosanoid and related compounds have now been independently confirmed and extended by many investigators worldwide [3, for recent reviews, see refs. 33, 34, and 35, 36, 37]. …”

Section: Pro-resolving Gpcrsmentioning

confidence: 99%

Novel Anti-Inflammatory-Pro-Resolving Mediators and Their Receptors

Serhan¹,

Krishnamoorthy²,

Recchiuti³

et al. 2011

CTMC

244

200

View full text Add to dashboard Cite

Resolution of inflammation, an actively coordinated program, is essential to maintain host health. It involves effective removal of inflammatory stimuli and the spatio-temporal control of leukocyte trafficking as well as chemical mediator generation. During the active resolution process, new classes of small, local acting endogenous autacoids, namely the lipoxins, D and E series resolvins, (neuro)protectins, and maresins have been identified. These specialized pro-resolving lipid mediators (SPM) prevent excessive inflammation and promote removal of microbes and apoptotic cells, thereby expediting resolution and return to tissue homeostasis. As part of their molecular mechanism, SPM exert their potent actions via activating specific pro-resolving G-protein coupled receptors. Together these SPM and their receptors provide new concepts and opportunities for therapeutics, namely promoting active resolution as opposed to the conventionally used enzyme inhibitors and receptor antagonists. This approach may offer new targets suitable for drug design for treating inflammation related diseases, for the new terrain of resolution pharmacology.

show abstract

“…We suggest that good candidate molecules for this AE-derived suppressive effect are the family of resolving mediators of inflammation which include the lipoxins, resolvins and protectins [23]. Several lines of evidence support involvement of this class of mediators: i) they have already been shown to be important in epithelial cell function and repair [24] and to have a potential role in airway hyperresponsiveness [25−27] and asthma [28]; ii) they work through G 0 /Gi protein coupled receptors [29]; iii) their synthesis often requires a contribution from AEC [30]; iv) we have demonstrated for the first time that lipoxin A4, resolvin D 1 and resolvin D 2 , are potent inhibitors of HLMC degranulation and v) biochemical fractionation indicates that the activity in AEC supernatant is a <10 kDa lipid which would fit the profile of a resolving mediator.…”

Section: Discussionmentioning

confidence: 98%

Primary Human Airway Epithelial Cell-Dependent Inhibition of Human Lung Mast Cell Degranulation

et al. 2012

View full text Add to dashboard Cite

IntroductionChronic mast cell activation is a characteristic feature of asthma. BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. The aim of this study was to examine the regulation of HLMC degranulation by primary AEC from healthy and asthmatic subjects, and investigate further the inhibitory mechanism.MethodsHLMC were co-cultured with both BEAS-2B and primary AEC grown as monolayers or air-liquid interface (ALI) cultures.ResultsBoth constitutive and IgE-dependent HLMC histamine release were attenuated by BEAS-2B, primary AEC monolayers and ALI cultures. This occurred in the absence of HLMC-AEC contact indicating the presence of a soluble factor. Unlike healthy ALI AEC, asthmatic ALI-AEC did not significantly reduce constitutive histamine release. AEC inhibitory activity was transferable in primary AEC monolayer supernatant, but less active than with Transwell co-culture, suggesting that the inhibitory factor was labile. The AEC inhibitory effects were attenuated by both AEC wounding and pertussis toxin, indicating the involvement of a G0/Gi receptor coupled mechanism. Solid phase extraction of lipids (<10 kDa) removed the AEC inhibitory activity. The lipid derivatives resolvin D1 and D2 and lipoxin A4 attenuated HLMC histamine release in a dose-dependent fashion but were not detectable in co-culture supernatants.ConclusionsPrimary AEC suppress HLMC constitutive and IgE-dependent histamine secretion through the release of a soluble, labile lipid mediator(s) that signals through the G0/Gi receptor coupled mechanism. Manipulation of this interaction may have a significant therapeutic role in asthma.

show abstract

The Lipoxin A4 Receptor Is Coupled to SHP-2 Activation

Cited by 39 publications

References 47 publications

ATL‐1, an analogue of aspirin‐triggered lipoxin A₄, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

ATL‐1, an analogue of aspirin‐triggered lipoxin A₄, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

Novel Anti-Inflammatory-Pro-Resolving Mediators and Their Receptors

Primary Human Airway Epithelial Cell-Dependent Inhibition of Human Lung Mast Cell Degranulation

Contact Info

Product

Resources

About

The Lipoxin A4 Receptor Is Coupled to SHP-2 Activation

Cited by 39 publications

References 47 publications

ATL‐1, an analogue of aspirin‐triggered lipoxin A4, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

ATL‐1, an analogue of aspirin‐triggered lipoxin A4, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

Novel Anti-Inflammatory-Pro-Resolving Mediators and Their Receptors

Primary Human Airway Epithelial Cell-Dependent Inhibition of Human Lung Mast Cell Degranulation

Contact Info

Product

Resources

About

ATL‐1, an analogue of aspirin‐triggered lipoxin A₄, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

ATL‐1, an analogue of aspirin‐triggered lipoxin A₄, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor