Nitric-oxide synthase trafficking inducer is a pleiotropic regulator of endothelial cell function and signaling

Chakraborty, Shreeta and Ain, Rupasri (2017) Nitric-oxide synthase trafficking inducer is a pleiotropic regulator of endothelial cell function and signaling. The Journal of Biological Chemistry, 292 (16). pp. 6600-6620.

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    Abstract

    Endothelial nitric-oxide synthase (eNOS) and its bioactive product, nitric oxide (NO), mediate many endothelial cell functions, including angiogenesis and vascular permeability. For example, vascular endothelial growth factor (VEGF)-mediated angiogenesis is inhibited upon reduction of NO bioactivity both in vitro and in vivo. Moreover, genetic disruption or pharmacological inhibition of eNOS attenuates angiogenesis during tissue repair, resulting in delayed wound closure. These observations emphasize that eNOS-derived NO can promote angiogenesis. Intriguingly, eNOS activity is regulated by nitric-oxide synthase trafficking inducer (NOSTRIN), which sequesters eNOS, thereby attenuating NO production. This has prompted significant interest in NOSTRIN’s function in endothelial cells. We show here that NOSTRIN affects the functional transcriptome of endothelial cells by down-regulating several genes important for invasion and angiogenesis. Interestingly, the effects of NOSTRIN on endothelial gene expression were independent of eNOS activity. NOSTRIN also affected the expression of secreted cytokines involved in inflammatory responses, and ectopic NOSTRIN overexpression functionally restricted endothelial cell proliferation, invasion, adhesion, and VEGF-induced capillary tube formation. Furthermore, NOSTRIN interacted directly with TNF receptor-associated factor 6 (TRAF6), leading to the suppression of NFB activity and inhibition of AKT activation via phosphorylation. Interestingly, TNF--induced NFB pathway activation was reversed by NOSTRIN. We found that the SH3 domain of NOSTRIN is involved in the NOSTRINTRAF6 interaction and is required for NOSTRIN-induced down-regulation of endothelial cell proteins. These results have broad biological implications, as aberrant NOSTRIN expression leading to deactivation of the NFB pathway, in turn triggering an anti-angiogenic cascade, might inhibit tumorigenesis and cancer progression.

    Item Type: Article
    URI: http://www.eprints.iicb.res.in/id/eprint/2663
    Subjects: Cell Biology & Physiology
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Ms Sutapa Ganguly
    Date Deposited: 01 Jun 2017 16:59
    Last Modified: 01 Jun 2017 17:01
    Official URL: http://dx.doi.org/10.1074/jbc.M116.742627
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