Neuroglobin Regulates Wnt/β-Catenin and NFκB Signaling Pathway through Dvl1

Abstract

Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/β-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined the role of Neuroglobin in regulating Dishevelled-1 and the downstream Wnt/β-Catenin and NFκB signaling pathway. We found that Neuroglobin directly interacts with Dishevelled-1 by co-immunoprecipitation, and the two proteins are co-localized in both cytoplasma and nucleus of SK-N-SH cells. Moreover, the ectopic expression of Neuroglobin promotes the degradation of exogenous and endogenous Dishevelled-1 through the proteasomal degradation pathway. Furthermore, our results showed that Neuroglobin significantly inhibits the luciferase activity of Topflash reporter and the expression of β-Catenin mediated by Dishevelled-1 in SK-N-SH cells. In addition, we also documented that Neuroglobin enhances TNF-α-induced NFκB activation via down-regulating Dishevelled-1. Finally, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assays showed that Neuroglobin is an important neuroprotectant that protects SK-N-SH cells from TNF-α-induced decrease in cell viability. Taken together, these findings demonstrated that Neuroglobin functions as an important modulator of the Wnt/β-Catenin and NFκB signaling pathway through regulating Dishevelled-1.

Identification and Validation of Prognostic Markers for Lung Squamous Cell Carcinoma Associated with Chronic Obstructive Pulmonary Disease

“…Overexpression of DVL is known to enhance the activation of Wnt signaling and may play a role in the progression of several cancers [27][28][29][30][31][32][33][34][35][36][37]. e proto-oncogene DVLl is an important component of the Wnt/β-catenin signaling pathway and is a key cytoplasmic regulator that prevents degradation of the β-catenin protein, and its high expression in tumors is associated with malignancy [38]. Previous studies have reported that both DVL1 and DVL3 proteins are overexpressed in NSCLC and are associated with a poor prognosis.…”

The Role of Neuroglobin in the Sleep-Wake Cycle

“…20 This effect seems to be related to the regulatory impact of Ngb on the Wnt/βcatenin and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathways, which induce the proteasomal degradation of Disheveled-1. 21 Although most of the details of the mechanisms through which Ngb exerts its neuroprotective activity are unknown, colocalization studies in cells of the nervous system suggest a direct interaction between Ngb and mitochondria. It has been suggested that Ngb could participate in regulating energy metabolism and apoptosis mechanisms through its interaction with ferric cytochrome c. This antiapoptotic function of ferric cytochrome c requires the participation of Ngb-reducing activity on ferric cytochrome C, which prevents the activation of caspase-9.…”

“… 20 This effect seems to be related to the regulatory impact of Ngb on the Wnt/β-catenin and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathways, which induce the proteasomal degradation of Disheveled-1. 21 …”

Structural and (Pseudo-)Enzymatic Properties of Neuroglobin: Its Possible Role in Neuroprotection

“…Furthermore, the specific effect of increasing the amount of Ngb in retinal cells has been demonstrated by the injection of exogenous Ngb after a transient hypoxia, which turned out to be effective in decreasing the levels of inflammatory chemokines (IL-6, TNFα, IL-1B, RANTES, MCP-1, and VEGF) and microglia activation [ 150 ]. This effect appears to be linked to the regulatory effect of Ngb on the Wnt/β-catenin and NF- k B signaling pathways, which is exerted mostly through the induction of the proteasomal degradation of Dishevelled-1, a key hub protein eliciting these two processes [ 151 ].…”