Hvidberg V, Jacobsen C, Strong RK, Cowland JB, Moestrup SK, Borregaard NThe endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 579:773-777

Institute of Medical Biochemistry, University of Aarhus, Denmark.
FEBS Letters (Impact Factor: 3.17). 02/2005; 579(3):773-7. DOI: 10.1016/j.febslet.2004.12.031
Source: PubMed


Neutrophil-gelatinase-associated lipocalin (NGAL) is a prominent protein of specific granules of human neutrophils also synthesized by epithelial cells during inflammation. NGAL binds bacterial siderophores preventing bacteria from retrieving iron from this source. Also, NGAL may be important in delivering iron to cells during formation of the tubular epithelial cells of the primordial kidney. No cellular receptor for NGAL has been described. We show here that megalin, a member of the low-density lipoprotein receptor family expressed in polarized epithelia, binds NGAL with high affinity, as shown by surface plasmon resonance analysis. Furthermore, a rat yolk sac cell line known to express high levels of megalin, endocytosed NGAL by a mechanism completely blocked by an antibody against megalin.

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    • "Similar to other lipocalin family members, LCN2 is involved in diverse cellular processes, including the transport of small hydrophobic molecules, protection of MMP-9 from proteolytic degradation, and cell signaling [2] [3] [4]. Furthermore, LCN2 can tightly bind to bacterial siderophore through a cell surface receptor, possibly serving as a potent bacteriostatic agent by sequestering iron, regulating innate immunity and protecting kidney epithelial cells from ischemia-reperfusion injury [5] [6] [7]. "
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    ABSTRACT: Lipocalin 2 (LCN2) is a poor prognostic factor in esophageal squamous cell carcinoma (ESCC), however its functional roles and molecular mechanisms of action remain to be clarified. Here, we described the functions and signaling pathways for LCN2 in ESCC. Overexpression of LCN2 in ESCC cells accelerated cell migration and invasion in vitro, and promoted lung metastasis in vivo. Blocking LCN2 expression inhibited its pro-oncogenic effect. Either overexpression of LCN2 or treatment with recombinant human LCN2 protein enhanced the activation of MEK/ERK pathway, which in turn increases endogenous LCN2 to increase MMP-9 activity. The decreased p-cofilin and increased p-ERM induced by pERK1/2 cause the cytoskeleton F-actin rearrangement and alter the behavior of ESCC cells mediated by LCN2. As a consequence, activation of MMP-9 and the rearrangement of F-actin throw light on the mechanisms for LCN2 in ESCC. These results imply LCN2 promotes the migration and invasion of ESCC cells through a novel positive feedback loop. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 07/2015; 1853(10 Pt A). DOI:10.1016/j.bbamcr.2015.07.007 · 4.66 Impact Factor
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    • "Because of its small size, NGAL filters freely through the glomerular barrier. Under normal conditions, filtered NGAL is reabsorbed in the tubules with the concourse of the proximal tubule endocytic complex formed by megalin and cubilin [49]. In this sense, our experiments show that, although the megalin/cubilin complex participates in NGAL reabsorption, there are other redundant mechanisms capable of achieving full NGAL reuptake shortly after megalin/cubilin voidance, as demonstrated in figure 7. "
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    ABSTRACT: Background Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner. Methods Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls). Results Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors. Conclusions Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion.
    PLoS ONE 08/2014; 9(8):e105988. DOI:10.1371/journal.pone.0105988 · 3.23 Impact Factor
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    • "We showed that LCN2, when highly secreted by DCs, plays a role in promoting the apoptosis of T-cells in a manner that is CD8+ T-cell-specific. This might be due to the expression of the Lcn2 receptor on the T-cell surface [54]. LCN2 binds its Lcn2R and is internalized to deliver iron, which is important for the survival of T-cells. "
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    ABSTRACT: Lipocalin 2 (LCN2), which is highly expressed by dendritic cells (DCs) when treated with dexamethasone (Dex) and lipopolysaccharide (LPS), plays a key role in the defence against bacteria and is also involved in the autocrine apoptosis of T-cells. However, the function of LCN2 when secreted by DCs is unknown: this is a critical gap in our understanding of the regulation of innate and adaptive immune systems. Tolerance, stimulation and suppression are functions of DCs that facilitate the fine-tuning of the immune responses and which are possibly influenced by LCN2 secretion. We therefore examined the role of LCN2 in DC/T-cell interaction. WT or Lcn2-/- bone marrow-derived DCs were stimulated with LPS or LPS+IFN-γ with and without Dex and subsequently co-cultured with T-cells from ovalbumin-specific TCR transgenic (OT-I and OT-II) mice. We found that CD8+ T-cell apoptosis was highly reduced when Lcn2-/- DCs were compared with WT. An in vivo CTL assay, using LPS-treated DCs, showed diminished killing ability in mice that had received Lcn2-/- DCs compared with WT DCs. As a consequence, we analysed T-cell proliferation and found that LCN2 participates in T-cell-priming in a dose-dependent manner and promotes a TH1 microenvironment. DC-secreted LCN2, whose function has previously been unknown, may in fact have an important role in regulating the balance between TH1 and TH2. Our results yield insights into DC-secreted LCN2 activity, which could play a pivotal role in cellular immune therapy and in regulating immune responses.
    PLoS ONE 07/2014; 9(7):e101881. DOI:10.1371/journal.pone.0101881 · 3.23 Impact Factor
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