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.
    Full-text · Article · Jul 2015 · Biochimica et Biophysica Acta
    • "The role of LCN2 in iron delivery to cells, via the cellular uptake of the LCN2-iron complex (Yang et al., 2002), requires the existence of cellular receptors that mediate LCN2 uptake with affinity. Hvidberg and colleagues (2005) were the first to demonstrate megalin as one of the cellular receptors for LCN2, since it mediated the endocytosis of LCN2 in polarized epithelia (Hvidberg et al., 2005). In the same year, the isolation and identification of 24p3R revealed the existence of a fine-tuning mediation of iron content in the cell by LCN2 (Devireddy et al., 2005). "
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    ABSTRACT: Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in aging-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jul 2015 · Progress in Neurobiology
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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.
    Full-text · Article · Aug 2014 · PLoS ONE
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