A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma

Kondapalli, Kalyan C.; Llongueras, José P.; Capilla-González, Vivian; Prasad, Hari; Hack, Anniesha; Smith, Christopher L.; Guerrero-Cázares, Hugo; Quiñones‐Hinojosa, Alfredo; Rao, Rajini

doi:10.1038/ncomms7289

Cited by 89 publications

(183 citation statements)

References 57 publications

(74 reference statements)

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“…NHE9 Controls Trafficking of Transferrin Receptors-Endosomal pH is critical for turnover of plasma membrane proteins (27,28). Transferrin-bound iron is a major contributor to hBMVECs total cellular iron (2,14,48).…”

Section: Nhe9 Localizes To Early and Recycling Endosomes And Regulatementioning

confidence: 99%

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Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserIron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.There is high demand for iron in the brain, one of the most metabolically active organs in the body (1, 2). Iron is a co-factor of several proteins involved in specialized brain cell functions such as synthesis of neurotransmitters and myelination (3-5). Iron is also necessary for housekeeping functions such as mitochondrial respiration and DNA synthesis, crucial for brain function (5). Insufficient or surplus iron in the brain has been associated with various neurological diseases (6 -10). Although iron deficiency is associated with cognitive and brain structural deficits, excess brain iron is implicated in Alzheimer's, Parkinson's, and other neurodegenerative diseases (10, 11). Therefore, it is not surprising that iron levels are tightly regulated in the brain (10).Iron entry into the brain is regulated by the blood-brain barrier (BBB) 3 (10). This physiological barrier is characterized by tight junctions between brain microvascular endothelial cells (BMVECs) that block passive diffusion of iron into the brain (12). BMVECs are polarized cells with one surface (apical) facing the blood and the other (basal or abluminal) facing interstitial fluid of the brain. BMVECs and ensheathing astrocytes form the regulatory axis of the BBB, modulating iron transport from blood into the brain interstitium (2, 13). It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine fac...

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Section: Nhe9 Localizes To Early and Recycling Endosomes And Regulatementioning

confidence: 99%

“…NHE9 belongs to a subfamily of endosomal Na ϩ (K (28). On the other hand, loss of NHE9 exchanger function as a result of mutations in SLC9A9 leads to hyperacidification of sorting endosomes (27).…”

mentioning

confidence: 99%

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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“…BTICs: GBM612 cells were used and previously validated by Johns Hopkins Genetic Resources Core Facility (Li et al, 2014). GBM612 cells isolated from intra-operative tissue are multipotent and are able to form diffuse tumors when implanted into animal models (Guerrero-Cázares et al, 2009;Li et al, 2014;Kondapalli et al, 2015). BTICs were grown in culture flasks coated with laminin and cultured in DMEM/F12 media supplemented with 2% B-27, 1% antibiotic-antimyotic, 20 ng ml −1 FGF and 20 ng ml −1 EGF.…”

Section: Cell Linesmentioning

confidence: 99%

Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

Huang

Schiapparelli

Kozielski

et al. 2017

Journal of Cell Science

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Endogenous electric fields modulate many physiological processes by promoting directional migration, a process known as galvanotaxis. Despite the importance of galvanotaxis in development and disease, the mechanism by which cells sense and migrate directionally in an electric field remains unknown. Here, we show that electrophoresis of cell surface heparan sulfate (HS) critically regulates this process. HS was found to be localized at the anode-facing side in fetal neural progenitor cells (fNPCs), fNPCderived astrocytes and brain tumor-initiating cells (BTICs), regardless of their direction of galvanotaxis. Enzymatic removal of HS and other sulfated glycosaminoglycans significantly abolished or reversed the cathodic response seen in fNPCs and BTICs. Furthermore, Slit2, a chemorepulsive ligand, was identified to be colocalized with HS in forming a ligand gradient across cellular membranes. Using both imaging and genetic modification, we propose a novel mechanism for galvanotaxis in which electrophoretic localization of HS establishes cell polarity by functioning as a co-receptor and provides repulsive guidance through Slit-Robo signaling.

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“…This helps to confirm a possible etiological relationship between the receptor (EGFR) and its ligand (EGF). In glioblastoma cells, when researchers administered drugs that countered NHE9 proteins (above), as well as drugs that countered EGFR proteins, the cells were more readily killed, compared to cells that were only treated with EGFR-countering medication [84]. This suggests a relationship between NHE9 and EGFR, and, also, if EGFR is elevated, in autism, and this elevation is associated with the etiology of autism, it might represent an important way to lower EGFR levels.…”

Section: Egfrmentioning

confidence: 95%

“…Data demonstrate that endolysosomal pH is critical for receptor sorting and turnover. By functioning as a leak pathway for protons, the Na+/H+ exchanger NHE9 limits luminal acidification to circumvent EGFR turnover and prolongs downstream signaling pathways [84].…”

Section: Pathway Genesmentioning

confidence: 99%

Intracellular Pathways Associated with the Etiology of Autism

Russo¹

2017

Autism - Paradigms, Recent Research and Clinical Applications

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This chapter explores the relationship between the genes and proteins of the Akt and MAPK pathways and autism. This chapter presents the biology of these two pathways, their genes and cascading proteins, and then, it looks at the research that has connected these molecules to autism. Finally, it imparts current and future therapeutic modalities that might exploit abnormalities in these genes and proteins, change them and ultimately alter aberrant autistic behaviors.

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A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma

Cited by 89 publications

References 57 publications

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

Intracellular Pathways Associated with the Etiology of Autism

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