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AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.
Maacha S, Hong J, von Lersner A, Zijlstra A, Belkhiri A
(2018) Neoplasia 20: 1008-1022
MeSH Terms: Adenocarcinoma, Animals, Benzocycloheptenes, Biological Transport, Cathepsin B, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane, Epithelial-Mesenchymal Transition, Esophageal Neoplasms, Gene Expression Regulation, Neoplastic, Humans, Hydrogen-Ion Concentration, Lactates, Lysosomes, Monocarboxylic Acid Transporters, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Symporters, Triazoles
Show Abstract · Added April 10, 2019
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Bis(monoacylglycero)phosphate lipids in the retinal pigment epithelium implicate lysosomal/endosomal dysfunction in a model of Stargardt disease and human retinas.
Anderson DMG, Ablonczy Z, Koutalos Y, Hanneken AM, Spraggins JM, Calcutt MW, Crouch RK, Caprioli RM, Schey KL
(2017) Sci Rep 7: 17352
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Disease Models, Animal, Endosomes, Humans, Lipids, Lysophospholipids, Lysosomes, Macular Degeneration, Mice, Mice, Knockout, Monoglycerides, Retina, Retinal Pigment Epithelium
Show Abstract · Added March 22, 2018
Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N-retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4 Stargardt model mice compared to their relevant background strain. Extensive analysis by LC-MS/MS in both positive and negative ion mode was required to accurately confirm the identity of one highly expressed lipid class, bis(monoacylgylercoro)phosphate (BMP) lipids, and to distinguish them from isobaric species. The same BMP lipids were also detected in the RPE of healthy human retina. BMP lipids have been previously associated with the endosomal/lysosomal storage diseases Niemann-Pick and neuronal ceroid lipofuscinosis and have been reported to regulate cholesterol levels in endosomes. These results suggest that perturbations in lipid metabolism associated with late endosomal/lysosomal dysfunction may play a role in the pathogenesis of Stargardt disease and is evidenced in human retinas.
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14 MeSH Terms
MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia.
Evans BC, Hocking KM, Osgood MJ, Voskresensky I, Dmowska J, Kilchrist KV, Brophy CM, Duvall CL
(2015) Sci Transl Med 7: 291ra95
MeSH Terms: Animals, Endocytosis, Endosomes, Humans, Hyperplasia, Intracellular Signaling Peptides and Proteins, Lysosomes, Male, Myocytes, Smooth Muscle, Nanoparticles, Peptides, Phenotype, Phosphorylation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Rabbits, Saphenous Vein, Treatment Outcome, Tunica Intima, Vascular Grafting
Show Abstract · Added March 14, 2018
Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen-activated protein kinase (MAPK)-activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3',5'-monophosphate) element-binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i-treated grafts. The decrease in IH in MK2i-NP-treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure.
Copyright © 2015, American Association for the Advancement of Science.
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20 MeSH Terms
Directional cell movement through tissues is controlled by exosome secretion.
Sung BH, Ketova T, Hoshino D, Zijlstra A, Weaver AM
(2015) Nat Commun 6: 7164
MeSH Terms: Animals, Cell Adhesion, Cell Line, Tumor, Cell Movement, Chick Embryo, Chorioallantoic Membrane, Endosomes, Exosomes, Extracellular Matrix, Fibronectins, Green Fluorescent Proteins, Humans, Integrins, Lysosomes, Neoplasm Transplantation, Tetraspanin 30
Show Abstract · Added February 15, 2016
Directional cell movement through tissues is critical for multiple biological processes and requires maintenance of polarity in the face of complex environmental cues. Here we use intravital imaging to demonstrate that secretion of exosomes from late endosomes is required for directionally persistent and efficient in vivo movement of cancer cells. Inhibiting exosome secretion or biogenesis leads to defective tumour cell migration associated with increased formation of unstable protrusions and excessive directional switching. In vitro rescue experiments with purified exosomes and matrix coating identify adhesion assembly as a critical exosome function that promotes efficient cell motility. Live-cell imaging reveals that exosome secretion directly precedes and promotes adhesion assembly. Fibronectin is found to be a critical motility-promoting cargo whose sorting into exosomes depends on binding to integrins. We propose that autocrine secretion of exosomes powerfully promotes directionally persistent and effective cell motility by reinforcing otherwise transient polarization states and promoting adhesion assembly.
2 Communities
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16 MeSH Terms
Plasmolipin--a new player in endocytosis and epithelial development.
Le Guelte A, Macara IG
(2015) EMBO J 34: 1147-8
MeSH Terms: Animals, Endosomes, Epithelial Cells, Epithelium, Gene Expression Regulation, Developmental, Lysosomes
Added April 10, 2018
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MeSH Terms
A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy.
Hawkins A, Guttentag SH, Deterding R, Funkhouser WK, Goralski JL, Chatterjee S, Mulugeta S, Beers MF
(2015) Am J Physiol Lung Cell Mol Physiol 308: L33-47
MeSH Terms: ATP-Binding Cassette Transporters, Adaptor Proteins, Signal Transducing, Amino Acid Substitution, Autophagy, Autophagy-Related Protein 8 Family, Female, Gene Expression Regulation, Genetic Diseases, Inborn, HEK293 Cells, Humans, Infant, Lung Diseases, Interstitial, Lysosomes, Membrane Potential, Mitochondrial, Microfilament Proteins, Microtubule-Associated Proteins, Mitochondria, Mutation, Missense, Proteostasis Deficiencies, Pulmonary Surfactant-Associated Protein C, Sequestosome-1 Protein, Ubiquitin-Protein Ligases, Vacuoles, rab GTP-Binding Proteins
Show Abstract · Added January 20, 2015
Mutation of threonine for isoleucine at codon 73 (I73T) in the human surfactant protein C (hSP-C) gene (SFTPC) accounts for a significant portion of SFTPC mutations associated with interstitial lung disease (ILD). Cell lines stably expressing tagged primary translation product of SP-C isoforms were generated to test the hypothesis that deposition of hSP-C(I73T) within the endosomal system promotes disruption of a key cellular quality control pathway, macroautophagy. By fluorescence microscopy, wild-type hSP-C (hSP-C(WT)) colocalized with exogenously expressed human ATP binding cassette class A3 (hABCA3), an indicator of normal trafficking to lysosomal-related organelles. In contrast, hSP-C(I73T) was dissociated from hABCA3 but colocalized to the plasma membrane as well as the endosomal network. Cells expressing hSP-C(I73T) exhibited increases in size and number of cytosolic green fluorescent protein/microtubule-associated protein 1 light-chain 3 (LC3) vesicles, some of which colabeled with red fluorescent protein from the gene dsRed/hSP-C(I73T). By transmission electron microscopy, hSP-C(I73T) cells contained abnormally large autophagic vacuoles containing organellar and proteinaceous debris, which phenocopied ultrastructural changes in alveolar type 2 cells in a lung biopsy from a SFTPC I73T patient. Biochemically, hSP-C(I73T) cells exhibited increased expression of Atg8/LC3, SQSTM1/p62, and Rab7, consistent with a distal block in autophagic vacuole maturation, confirmed by flux studies using bafilomycin A1 and rapamycin. Functionally, hSP-C(I73T) cells showed an impaired degradative capacity for an aggregation-prone huntingtin-1 reporter substrate. The disruption of autophagy-dependent proteostasis was accompanied by increases in mitochondria biomass and parkin expression coupled with a decrease in mitochondrial membrane potential. We conclude that hSP-C(I73T) induces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD.
Copyright © 2015 the American Physiological Society.
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24 MeSH Terms
The p75 neurotrophin receptor evades the endolysosomal route in neuronal cells, favouring multivesicular bodies specialised for exosomal release.
Escudero CA, Lazo OM, Galleguillos C, Parraguez JI, Lopez-Verrilli MA, Cabeza C, Leon L, Saeed U, Retamal C, Gonzalez A, Marzolo MP, Carter BD, Court FA, Bronfman FC
(2014) J Cell Sci 127: 1966-79
MeSH Terms: Animals, Endosomes, Exosomes, Lysosomes, Microscopy, Fluorescence, Multivesicular Bodies, Neurons, PC12 Cells, RNA Interference, Rats, Receptors, Nerve Growth Factor
Show Abstract · Added March 17, 2014
The p75 neurotrophin receptor (p75, also known as NGFR) is a multifaceted signalling receptor that regulates neuronal physiology, including neurite outgrowth, and survival and death decisions. A key cellular aspect regulating neurotrophin signalling is the intracellular trafficking of their receptors; however, the post-endocytic trafficking of p75 is poorly defined. We used sympathetic neurons and rat PC12 cells to study the mechanism of internalisation and post-endocytic trafficking of p75. We found that p75 internalisation depended on the clathrin adaptor protein AP2 and on dynamin. More surprisingly, p75 evaded the lysosomal route at the level of the early endosome, instead accumulating in two different types of endosomes, Rab11-positive endosomes and multivesicular bodies (MVBs) positive for CD63, a marker of the exosomal pathway. Consistently, depolarisation by KCl induced the liberation of previously endocytosed full-length p75 into the extracellular medium in exosomes. Thus, p75 defines a subpopulation of MVBs that does not mature to lysosomes and is available for exosomal release by neuronal cells.
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1 Members
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11 MeSH Terms
EphA2 signaling following endocytosis: role of Tiam1.
Boissier P, Chen J, Huynh-Do U
(2013) Traffic 14: 1255-71
MeSH Terms: Animals, Cell Line, Tumor, Cell Membrane, Endocytosis, Guanine Nucleotide Exchange Factors, Humans, Lysosomes, Mice, Receptor, EphA2, Signal Transduction, T-Lymphoma Invasion and Metastasis-inducing Protein 1, rac1 GTP-Binding Protein
Show Abstract · Added March 5, 2014
Eph receptors and their membrane-bound ligands, the ephrins, represent a complex subfamily of receptor tyrosine kinases (RTKs). Eph/ephrin binding can lead to various and opposite cellular behaviors such as adhesion versus repulsion, or cell migration versus cell-adhesion. Recently, Eph endocytosis has been identified as one of the critical steps responsible for such diversity. Eph receptors, as many RTKs, are rapidly endocytosed following ligand-mediated activation and traffic through endocytic compartments prior to degradation. However, it is becoming obvious that endocytosis controls signaling in many different manners. Here we showed that activated EphA2 are degraded in the lysosomes and that about 35% of internalized receptors are recycled back to the plasma membrane. Our study is also the first to demonstrate that EphA2 retains the capacity to signal in endosomes. In particular, activated EphA2 interacted with the Rho family GEF Tiam1 in endosomes. This association led to Tiam1 activation, which in turn increased Rac1 activity and facilitated Eph/ephrin endocytosis. Disrupting Tiam1 function with RNA interference impaired both ephrinA1-dependent Rac1 activation and ephrinA1-induced EphA2 endocytosis. In summary, our findings shed new light on the regulation of EphA2 endocytosis, intracellular trafficking and signal termination and establish Tiam1 as an important modulator of EphA2 signaling.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
1 Communities
1 Members
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12 MeSH Terms
Lysosome-mediated processing of chromatin in senescence.
Ivanov A, Pawlikowski J, Manoharan I, van Tuyn J, Nelson DM, Rai TS, Shah PP, Hewitt G, Korolchuk VI, Passos JF, Wu H, Berger SL, Adams PD
(2013) J Cell Biol 202: 129-43
MeSH Terms: Autophagy, Biological Transport, Cell Membrane Permeability, Cell Nucleus, Cells, Cultured, Cellular Senescence, Chromatin, Chromatin Assembly and Disassembly, Cytoplasm, Fibroblasts, Histones, Humans, Laminin, Lysosomes, Nuclear Envelope, Proteolysis, Time-Lapse Imaging
Show Abstract · Added March 17, 2014
Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C-negative, but strongly γ-H2AX-positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression.
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17 MeSH Terms
AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve.
Er EE, Mendoza MC, Mackey AM, Rameh LE, Blenis J
(2013) Sci Signal 6: ra45
MeSH Terms: Blotting, Western, Cell Line, Endocytosis, Endosomes, Enzyme Activation, Epidermal Growth Factor, ErbB Receptors, HEK293 Cells, Humans, Lysosomes, Microscopy, Confocal, Models, Biological, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Transport, Proteolysis, Proto-Oncogene Proteins c-akt, RNA Interference, Signal Transduction
Show Abstract · Added November 26, 2018
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that controls cell proliferation, growth, survival, metabolism, and migration by activating the PI3K (phosphatidylinositol 3-kinase)-AKT and ERK (extracellular signal-regulated kinase)-RSK (ribosomal S6 kinase) pathways. EGFR signaling to these pathways is temporally and spatially regulated. Endocytic trafficking controls the access of EGFR to these downstream effectors and also its degradation, which terminates EGFR signaling. We showed that AKT facilitated the endocytic trafficking of EGFR to promote its degradation. Interfering with AKT signaling reduced both EGFR recycling and the rate of EGFR degradation. In AKT-impaired cells, EGFRs were unable to reach the cell surface or the lysosomal compartment and accumulated in the early endosomes, resulting in prolonged signaling and increased activation of ERK and RSK. Upon EGF stimulation, AKT phosphorylated and activated the kinase PIKfyve [FYVE-containing phosphatidylinositol 3-phosphate 5-kinase], which promoted vesicle trafficking to lysosomes. PIKfyve activation promoted EGFR degradation. Similar regulation occurred with platelet-derived growth factor receptor (PDGFR), suggesting that AKT phosphorylation and activation of PIKfyve is likely to be a common feedback mechanism for terminating RTK signaling and reducing receptor abundance.
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19 MeSH Terms