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Journal articles on the topic 'Endosomal signalling'

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Published: 10 December 2022
Last updated: 29 January 2023

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1

Tzafriri, A. Rami, and Elazer R. Edelman. "Endosomal receptor kinetics determine the stability of intracellular growth factor signalling complexes." Biochemical Journal 402, no. 3 (February 26, 2007): 537–49. http://dx.doi.org/10.1042/bj20060756.

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There is an emerging paradigm that growth factor signalling continues in the endosome and that cell response to a growth factor is defined by the integration of cell surface and endosomal events. As activated receptors in the endosome are exposed to a different set of binding partners, they probably elicit differential signals compared with when they are at the cell surface. As such, complete appreciation of growth factor signalling requires understanding of growth factor–receptor binding and trafficking kinetics both at the cell surface and in endosomes. Growth factor binding to surface receptors is well characterized, and endosomal binding is assumed to follow surface kinetics if one accounts for changes in pH. Yet, specific binding kinetics within the endosome has not been examined in detail. To parse the factors governing the binding state of endosomal receptors we analysed a whole-cell mathematical model of epidermal growth factor receptor trafficking and binding. We discovered that the stability of growth factor–receptor complexes within endosomes is governed by three primary independent factors: the endosomal dissociation constant, total endosomal volume and the number of endosomal receptors. These factors were combined into a single dimensionless parameter that determines the endosomal binding state of the growth factor–receptor complex and can distinguish different growth factors from each other and different cell states. Our findings indicate that growth factor binding within endosomal compartments cannot be appreciated solely on the basis of the pH-dependence of the dissociation constant and that the concentration of receptors in the endosomal compartment must also be considered.
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2

Cattaruzza, Fiore, Daniel P. Poole, and Nigel W. Bunnett. "Arresting inflammation: contributions of plasma membrane and endosomal signalling to neuropeptide-driven inflammatory disease." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 137–43. http://dx.doi.org/10.1042/bst20120343.

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GPCR (G-protein-coupled receptor) signalling at the plasma membrane is under tight control. In the case of neuropeptides such as SP (substance P), plasma membrane signalling is regulated by cell-surface endopeptidases (e.g. neprilysin) that degrade extracellular neuropeptides, and receptor interaction with β-arrestins, which uncouple receptors from heterotrimeric G-proteins and mediate receptor endocytosis. By recruiting GPCRs, kinases and phosphatases to endocytosed GPCRs, β-arrestins assemble signalosomes that can mediate a second wave of signalling by internalized receptors. Endosomal peptidases, such as ECE-1 (endothelin-converting enzyme-1), can degrade SP in acidified endosomes, which destabilizes signalosomes and allows receptors, freed from β-arrestins, to recycle and resensitize. By disassembling signalosomes, ECE-1 terminates β-arrestin-mediated endosomal signalling. These mechanisms have been studied in model cell systems, and the relative importance of plasma membrane and endosomal signalling to complex pathophysiological processes, such as inflammation, pain and proliferation, is unclear. However, deletion or inhibition of metalloendopeptidases that control neuropeptide signalling at the plasma membrane and in endosomes has marked effects on inflammation. Neprilysin deletion exacerbates inflammation because of diminished degradation of pro-inflammatory SP. Conversely, inhibition of ECE-1 attenuates inflammation by preventing receptor recycling/resensitization, which is required for sustained pro-inflammatory signals from the plasma membrane. β-Arrestin deletion also affects inflammation because of the involvement of β-arrestins in pro-inflammatory signalling and migration of inflammatory cells. Knowledge of GPCR signalling in specific subcellular locations provides insights into pathophysiological processes, and can provide new opportunities for therapy. Selective targeting of β-arrestin-mediated endosomal signalling or of mechanisms of receptor recycling/resensitization may offer more effective and selective treatments than global targeting of cell-surface signalling.
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3

Eden, Emily R., Thomas Burgoyne, James R. Edgar, Alexander Sorkin, and Clare E. Futter. "The relationship between ER–multivesicular body membrane contacts and the ESCRT machinery." Biochemical Society Transactions 40, no. 2 (March 21, 2012): 464–68. http://dx.doi.org/10.1042/bst20110774.

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Activated EGFR (epidermal growth factor receptor) undergoes ESCRT (endosomal sorting complex required for transport)-mediated sorting on to ILVs (intraluminal vesicles) of endosomes before degradation in the lysosome. Sorting of endocytosed EGFR on to ILVs removes the catalytic domain of the EGFR from the cytoplasm, resulting in termination of receptor signalling. EGFR signalling is also subject to down-regulation through receptor dephosphorylation by the ER (endoplasmic reticulum)-localized PTP1B (protein tyrosine phosphatase 1B). PTP1B on the cytoplasmic face of the ER interacts with endocytosed EGFR via direct membrane contacts sites between the ER and endosomes. In the present paper, we review the relationship between ER–endosome membrane contact sites and ILV formation, and their potential role in the regulation of EGFR sorting on to ILVs, through PTP1B-mediated dephosphorylation of both EGFR and components of the ESCRT machinery.
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4

Alanko, Jonna, Anja Mai, Guillaume Jacquemet, Kristine Schauer, Riina Kaukonen, Markku Saari, Bruno Goud, and Johanna Ivaska. "Integrin endosomal signalling suppresses anoikis." Nature Cell Biology 17, no. 11 (October 5, 2015): 1412–21. http://dx.doi.org/10.1038/ncb3250.

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5

Villasmil, Michelle L., Vytas A. Bankaitis, and Carl J. Mousley. "The oxysterol-binding protein superfamily: new concepts and old proteins." Biochemical Society Transactions 40, no. 2 (March 21, 2012): 469–73. http://dx.doi.org/10.1042/bst20120012.

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The Kes1 OSBP (oxysterol-binding protein) is a key regulator of membrane trafficking through the TGN (trans-Golgi network) and endosomal membranes. We demonstrated recently that Kes1 acts as a sterol-regulated rheostat for TGN/endosomal phosphatidylinositol 4-phosphate signalling. Kes1 utilizes its dual lipid-binding activities to integrate endosomal lipid metabolism with TORC1 (target of rapamycin complex 1)-dependent proliferative pathways and transcriptional control of nutrient signalling.
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6

Müller-Calleja, Nadine, Davit Manukyan, Antje Canisius, Dennis Strand, and Karl J. Lackner. "Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase." Annals of the Rheumatic Diseases 76, no. 5 (November 30, 2016): 891–97. http://dx.doi.org/10.1136/annrheumdis-2016-210012.

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ObjectivesHydroxychloroquine (HCQ) has been used for decades to treat patients with rheumatic diseases, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis or the antiphospholipid syndrome (APS). We hypothesise that HCQ might target endosomal NADPH oxidase (NOX), which is involved in the signal transduction of cytokines as well as antiphospholipid antibodies (aPL).MethodsFor in vitro experiments, monocytic cells were stimulated with tumour necrosis factor α (TNFα), interleukin-1β (IL-1β) or a human monoclonal aPL and the activity of NOX was determined by flow cytometry. The expression of genes known to be induced by these stimuli was quantified by quantitative reverse transcription PCR. Live cell imaging was performed by confocal laser scanning microscopy. Finally, the effects of HCQ on NOX-induced signal transduction were analysed in an in vivo model of venous thrombosis.ResultsHCQ strongly reduces or completely prevents the induction of endosomal NOX by TNFα, IL-1β and aPL in human monocytes and MonoMac1 cells. As a consequence, induction of downstream genes by these stimuli is reduced or abrogated. This effect of HCQ is not mediated by direct interference with the agonists but by inhibiting the translocation of the catalytic subunit of NOX2 (gp91phox) into the endosome. In vivo, HCQ protects mice from aPL-induced and NOX2-mediated thrombus formation.ConclusionsWe describe here a novel mechanism of action of HCQ, that is, interference with the assembly of endosomal NOX2. Since endosomal NOX2 is involved in many inflammatory and prothrombotic signalling pathways, this activity of HCQ might explain many of its beneficial effects in rheumatic diseases including the APS.
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7

Qiu, Shirley, and Marceline Côté. "From hitchhiker to hijacker: pathogen exploitation of endosomal phosphoinositides." Biochemistry and Cell Biology 97, no. 1 (February 2019): 1–9. http://dx.doi.org/10.1139/bcb-2017-0317.

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Signalling through phosphoinositide lipids is essential for regulating many cellular processes, including endosomal trafficking. A number of intracellular pathogens have found ways to subvert host trafficking pathways via exploitation of endosomal phosphoinositides. This review will discuss how pathogens such as bacteria, viruses, and eukaryotic parasites depend on endosomal phosphoinositides for infection as well as the mechanisms through which some are able to actively manipulate these signalling lipids to facilitate invasion, survival, replication, and immune evasion.
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8

Rodahl, Lina M., Susanne Stuffers, Viola H. Lobert, and Harald Stenmark. "The role of ESCRT proteins in attenuation of cell signalling." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 137–42. http://dx.doi.org/10.1042/bst0370137.

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The ESCRT (endosomal sorting complex required for transport) machinery consists of four protein complexes that mediate sorting of ubiquitinated membrane proteins into the intraluminal vesicles of multivesicular endosomes, thereby targeting them for degradation in lysosomes. In the present paper, we review how ESCRT-mediated receptor down-regulation affects signalling downstream of Notch and growth factor receptors, and how ESCRTs may control cell proliferation, survival and cytoskeletal functions and contribute to tumour suppression.
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9

Shelke, Ganesh Vilas, Yanan Yin, Su Chul Jang, Cecilia Lässer, Stefan Wennmalm, Hans Jürgen Hoffmann, Li Li, Yong Song Gho, Jonas Andreas Nilsson, and Jan Lötvall. "Endosomal signalling via exosome surface TGFβ-1." Journal of Extracellular Vesicles 8, no. 1 (September 20, 2019): 1650458. http://dx.doi.org/10.1080/20013078.2019.1650458.

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10

Meenhuis, Annemarie, Carola Verwijmeren, Onno Roovers, and Ivo P. Touw. "The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of the CSF3 receptor." Biochemical Journal 434, no. 2 (February 11, 2011): 343–51. http://dx.doi.org/10.1042/bj20101628.

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Ubiquitination of the CSF3R [CSF3 (colony-stimulating factor 3) receptor] occurs after activated CSF3Rs are internalized and reside in early endosomes. CSF3R ubiquitination is crucial for lysosomal routing and degradation. The E3 ligase SOCS3 (suppressor of cytokine signalling 3) has been shown to play a major role in this process. Deubiquitinating enzymes remove ubiquitin moieties from target proteins by proteolytic cleavage. Two of these enzymes, AMSH [associated molecule with the SH3 domain of STAM (signal transducing adaptor molecule)] and UBPY (ubiquitin isopeptidase Y), interact with the general endosomal sorting machinery. Whether deubiquitinating enzymes control CSF3R trafficking from early towards late endosomes is unknown. In the present study, we asked whether AMSH, UBPY or a murine family of deubiquitinating enzymes could fulfil such a role. This DUB family (deubiquitin enzyme family) comprises four members (DUB1, DUB1A, DUB2 and DUB2A), which were originally described as being haematopoietic-specific and cytokine-inducible, but their function in cytokine receptor routing and signalling has remained largely unknown. We show that DUB2A expression is induced by CSF3 in myeloid 32D cells and that DUB2 decreases ubiquitination and lysosomal degradation of the CSF3R, leading to prolonged signalling. These results support a model in which CSF3R ubiquitination is dynamically controlled at the early endosome by feedback mechanisms involving CSF3-induced E3 ligase (SOCS3) and deubiquitinase (DUB2A) activities.
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11

Raiborg, C., K. G. Bache, A. Mehlum, and H. Stenmark. "Function of Hrs in endocytic trafficking and signalling." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 472–75. http://dx.doi.org/10.1042/bst0290472.

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The hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs, becomes tyrosine-phosphorylated upon the binding of various growth factors and cytokines to their receptors. This protein is essential for ventral folding morphogenesis, and it shares structural similarity with Vps27p, which is involved in vacuolar protein sorting in yeast. Since Hrs is localized to endosomes and has been implicated in the regulation of signal transduction as well as membrane trafficking, it has been regarded as a potential co-ordinator of endosomal receptor sorting and signalling. Here we discuss the possible functions of Hrs in light of its interactions with phosphatidylinositol 3-phosphate and multiple proteins.
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12

Zhang, Ming, Li Chen, Shicong Wang, and Tuanlao Wang. "Rab7: roles in membrane trafficking and disease." Bioscience Reports 29, no. 3 (April 27, 2009): 193–209. http://dx.doi.org/10.1042/bsr20090032.

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The endocytosis pathway controls multiple cellular and physiological events. The lysosome is the destination of newly synthesized lysosomal hydrolytic enzymes. Internalized molecules or particles are delivered to the lysosome for degradation through sequential transport along the endocytic pathway. The endocytic pathway is also emerging as a signalling platform, in addition to the well-known role of the plasma membrane for signalling. Rab7 is a late endosome-/lysosome-associated small GTPase, perhaps the only lysosomal Rab protein identified to date. Rab7 plays critical roles in the endocytic processes. Through interaction with its partners (including upstream regulators and downstream effectors), Rab7 participates in multiple regulation mechanisms in endosomal sorting, biogenesis of lysosome [or LRO (lysosome-related organelle)] and phagocytosis. These processes are closely related to substrates degradation, antigen presentation, cell signalling, cell survival and microbial pathogen infection. Consistently, mutations or dysfunctions of Rab7 result in traffic disorders, which cause various diseases, such as neuropathy, cancer and lipid metabolism disease. Rab7 also plays important roles in microbial pathogen infection and survival, as well as in participating in the life cycle of viruses. Here, we give a brief review on the central role of Rab7 in endosomal traffic and summarize the studies focusing on the participation of Rab7 in disease pathogenesis. The underlying mechanism governed by Rab7 and its partners will also be discussed.
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13

Rutherford, Anna C., and Peter J. Cullen. "Phosphoinositides: Navigation through the endosomal maze." Biochemist 31, no. 5 (October 1, 2009): 20–25. http://dx.doi.org/10.1042/bio03105020.

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For many years, the phosphoinositide (PI) family of membrane lipids was studied because of its importance as intermediates in signal transduction pathways. Over the last decade, it has become increasingly clear that, in addition to these signalling functions, PIs are one of the key regulators governing the identity of intracellular membranes and the flux of membrane through the cell.
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14

Scott, Alice, and Harry Mellor. "VEGF receptor trafficking in angiogenesis." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1184–88. http://dx.doi.org/10.1042/bst0371184.

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The intracellular trafficking of receptors provides a way to control the overall sensitivity of a cell to receptor stimulation. These sorting pathways are also used to shape the balance of signals that are generated in response to receptor activation. The major pro-angiogenic growth factor receptor is VEGFR2 (vascular endothelial growth factor 2). VEGFR2 activates a very similar set of signalling pathways to other RTKs (receptor tyrosine kinases); however, its intracellular trafficking is very different. Furthermore, VEGFR2 can form a complex with a range of different angiogenic regulators that in turn regulate the trafficking of VEGFR2 through the endosomal pathway. This regulated trafficking of VEGFR2 has important consequences for angiogenic signalling and is a clear demonstration of how the endosomal pathway plays a critical role in connecting receptor signalling pathways to cellular events.
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15

Le Borgne, Roland. "Regulation of Notch signalling by endocytosis and endosomal sorting." Current Opinion in Cell Biology 18, no. 2 (April 2006): 213–22. http://dx.doi.org/10.1016/j.ceb.2006.02.011.

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16

Prinz, Nadine, Natascha Clemens, Antje Canisius, and Karl Lackner. "Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells." Thrombosis and Haemostasis 109, no. 03 (2013): 525–31. http://dx.doi.org/10.1160/th12-06-0421.

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SummaryAntiphospholipid antibodies (aPL) have been shown to induce tissue factor (TF) expression in monocytes and endothelial cells. However, the underlying signal transduction has been more or less elusive in the past. We have recently shown that aPL enter the lysosomal route in monocytes and dendritic cells, and subsequently activate endosomal NADPH-oxidase (NOX). The generation of superoxide which is dismutated to hydrogen peroxide upregulates the intracellular toll like receptors (TLR) 7 and 8, and leads to robust production of inflammatory cytokines. Here we show that induction of TF by aPL follows the same signaling pathway. Inhibition of endosomal NOX by the anion channel blocker niflumic acid or capture of superoxide by the radical scavenger N-acetylcysteine blocks TF induction by aPL. Furthermore, monocytes from mice deficient in NOX2 do not increase TF surface expression in response to aPL, while cells from mice deficient in glutathione peroxidase- 1 (GPx-1) show an increased response. Unexpectedly, also induction of TF by tumour necrosis factor (TNF)⍺ and lipopolysaccharide (LPS) was strongly dependent on the activation of endosomal NOX. While TNF⍺ apparently depends almost fully on endosomal NOX, signalling of LPS is only partially dependent on this pathway. These data provide further insight into the well-known role of reactive oxygen species in the induction of TF expression and suggest that endosomal signalling may represent a central coordinating point in this process.
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17

Li, Qiang, Yulong Zhang, Jennifer J. Marden, Botond Banfi, and John F. Engelhardt. "Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury." Biochemical Journal 411, no. 3 (April 14, 2008): 531–41. http://dx.doi.org/10.1042/bj20071534.

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c-Src has been shown to activate NF-κB (nuclear factor κB) following H/R (hypoxia/reoxygenation) by acting as a redox-dependent IκBα (inhibitory κB) tyrosine kinase. In the present study, we have investigated the redox-dependent mechanism of c-Src activation following H/R injury and found that ROS (reactive oxygen species) generated by endosomal Noxs (NADPH oxidases) are critical for this process. Endocytosis following H/R was required for the activation of endosomal Noxs, c-Src activation, and the ability of c-Src to tyrosine-phosphorylate IκBα. Quenching intra-endosomal ROS during reoxygenation inhibited c-Src activation without affecting c-Src recruitment from the plasma membrane to endosomes. However, siRNA (small interfering RNA)-mediated knockdown of Rac1 prevented c-Src recruitment into the endosomal compartment following H/R. Given that Rac1 is a known activator of Nox1 and Nox2, we investigated whether these two proteins were required for c-Src activation in Nox-deficient primary fibroblasts. Findings from these studies suggest that both Nox1 and Nox2 participate in the initial redox activation of c-Src following H/R. In summary, our results suggest that Rac1-dependent Noxs play a critical role in activating c-Src following H/R injury. This signalling pathway may be a useful therapeutic target for ischaemia/reperfusion-related diseases.
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18

Gingras, Marie-Claude, Jalal M. Kazan, and Arnim Pause. "Role of ESCRT component HD-PTP/PTPN23 in cancer." Biochemical Society Transactions 45, no. 3 (June 15, 2017): 845–54. http://dx.doi.org/10.1042/bst20160332.

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Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the Endosomal Sorting Complexes Required for Transport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the bona fide role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/PTPN23 was recently identified as a novel haplo-insufficient tumour suppressor in vitro and in vivo, in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/PTPN23 in tumorigenesis.
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19

Morgan, Anthony J., Frances M. Platt, Emyr Lloyd-Evans, and Antony Galione. "Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease." Biochemical Journal 439, no. 3 (October 13, 2011): 349–78. http://dx.doi.org/10.1042/bj20110949.

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Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.
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20

Cullen, Peter J. "Endosomal sorting and signalling: an emerging role for sorting nexins." Nature Reviews Molecular Cell Biology 9, no. 7 (June 4, 2008): 574–82. http://dx.doi.org/10.1038/nrm2427.

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21

Barrow, R., L. Menard, and S. Kermorgant. "454 c-Met endosomal signalling and breast cancer cell migration." European Journal of Cancer Supplements 8, no. 5 (June 2010): 116. http://dx.doi.org/10.1016/s1359-6349(10)71255-6.

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22

Iraburu, Maria J., Tommy Garner, and Cristina Montiel-Duarte. "Revising Endosomal Trafficking under Insulin Receptor Activation." International Journal of Molecular Sciences 22, no. 13 (June 29, 2021): 6978. http://dx.doi.org/10.3390/ijms22136978.

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The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.
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23

DiNicolantonio, James J., and Mark McCarty. "Thrombotic complications of COVID-19 may reflect an upregulation of endothelial tissue factor expression that is contingent on activation of endosomal NADPH oxidase." Open Heart 7, no. 1 (June 2020): e001337. http://dx.doi.org/10.1136/openhrt-2020-001337.

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The high rate of thrombotic complications associated with COVID-19 seems likely to reflect viral infection of vascular endothelial cells, which express the ACE2 protein that enables SARS-CoV-2 to invade cells. Various proinflammatory stimuli can promote thrombosis by inducing luminal endothelial expression of tissue factor (TF), which interacts with circulating coagulation factor VII to trigger extrinsic coagulation. The signalling mechanism whereby these stimuli evoke TF expression entails activation of NADPH oxidase, upstream from activation of the NF-kappaB transcription factor that drives the induced transcription of the TF gene. When single-stranded RNA viruses are taken up into cellular endosomes, they stimulate endosomal formation and activation of NADPH oxidase complexes via RNA-responsive toll-like receptor 7. It is therefore proposed that SARS-CoV-2 infection of endothelial cells evokes the expression of TF which is contingent on endosomal NADPH oxidase activation. If this hypothesis is correct, hydroxychloroquine, spirulina (more specifically, its chromophore phycocyanobilin) and high-dose glycine may have practical potential for mitigating the elevated thrombotic risk associated with COVID-19.
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Linnemannstöns, Karen, Leonie Witte, Pradhipa Karuna M, Jeanette Clarissa Kittel, Adi Danieli, Denise Müller, Lena Nitsch, et al. "Ykt6-dependent endosomal recycling is required for Wnt secretion in the Drosophila wing epithelium." Development 147, no. 15 (July 1, 2020): dev185421. http://dx.doi.org/10.1242/dev.185421.

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ABSTRACTMorphogens are important signalling molecules for tissue development and their secretion requires tight regulation. In the wing imaginal disc of flies, the morphogen Wnt/Wingless is apically presented by the secreting cell and re-internalized before final long-range secretion. Why Wnt molecules undergo these trafficking steps and the nature of the regulatory control within the endosomal compartment remain unclear. Here, we have investigated how Wnts are sorted at the level of endosomes by the versatile v-SNARE Ykt6. Using in vivo genetics, proximity-dependent proteomics and in vitro biochemical analyses, we show that most Ykt6 is present in the cytosol, but can be recruited to de-acidified compartments and recycle Wnts to the plasma membrane via Rab4-positive recycling endosomes. Thus, we propose a molecular mechanism by which producing cells integrate and leverage endocytosis and recycling via Ykt6 to coordinate extracellular Wnt levels.
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Li, Xinran, Abigail G. Garrity, and Haoxing Xu. "Regulation of membrane trafficking by signalling on endosomal and lysosomal membranes." Journal of Physiology 591, no. 18 (August 20, 2013): 4389–401. http://dx.doi.org/10.1113/jphysiol.2013.258301.

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26

Barrow-McGee, Rachel, and Stéphanie Kermorgant. "Met endosomal signalling: In the right place, at the right time." International Journal of Biochemistry & Cell Biology 49 (April 2014): 69–74. http://dx.doi.org/10.1016/j.biocel.2014.01.009.

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Al-Fahad, Dhurgham, Bandar Fahad Alharbi, Clementino Ibeas Bih, and Philip Richard Dash. "Nitric oxide may regulate focal adhesion turnover and cell migration in MDA-MB-231 breast cancer cells by modulating early endosome trafficking." Medical Journal of Cell Biology 9, no. 2 (June 1, 2021): 60–72. http://dx.doi.org/10.2478/acb-2021-0010.

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Abstract Cell migration is an essential process for wound healing, metastasis and inflammation. Focal adhesions (FA) are local regions of plasma membrane consisting of multiprotein complexes providing adhesive contact between the cell and the extracellular matrix (ECM). FA turnover regulates different signalling pathways implicated in various cellular responses (e.g. cell migration). Endocytosis, specifically the dynamin and clathrin pathways, is known to regulate cell migration by modulating FA dynamics. In this study, we investigated whether NO activity regulates cell migration, FA dynamics and early endosome trafficking in MDA-MB-231 cells. The assessment of cell migration showed a slowing down of cell migration and an increased duration of FA turnover in cells treated with inhibitors of NO synthase (NOS) such as L-NAME or 1400W. In addition, these treatments were found to exhibit no effect on transferrin and dextran uptake mediated by endocytosis and micropinocytosis, respectively. The number of early endosome antigen 1 (EEA1)-positive endosomes was reduced while their sizes were found to increase in cells treated with L-NAME or 1400W. In contrast, these inhibitors did not affect the number nor the size of Rab5-positive endosomes. Furthermore, we demonstrated that EEA1, endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) were colocalised. Using the biotin switch assay followed by western blot, we showed that early endosome proteins such as APPL1, EEA1, Rab5 were found to be S-nitrosylated. These results were further supported by the sequence analysis performed with the GPS-SNO algorithm which predicted the S-nitrosylation of these endosomal proteins. Taken together, our findings suggest that NO might be involved in cell migration and FA turnover through early endosome trafficking in MDA-MB-231 cells. Running title: Nitric oxide in MDA-MB-231 breast cancer cells
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28

Sorkin, A. "Internalization of the epidermal growth factor receptor: role in signalling." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 480–84. http://dx.doi.org/10.1042/bst0290480.

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The interaction of the activated epidermal growth factor (EGF) receptor (EGFR) with the Src homology 2 (SH2) domain of Grb2 (growth-factor-receptor-bound protein 2) initiates signalling through Ras and mitogen-activated protein kinase. Grb2 can bind EGFR directly or through another SH2-containing protein, She. Activation of EGFRs by ligand also triggers rapid endocytosis of EGF-receptor complexes. To analyse the spatial and temporal regulation of EGFR interactions with SH2 domains in living cells, we have combined imaging microscopy with a modified method of measuring fluorescence resonance energy transfer (FRET) on a pixel-by-pixel basis using EGFR fused to cyan fluorescent protein (CFP) in pair with Grb2 or She fused to yellow fluorescent protein (YFP). Stimulation by EGF resulted in the recruitment of Grb2-YFP and YFP-Shc to cellular compartments that contained EGFR-CFP, and a large increase in the FRET signal. In particular, FRET measurements indicated that activated EGFR-CFP interacted with YFP-Shc and Grb2-YFP in membrane ruffles and endosomes. These results demonstrate that signalling via EGFRs can occur in the endosomal compartment. Moreover, in contrast with previous biochemical studies, FRET experiments show that a large pool of Grb2 and Shc is associated with EGFRs for a prolonged period after EGF stimulation.
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Žárský, Viktor, and Martin Potocký. "Recycling domains in plant cell morphogenesis: small GTPase effectors, plasma membrane signalling and the exocyst." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 723–28. http://dx.doi.org/10.1042/bst0380723.

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The Rho/Rop small GTPase regulatory module is central for initiating exocytotically ACDs (active cortical domains) in plant cell cortex, and a growing array of Rop regulators and effectors are being discovered in plants. Structural membrane phospholipids are important constituents of cells as well as signals, and phospholipid-modifying enzymes are well known effectors of small GTPases. We have shown that PLDs (phospholipases D) and their product, PA (phosphatidic acid), belong to the regulators of the secretory pathway in plants. We have also shown that specific NOXs (NADPH oxidases) producing ROS (reactive oxygen species) are involved in cell growth as exemplified by pollen tubes and root hairs. Most plant cells exhibit several distinct plasma membrane domains (ACDs), established and maintained by endocytosis/exocytosis-driven membrane protein recycling. We proposed recently the concept of a ‘recycling domain’ (RD), uniting the ACD and the connected endosomal recycling compartment (endosome), as a dynamic spatiotemporal entity. We have described a putative GTPase–effector complex exocyst involved in exocytic vesicle tethering in plants. Owing to the multiplicity of its Exo70 subunits, this complex, along with many RabA GTPases (putative recycling endosome organizers), may belong to core regulators of RD organization in plants.
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Bruns, Alexander F., Leyuan Bao, John H. Walker, and Sreenivasan Ponnambalam. "VEGF-A-stimulated signalling in endothelial cells via a dual receptor tyrosine kinase system is dependent on co-ordinated trafficking and proteolysis." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1193–97. http://dx.doi.org/10.1042/bst0371193.

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The mammalian endothelium expresses two related but distinct receptor tyrosine kinases, VEGFR1 and VEGFR2 [VEGF (vascular endothelial growth factor) receptor 1 and 2], that regulate the vascular response to a key cytokine, VEGF-A. In the present review, we suggest a model for integrating the signals from these receptor tyrosine kinases by co-ordinating the spatial and temporal segregation of these membrane proteins linked to distinct signalling outputs associated with each intracellular location. Activation of pro-angiogenic VEGFR2 stimulates a programme of tyrosine phosphorylation, ubiquitination and proteolysis. This is linked to ESCRT (endosomal sorting complex required for transport)-mediated recognition of activated VEGFR2 and sorting in endosomes before arrival in lysosomes for terminal degradation. In addition, Rab GTPases regulate key events in VEGFR2 trafficking between the plasma membrane, early and late endosomes, with distinct roles for Rab4a, Rab5a and Rab7a. Manipulation of GTPase levels affects not only VEGFR2 activation and intracellular signalling, but also functional outputs such as VEGF-A-stimulated endothelial cell migration. In contrast, VEGFR1 displays stable Golgi localization that can be perturbed by cell stimuli that elevate cytosolic Ca2+ ion levels. One model is that VEGFR1 translocates from the trans-Golgi network to the plasma membrane via a calcium-sensitive trafficking step. This allows rapid and preferential sequestration of VEGF-A by the higher-affinity VEGFR1, thus blocking further VEGFR2 activation. Recycling or degradation of VEGFR1 allows resensitization of the VEGFR2-dependent signalling pathway. Thus a dual VEGFR system with a built-in negative-feedback loop is utilized by endothelial cells to sense a key cytokine in vascular tissues.
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31

Wooten, M. W., and T. Geetha. "The role of ubiquitin in neurotrophin receptor signalling and sorting." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 757–60. http://dx.doi.org/10.1042/bst0340757.

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NGF (nerve growth factor) binding to TrkA (tropomyosin receptor kinase A) induces dimerization, autophosphorylation and internalization of the receptor to signalling vesicles for delivery of differentiation signals. TrkA interacts with p75 receptor through the p62–TRAF-6 (tumour-necrosis-factor-receptor-associated factor 6) complex bridging the two receptors. The atypical protein kinase C is activated and recruited to the receptor complex as well. TrkA is Lys63-polyubiquitinated on Lys485 by the E3 (ubiquitin ligase), TRAF-6, and E2 (ubiquitin-conjugating enzyme), UbcH7. Inhibition of polyubiquitination has been observed to interrupt signalling and internalization. Furthermore, an absence of p62 prevents endosomal localization and signalling. Altogether, these findings reveal Lys63-linked polyubiquitin chains and the shuttling protein p62 co-ordinately regulate TrkA internalization, trafficking and sorting.
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Matarrese, Paola, Valeria Manganelli, Tina Garofalo, Antonella Tinari, Lucrezia Gambardella, Kenneth Ndebele, Roya Khosravi-Far, Maurizio Sorice, Mauro Degli Esposti, and Walter Malorni. "Endosomal compartment contributes to the propagation of CD95/Fas-mediated signals in type II cells." Biochemical Journal 413, no. 3 (July 15, 2008): 467–78. http://dx.doi.org/10.1042/bj20071704.

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Participation of diverse organelles in the intracellular signalling that follows CD95/Fas receptor ligation encompasses a series of subcellular changes that are mandatory for, or even bolster, the apoptotic cascade. In the present study, we analysed the role of endocytosis in the propagation of cell death signalling after CD95/Fas engagement in type II cells (CEM cells). We show that this receptor–ligand interaction triggers endocytosis independently of any caspase activation. This FasL (Fas ligand)-induced endocytosis also leads to an early and directional ‘movement’ of endocytic vesicles towards the mitochondrial compartment. In turn, this cross-talk between endosomal and mitochondrial compartments was followed by the loss of the mitochondrial membrane potential and apoptosis execution. This cell remodelling was absent in receptor-independent cell death, such as that induced by the mitochondriotropic drug staurosporine, and in a CEM cell line selected for its multidrug resistance (CEM VBL100). In these cells a reduced FasL (Fas ligand)-induced endocytosis and a reduced organelle cross-talk corresponded to a reduced apoptosis. Altogether, these findings suggest a key role of endocytosis in the propagation and amplification of the CD95/Fas-activated signalling leading to type II cell demise.
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Jacomin, Anne-Claire, Raksha Gohel, Zunoon Hussain, Agnes Varga, Tamas Maruzs, Mark Eddison, Margaux Sica, et al. "Degradation of arouser by endosomal microautophagy is essential for adaptation to starvation in Drosophila." Life Science Alliance 4, no. 2 (December 14, 2020): e202000965. http://dx.doi.org/10.26508/lsa.202000965.

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Hunger drives food-seeking behaviour and controls adaptation of organisms to nutrient availability and energy stores. Lipids constitute an essential source of energy in the cell that can be mobilised during fasting by autophagy. Selective degradation of proteins by autophagy is made possible essentially by the presence of LIR and KFERQ-like motifs. Using in silico screening of Drosophila proteins that contain KFERQ-like motifs, we identified and characterized the adaptor protein Arouser, which functions to regulate fat storage and mobilisation and is essential during periods of food deprivation. We show that hypomorphic arouser mutants are not satiated, are more sensitive to food deprivation, and are more aggressive, suggesting an essential role for Arouser in the coordination of metabolism and food-related behaviour. Our analysis shows that Arouser functions in the fat body through nutrient-related signalling pathways and is degraded by endosomal microautophagy. Arouser degradation occurs during feeding conditions, whereas its stabilisation during non-feeding periods is essential for resistance to starvation and survival. In summary, our data describe a novel role for endosomal microautophagy in energy homeostasis, by the degradation of the signalling regulatory protein Arouser.
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Tatematsu, Megumi, Tsukasa Seya, and Misako Matsumoto. "Beyond dsRNA: Toll-like receptor 3 signalling in RNA-induced immune responses." Biochemical Journal 458, no. 2 (February 14, 2014): 195–201. http://dx.doi.org/10.1042/bj20131492.

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The innate immune system recognizes pathogen- and damage-associated molecular patterns using pattern-recognition receptors that activate a wide range of signalling cascades to maintain host homoeostasis against infection and inflammation. Endosomal TLR3 (Toll-like receptor 3), a type I transmembrane protein, senses RNAs derived from cells with viral infection or sterile tissue damage, leading to the induction of type I interferon and cytokine production, as well as dendritic cell maturation. It has been accepted that TLR3 recognizes perfect dsRNA, but little has been addressed experimentally with regard to the structural features of virus- or host-derived RNAs that activate TLR3. Recently, a TLR3 agonist was identified, which was a virus-derived ‘structured’ RNA with incomplete stem structures. Both dsRNA and structured RNA are similarly internalized through clathrin- and raftlin-dependent endocytosis and delivered to endosomal TLR3. The dsRNA uptake machinery, in addition to TLR3, is critical for extracellular viral RNA-induced immune responses. A wide spectrum of TLR3 ligand structures beyond dsRNA and their delivery systems provide new insights into the physiological role of TLR3 in virus- or host-derived RNA-induced immune responses. In the present paper, we focus on the system for extracellular recognition of RNA and its delivery to TLR3.
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Sposini, Silvia, and Aylin C. Hanyaloglu. "Driving gonadotrophin hormone receptor signalling: the role of membrane trafficking." Reproduction 156, no. 6 (December 2018): R195—R208. http://dx.doi.org/10.1530/rep-18-0423.

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Our understanding of G protein-coupled receptor (GPCR) signalling has significantly evolved over the past decade, whereby signalling not only occurs from the plasma membrane but continues, or is reactivated, following internalisation in to endosomal compartments. The spatial organisation of GPCRs is thus essential to decode dynamic and complex signals and to activate specific downstream pathways that elicit the appropriate cellular response. For the gonadotrophin hormone receptors, membrane trafficking has been demonstrated to play a significant role in regulating its signal activity that in turn would impact at physiological and even pathophysiological level. Here, we will describe the developments in our understanding of the role of ‘location’ in gonadotrophin hormone receptor signalling, and how these receptors have unveiled fundamental mechanisms of signal regulation likely to be pertinent for other GPCRs. We will also discuss the potential impact of spatially controlled gonadotrophin hormone receptor signalling in both health and disease, and the therapeutic possibilities this new understanding of these receptors, so key in reproduction, offers.
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36

Norwood, Suzanne, Natalya Leneva, Rajesh Ghai, Nathan Cowieson, Anthony Duff, Kathleen Wood, and Brett Collins. "Structural characterisation of retromer complexes." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C417. http://dx.doi.org/10.1107/s2053273314095825.

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Retromer is a peripheral membrane protein complex that plays a critical role in a broad range of physiological, developmental and pathological processes including Wnt signalling, toxin transport and amyloid production in Alzheimer's disease. The classical mammalian retromer complex consists of a core heterotrimeric cargo recognition sub-complex (VPS26, VPS29 and VPS35) associated with a dimer of proteins from the SNX–BAR sorting nexin family that drives membrane deformation and tubulation. By recruiting the cargo-selective sub-complex to the forming tubules, the SNX–BAR coat complex mediates the retrograde transport of proteins from endosomes to the trans-Golgi network. Recent studies, however, have highlighted the molecular and functional diversity of retromer and the identification of new interacting proteins has revealed that the role of retromer extends to aspects of endosome-to-plasma membrane sorting and regulation of signalling events. Emerging evidence indicates that cargo specificity is mediated by specific sorting nexins. These include SNX3, involved in the trafficking of the Wntless/MIG-14 protein, and SNX27, a PX-FERM protein that mediates the retrieval of the β2-adrenergic receptor.Using the MX and SAXS/WAXS beamlines at the Australian Synchrotron, we have acquired crystallographic and small angle scattering data to determine how the core cargo recognition sub-complex assembles and to characterise the retromer-associated sorting nexins. We are using this structural information in combination with biochemical and biological studies in a synergistic approach to understand retromer-mediated endosomal protein sorting and how this fascinating protein complex contributes to a diverse set of cellular processes. The retromer complex is conserved across all eukaryotes. We are also currently exploring the structure of these proteins in the thermophilic fungus Chaetomium thermophilum and initial crystallisation experiments have produced some promising results.
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37

Eden, Emily R., Ian J. White, and Clare E. Futter. "Down-regulation of epidermal growth factor receptor signalling within multivesicular bodies." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 173–77. http://dx.doi.org/10.1042/bst0370173.

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Activated EGFR (epidermal growth factor receptor) undergoes ESCRT (endosomal sorting complex required for transport)-mediated sorting on to the intraluminal vesicles of MVBs (multivesicular bodies) before degradation in the lysosome. Sorting of endocytosed EGFR on to the intraluminal vesicles of MVBs removes the catalytic domain of the EGFR from the cytoplasm, resulting in termination of receptor signalling. The formation of intraluminal vesicles that contain EGFR is promoted by EGF stimulation in a mechanism that depends on the EGFR substrate, annexin 1. Signalling from endocytosed EGFR is also subject to down-regulation through receptor dephosphorylation by PTPs (protein tyrosine phosphatases), such as PTP1B, an enzyme thought to reside on the ER (endoplasmic reticulum). In the present paper, we review how the phosphorylation state of components of the MVB sorting machinery, as well as the EGFR, may play a critical role in regulating EGFR sorting and signalling.
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38

Lu, Jing, and Gary B. Willars. "Endothelin-converting enzyme-1 regulates glucagon-like peptide-1 receptor signalling and resensitisation." Biochemical Journal 476, no. 3 (February 8, 2019): 513–33. http://dx.doi.org/10.1042/bcj20180853.

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Abstract Following nutrient ingestion, glucagon-like peptide 1 (GLP-1) is secreted from intestinal L-cells and mediates anti-diabetic effects, most notably stimulating glucose-dependent insulin release from pancreatic β-cells but also inhibiting glucagon release, promoting satiety and weight reduction and potentially enhancing or preserving β-cell mass. These effects are mediated by the GLP-1 receptor (GLP-1R), which is a therapeutic target in type 2 diabetes. Although agonism at the GLP-1R has been well studied, desensitisation and resensitisation are perhaps less well explored. An understanding of these events is important, particularly in the design and use of novel receptor ligands. Here, using either HEK293 cells expressing the recombinant human GLP-1R or the pancreatic β-cell line, INS-1E with endogenous expressesion of the GLP-1R, we demonstrate GLP-1R desensitisation and subsequent resensitisation following removal of extracellular GLP-1 7-36 amide. Resensitisation is dependent on receptor internalisation, endosomal acidification and receptor recycling. Resensitisation is also regulated by endothelin-converting enzyme-1 (ECE-1) activity, most likely through proteolysis of GLP-1 in endosomes and the facilitation of GLP-1R dephosphorylation and recycling. Inhibition of ECE-1 activity also increases GLP-1-induced activation of extracellular signal-regulated kinase and generation of cAMP, suggesting processes dependent upon the lifetime of the internalised ligand–receptor complex.
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39

Fang, Zijian, Shiqian Chen, Yusman Manchanda, Stavroula Bitsi, Philip Pickford, Alessia David, Maria M. Shchepinova, et al. "Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells." International Journal of Molecular Sciences 21, no. 21 (November 9, 2020): 8404. http://dx.doi.org/10.3390/ijms21218404.

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The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.
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40

Yeh, Yi-Chun, Yu-Ping Lin, Holger Kramer, and Anant B. Parekh. "Single-nucleotide polymorphisms in Orai1 associated with atopic dermatitis inhibit protein turnover, decrease calcium entry and disrupt calcium-dependent gene expression." Human Molecular Genetics 29, no. 11 (October 10, 2019): 1808–23. http://dx.doi.org/10.1093/hmg/ddz223.

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Abstract Loss-of function mutations in Orai1 Ca2+ channels lead to a form of severe combined immunodeficiency, auto-immunity, muscle hypotonia and defects in dental enamel production and sweat gland function. Two single-nucleotide polymorphisms (SNPs) in Orai1 have been found and localize to the second extracellular loop. These polymorphisms associate with atopic dermatitis but how they affect Ca2+ signalling and cell function is unknown. Here, we find that Orai1–SNPs turnover considerably more slowly than wild type Orai1 and are more abundantly expressed in the plasma membrane. We show a central role for flotillin in the endocytotic recycling of Orai1 channels and that endocytosed wild type Orai1 is trafficked to Rab 7-positive late endosomes for lysosomal degradation. Orai1–SNPs escape the degradation pathway and instead enter Rab 11-positive recycling endosomes, where they are returned to the surface membrane through Arf6-dependent exocytosis. We find that Orai1–SNPs escape late endosomes through endosomal pH regulation of interaction between the channel and flotillin. We identify a pH-sensitive electrostatic interaction between positively charged arginine in extracellular loop 2 (K210) and a negatively charged aspartate (D112) in extracellular loop 1 that helps determine Orai1 turnover. The increase in membrane Orai1–SNP leads to a mis-match in Orai1–STIM stoichiometry, resulting in inhibition of Ca2+ entry and Ca2+-dependent gene expression. Our results identify new strategies for targeting atopic dermatitis.
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41

Bucci, Cecilia, and Maria De Luca. "Molecular basis of Charcot–Marie–Tooth type 2B disease." Biochemical Society Transactions 40, no. 6 (November 21, 2012): 1368–72. http://dx.doi.org/10.1042/bst20120197.

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CMT2B (Charcot–Marie–Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway. In neurons, Rab7 is important for endosomal trafficking and signalling of neurotrophins, and for retrograde axonal transport. Recent data on CMT2B-causing Rab7 mutant proteins show that these proteins exhibit altered koff rates and, as a consequence, they are mainly in the GTP-bound state and bind more strongly to Rab7 effector proteins. Notably, expression of CMT2B-causing Rab7 mutant proteins strongly inhibit neurite outgrowth in several cells lines and alter NGF (nerve growth factor) trafficking and signalling. These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. In the present paper, we discuss the current understanding of the molecular and cellular mechanisms underlying CMT2B, and we consider possible hypotheses in order to explain how alterations of Rab7 function lead to CMT2B.
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42

Poschet, Jens F., Joseph A. Fazio, Graham S. Timmins, Wojciech Ornatowski, Elizabeth Perkett, Monica Delgado, and Vojo Deretic. "Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide–cylic GMP signalling cascade." EMBO reports 7, no. 5 (April 13, 2006): 553–59. http://dx.doi.org/10.1038/sj.embor.7400674.

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43

Thapa, Narendra, Mo Chen, Hudson T. Horn, Suyong Choi, Tianmu Wen, and Richard A. Anderson. "Phosphatidylinositol 3-kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4." Nature Cell Biology 22, no. 11 (November 2020): 1357–70. http://dx.doi.org/10.1038/s41556-020-00596-4.

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44

Lyszkiewicz, Marcin, Daniel Kotlarz, Natalia Zietara, Gudrun Brandes, Jana Diestelhorst, Silke Glage, Eliash Hobeika, et al. "Complete Block of Early B Cell Differentiation in Mice Lacking the Endosomal Adaptor Protein p14." Blood 126, no. 23 (December 3, 2015): 1026. http://dx.doi.org/10.1182/blood.v126.23.1026.1026.

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Abstract Human primary immunodeficiency caused by a point mutation in the 3' untranslated region of the endosomal adaptor protein p14 (also known as Lamtor2) resulted in severely impaired function of neutrophils, B cells, T cells and melanocytes. However, complexity of the phenotype and scarcity of human material preclude in-depth studies. Therefore, to gain insight into the role of p14 in B cell development and function, we generated loxP conditional knock-out mice. Using mb-1-Cre mice we demonstrated that loss of p14 at the preB1 stage lead to a complete block of B cell development, resulting in the absence of IgM-positive B cells. Further, to test the significance of p14 deficiency in peripheral organs, we took advantage of CD19-Cre mice, which have limited efficiency in deleting target genes in the bone marrow, but reach up to 95% efficiency in spleen. Thus, we could demonstrate that later in B cell development, p14 was essential for the generation and activation of mature B lymphocytes. While B1 cell development was maintained, splenic follicular B cells were massively reduced in the absence of p14. Furthermore, activation of B cell receptor (BCR) resulted in impaired intracellular signalling and proliferation of p14 deficient B cells. In particular, lack of p14 lead to delayed internalization of BCR and endosomal processing associated with impaired mobilization of Ca++ from intracellular stores as well as aberrant phosphorylation of BCR-associated kinases. In conclusion, our data revealed that p14 is a critical regulator of B cell development and function, which acts by modulating BCR signalling. Disclosures No relevant conflicts of interest to declare.
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Walkley, Steven U., Jakub Sikora, Matthew Micsenyi, Cristin Davidson, and Kostantin Dobrenis. "Lysosomal compromise and brain dysfunction: examining the role of neuroaxonal dystrophy." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1436–41. http://dx.doi.org/10.1042/bst0381436.

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Lysosomal diseases are a family of over 50 disorders caused by defects in proteins critical for normal function of the endosomal/lysosomal system and characterized by complex pathogenic cascades involving progressive dysfunction of many organ systems, most notably the brain. Evidence suggests that compromise in lysosomal function is highly varied and leads to changes in multiple substrate processing and endosomal signalling, in calcium homoeostasis and endoplasmic reticulum stress, and in autophagocytosis and proteasome function. Neurons are highly vulnerable and show abnormalities in perikarya, dendrites and axons, often in ways seemingly unrelated to the primary lysosomal defect. A notable example is NAD (neuroaxonal dystrophy), which is characterized by formation of focal enlargements (spheroids) containing diverse organelles and other components consistent with compromise of retrograde axonal transport. Although neurons may be universally susceptible to NAD, GABAergic neurons, particularly Purkinje cells, appear most vulnerable and ataxia and related features of cerebellar dysfunction are a common outcome. As NAD is found early in disease and thus may be a contributor to Purkinje cell dysfunction and death, understanding its link to lysosomal compromise could lead to therapies designed to prevent its occurrence and thereby ameliorate cerebellar dysfunction.
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46

Marijanovic, Zrinka, Josiane Ragimbeau, José van der Heyden, Gilles Uzé, and Sandra Pellegrini. "Comparable potency of IFNα2 and IFNβ on immediate JAK/STAT activation but differential down-regulation of IFNAR2." Biochemical Journal 407, no. 1 (September 12, 2007): 141–51. http://dx.doi.org/10.1042/bj20070605.

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Type I IFNs (interferons) (IFNα/β) form a family of related cytokines that control a variety of cellular functions through binding to a receptor composed of IFNAR (IFNα receptor subunit) 1 and 2. Among type I IFNs, the α2 and β subtypes exhibit a large difference in their binding affinities to IFNAR1, and it was suggested that high concentrations of IFNAR1 may compensate for its low intrinsic binding affinity for IFNα2. We tested whether receptor-proximal signalling events are sensitive to IFNAR1 surface concentration by investigating the relationship between relative IFNAR1/IFNAR2 surface levels and IFNα2 and IFNβ signalling potencies in several cell lines. For this, we monitored the activation profile of JAK (Janus kinase)/STAT (signal transducer and activator of transcription) proteins, measured basal and ligand-induced surface decay of each receptor subunit and tested the effect of variable IFNAR1 levels on IFNα2 signalling potency. Our data show that the cell-surface IFNAR1 level is indeed a limiting factor for assembly of the functional complex, but an increased concentration of it does not translate into an IFNα/β differential JAK/STAT signalling nor does it change the dynamics of the engaged receptor. Importantly, however, our data highlight a differential effect upon routing of IFNAR2. Following binding of IFNα2, IFNAR2 is internalized, but, instead of being routed towards degradation as it is when complexed to IFNβ, it recycles back to the cell surface. These observations suggest strongly that the stability and the intracellular lifetime of the ternary complex account for the differential control of IFNAR2. Moreover, the present study opens up the attractive possibility that endosomal-initiated signalling may contribute to IFNα/β differential bioactivities.
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Landi, Alessia, Muriel Mari, Svenja Kleiser, Tobias Wolf, Christine Gretzmeier, Isabel Wilhelm, Dimitra Kiritsi, et al. "Pseudomonas aeruginosa lectin LecB impairs keratinocyte fitness by abrogating growth factor signalling." Life Science Alliance 2, no. 6 (November 15, 2019): e201900422. http://dx.doi.org/10.26508/lsa.201900422.

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Lectins are glycan-binding proteins with no catalytic activity and ubiquitously expressed in nature. Numerous bacteria use lectins to efficiently bind to epithelia, thus facilitating tissue colonisation. Wounded skin is one of the preferred niches for Pseudomonas aeruginosa, which has developed diverse strategies to impair tissue repair processes and promote infection. Here, we analyse the effect of the P. aeruginosa fucose-binding lectin LecB on human keratinocytes and demonstrate that it triggers events in the host, upon binding to fucosylated residues on cell membrane receptors, which extend beyond its role as an adhesion molecule. We found that LecB associates with insulin-like growth factor-1 receptor and dampens its signalling, leading to the arrest of cell cycle. In addition, we describe a novel LecB-triggered mechanism to down-regulate host cell receptors by showing that LecB leads to insulin-like growth factor-1 receptor internalisation and subsequent missorting towards intracellular endosomal compartments, without receptor activation. Overall, these data highlight that LecB is a multitask virulence factor that, through subversion of several host pathways, has a profound impact on keratinocyte proliferation and survival.
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Gulati, P., and G. Thomas. "Nutrient sensing in the mTOR/S6K1 signalling pathway." Biochemical Society Transactions 35, no. 2 (March 20, 2007): 236–38. http://dx.doi.org/10.1042/bst0350236.

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Nutrient overload induces constitutive S6K1 (S6 kinase 1) activation, which leads to insulin resistance by suppressing insulin-induced class I PI3K (phosphoinositide 3-kinase) signalling [Um, Frigerio, Watanabe, Picard, Joaquin, Sticker, Fumagalli, Allegrini, Kozma, Auwerx and Thomas (2004) Nature 431, 200–205]. This finding gave rise to the question of the mechanism by which nutrients, such as AAs (amino acids), enter the mTOR (mammalian target of rapamycin)/S6K1 signalling pathway. Counter to the prevailing view, our recent studies have shown that the AA input into the mTOR/S6K1 signalling pathway is not mediated by the tumour suppressor TSC1 (tuberous sclerosis complex 1)/TSC2 or its target, the proto-oncogene Rheb (Ras homologue enriched in brain). Instead, we found that the AA input was mediated by class 3 PI3K, or hVps34 (human vacuolar protein sorting 34). In brief, ectopic expression of hVps34 drives S6K1 activation, but only in the presence of AAs, and this effect is blocked by small interfering RNAs directed against hVps34. Moreover, stimulation of cells with AAs increases hVps34 activity, as indicated by the production of PI3P (phosphatidylinositol 3-phosphate). PI3P mediates the recruitment of proteins containing FYVE (Fab1p, YOTB, Vac1p and EEA1) or PX (Phox homology) domains to endosomal membranes, with PI3P-rich micro-domains acting as signalling platforms. Additional evidence indicating hVps34 as the mediator of AA input to S6K1 came from experiments in which S6K1 activation was attenuated by ectopic expression of a cDNA containing two FYVE domains, which bind to PI3P, preventing binding of proteins containing either FYVE or PX domains [Nobukuni, Joaquin, Roccio, Dann, Kim, Gulati, Byfield, Backer, Natt, Bos, Zwartkruis and Thomas (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 14238–14243].
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Luo, Yi, Zhong Cheng, C. Jane Dixon, John F. Hall, Emma Taylor, and Michael R. Boarder. "Endosomal signalling of epidermal growth factor receptors contributes to EGF-stimulated cell cycle progression in primary hepatocytes." European Journal of Pharmacology 654, no. 2 (March 2011): 173–80. http://dx.doi.org/10.1016/j.ejphar.2010.11.038.

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50

York, Harrison M., Joanne Coyle, and Senthil Arumugam. "To be more precise: the role of intracellular trafficking in development and pattern formation." Biochemical Society Transactions 48, no. 5 (September 11, 2020): 2051–66. http://dx.doi.org/10.1042/bst20200223.

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Living cells interpret a variety of signals in different contexts to elucidate functional responses. While the understanding of signalling molecules, their respective receptors and response at the gene transcription level have been relatively well-explored, how exactly does a single cell interpret a plethora of time-varying signals? Furthermore, how their subsequent responses at the single cell level manifest in the larger context of a developing tissue is unknown. At the same time, the biophysics and chemistry of how receptors are trafficked through the complex dynamic transport network between the plasma membrane–endosome–lysosome–Golgi–endoplasmic reticulum are much more well-studied. How the intracellular organisation of the cell and inter-organellar contacts aid in orchestrating trafficking, as well as signal interpretation and modulation by the cells are beginning to be uncovered. In this review, we highlight the significant developments that have strived to integrate endosomal trafficking, signal interpretation in the context of developmental biology and relevant open questions with a few chosen examples. Furthermore, we will discuss the imaging technologies that have been developed in the recent past that have the potential to tremendously accelerate knowledge gain in this direction while shedding light on some of the many challenges.
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