The Role Of Endocytic Sorting And Escrt Machinery In Regulation Of Cellular Migration And Receptor Signalling
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The Role Of Endocytic Sorting And Escrt Machinery In Regulation Of Cellular Migration And Receptor Signalling
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Author : Dmitri Kharitidi
language : en
Publisher:
Release Date : 2016
The Role Of Endocytic Sorting And Escrt Machinery In Regulation Of Cellular Migration And Receptor Signalling written by Dmitri Kharitidi and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016 with categories.
"The endocytic sorting of cell surface receptors is a crucial process for maintaining eukaryotic cell homeostasis and for organism's development and physiology. Several decades of research in this field have yielded the understanding of molecular processes governing endocytosis and postendocytic sorting of receptors. However the emergence of additional regulatory mechanisms for the individual receptors and discovery of new players of endocytic machinery provide new areas for investigation and research. This work provides understanding of the regulation of integrin [alpha]5[beta]1 and Tumor Necrosis Factor Receptor (TNFR) by endocytic sorting and ubiquitination, as well as the characterization of a novel endosomal sorting machinery.Our study of integrin [alpha]5[beta]1 trafficking has identified a dynamic mechanism for [alpha]5[beta]1 partitioning between the degradative and the recycling pathways, with a profound implication in cellular migration and invasion. The work presented here outlines the timecourse of integrin [alpha]5[beta]1 ubiquitination following ligand engagement, its deubiquitination by USP9x upon ligand dissociation in acidic endosomes, promoting the receptor resensitization and its cell surface return. The smaller fraction of integrins, that maintain their ubiquitination status, are targeted to the lysosomal degradation via the action of the ESCRT components (HD-PTP and UBAP1). Overall, this dynamic sorting of integrin receptors represents a novel mechanism of cell migration regulation by integrin recycling. Moreover, we have identified a key function for HD-PTP in the regulation of TNFR1 downstream signalling, affecting both NF-[kappa]B pathway and the induction of apoptosis following TNF[alpha] stimulation. TNFR1 endocytic sorting is poorly understood, and little is known about the role of ESCRT machinery in the sorting of TNFR1 or its downstream signalling. Our findings provide the first evidence for the negative regulation of TNFR1 signalling by ESCRT component HD-PTP, since its depletion leads to increased scaffolding of the TNFR1 signalling complex, accelerated NF-[kappa]B signalling and target gene expression. The impact of the endosomal sorting machinery of TNFR1 has potential implications in inflammation, apoptotic signalling, and cell survival. Finally, we identify and characterize novel binding partners of HD-PTP by mass spectrometry. Among these, we focus on Endofin, an endosomal protein capable of ubiquitin recognition, and essential for lysosomal sorting of polyubiquitinated cargo molecules. Endofin was proposed to act as an alternative ESCRT module, and we provide the evidence for its role in sorting of ubiquitinated receptors. Overall, these studies outline the key function of endocytic sorting mechanisms of cell surface receptors during cell migration and inflammation and propose a new ESCRT complex as a module involved in sorting of ubiquitinated molecules. Future studies are needed to examine the control of inflammatory response by ESCRT machinery and the function of ESCRTs in carcinogenesis. " --
Endocytosis And Signaling
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Author : Christophe Lamaze
language : en
Publisher: Springer
Release Date : 2018-08-10
Endocytosis And Signaling written by Christophe Lamaze and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-08-10 with Science categories.
This book focuses on the context dependency of cell signaling by showing how the endosomal system helps to structure and regulate signaling pathways. The location and concentration of signaling nodes regulate their activation cycles and engagement with distinct effector pathways. Whilst many cell signaling pathways are initiated from the cell surface, endocytosis provides an opportunity for modulating signaling networks’ output. In this book, first a series of reviews describe the endocytic and endosomal system and show how these subcellular platforms sort and regulate a wide range of signaling pathway components and phenotypic outputs. The book then reviews the latest scientific insights into how endocytic trafficking and subcellular location modulate a set of major pathways that are essential to normal cellular function and organisms’ development.
Roles Of Escrt Machinery In Endosomal Repair And Recycling
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Author : Michał Leszek Skowyra
language : en
Publisher:
Release Date : 2018
Roles Of Escrt Machinery In Endosomal Repair And Recycling written by Michał Leszek Skowyra and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with Electronic dissertations categories.
Endosomes function to sort, recycle, and degrade a wide range of substances from within and outside the cell. Materials such as incoming pathogens, membrane-destabilizing molecules, or particulates can damage endosomal vesicles. While terminally damaged compartments are degraded by autophagy, pathways that repair salvageable organelles are poorly understood. Here we propose that the ESCRT (Endosomal Sorting Complex Required for Transport) protein machinery, which mediates budding and fission events during endosomal trafficking, also plays an essential role in endosomal repair. ESCRTs rapidly acumulated on endosomes following acute injury by lysosomotropic peptides via a pathway that was independent of autophagy. We used live-cell imaging to demonstrate that ESCRTs responded to small disruptions in endolysosomal membranes and enabled compartments to recover from limited damage. ESCRT recruitment was also triggered by engulfed silica crystals, transfection reagents, osmotic rupture, and oxidative damage, and was especially pronounced in astrocytes and phagocytic cells. ESCRTs might thus provide a defense against endosomal damage likely to be relevant in various physiological and pathological contexts associated with endosomal leakage. The mechanism of ESCRT-facilitated repair and the architecture of the repair complex are unknown. A major challenge derives from the transient and multifactorial nature of ESCRT structures, which assemble from multiple subunits and are disassembled by the AAA-ATPase VPS4 (Vacuolar Protein Sorting 4). A VPS4 inhibitor would thus be of interest for blocking disassembly and stabilizing ESCRT complexes. We show that the quinazoline derivatives ML240 and DBeQ can inhibit in vitro the ATPase activity of human VPS4A. ML240 additionally caused ESCRTs to accumulate on endosomes and might therefore also inhibit VPS4 in cells. Both compounds are well-known inhibitors of the related AAA-ATPase VCP (Valosin Containing Protein)/p97, but the cellular effects of ML240 on ESCRTs were unrelated to inhibition of this enzyme. We thus propose that VPS4 can be targeted by quinazoline-based molecules, and anticipate that ML240 can provide a starting point for generating more selective VPS4 inhibitors. We note that ML240 also caused extensive tubulation of early endosomes and perturbed endosomal recycling pathways, independently of its effects on VPS4 and VCP. We speculate that the compound might additionally inhibit the microtubule-severing AAA-ATPase Spastin that is homologous to VPS4 and has been suspected to promote recycling tubule fission. ML240 might thus also be exploited to clarify the role of this enzyme in endosomal recycling. Despite its microtubule-severing activity, Spastin also binds the ESCRT-III proteins CHMP1B and IST1 and evidence supports an ill-defined role for all three factors in endosomal tubule fission. By examining structures formed by CHMP1B and Spastin's effect on their stability, we show that CHMP1B polymers form helical spirals that extrude membrane tubules into the cytoplasm, and that Spastin can resolubilize these polymers. ESCRTs and Spastin might thus comprise a distinct membrane fission machinery. We also demonstrate that CHMP1B polymers are phosphorylated and suggest a role for this modification in ESCRT complex formation.
Structures Signaling Mechanisms And Functions Of Types I And Iii Interferons
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Author : Ronald L. Rabin
language : en
Publisher: Frontiers Media SA
Release Date : 2021-04-23
Structures Signaling Mechanisms And Functions Of Types I And Iii Interferons written by Ronald L. Rabin and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021-04-23 with Medical categories.
Dr. Walter receives financial support from Pfizer. The other Topic Editor declares no competing interest with regards to the Research Topic theme.
Regulatory Mechanisms That Govern Membrane Deformation And Scission In The Escrt Mediated Endocytic Pathway
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Author :
language : en
Publisher:
Release Date : 2013
Regulatory Mechanisms That Govern Membrane Deformation And Scission In The Escrt Mediated Endocytic Pathway written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013 with categories.
Cells are able to respond to external stimuli and sense the surrounding environment by varying the lipid and protein composition of the plasma membrane. One way this is achieved is through receptor downregulation via the endocytic pathway. Once receptors are at the early endosome, the endosomal sorting complexes required for transport (ESCRT) machinery identifies and clusters ubiquitinylated receptors, induces membrane deformation, and drives vesicle scission. This intricate process generates intralumenal vesicles (ILVs) within an endosome, known as a multivesicular endosome (MVE). Upon ILV formation, receptors are sequestered from cytoplasmic effectors. A MVE fuses with the lysosome where the contents are degraded. A great deal of emphasis has been placed on understanding how the ESCRT machinery carries out this membrane deformation and scission process, but a cohesive mechanism remains unknown. In this thesis, I demonstrate that ESCRT-II and Vps20 generate a curvature sensing supercomplex that restricts Vps32 filament formation to highly curved membranes. Membrane remodeling is observed through this filament formation. I also show that ESCRT-II and Vps20 interact in solution, which raises the possibility that a curvature sensing supercomplex may exist within the cytoplasm. Furthermore, I demonstrate that Vps20 is in an open conformation in solution unlike the downstream ESCRT-III subunit, Vps24. This crucial finding suggests that all ESCRT-III subunits are not in the same conformation, which could help explain the distinct function of each ESCRT-III protein. Finally, I show that unmodified Vps32 can self-assemble independent of upstream ESCRT components and characterize a mechanism of Vps32 filament assembly, in vitro.
Trafficking Inside Cells
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Author : Nava Segev
language : en
Publisher: Springer Science & Business Media
Release Date : 2010-05-30
Trafficking Inside Cells written by Nava Segev and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-05-30 with Science categories.
This book covers the past, present and future of the intra-cellular trafficking field, which has made a quantum leap in the last few decades. It details how the field has developed and evolved as well as examines future directions.
Receptor Tyrosine Kinases Structure Functions And Role In Human Disease
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Author : Deric L. Wheeler
language : en
Publisher: Springer
Release Date : 2014-11-26
Receptor Tyrosine Kinases Structure Functions And Role In Human Disease written by Deric L. Wheeler and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014-11-26 with Science categories.
Receptor Tyrosine Kinase: Structure, Functions and Role in Human Disease, for the first time, systematically covers the shared structural and functional features of the RTK family. Receptor Tyrosine Kinases (RTKs) play critical roles in embryogenesis, normal physiology and several diseases. And over the last decade they have become the Number 1 targets of cancer drugs. To be able to conduct fundamental research or to attempt to develop pharmacological agents able to enhance or intercept them, it is essential first to understand the evolutionary origin of the 58 RTKs and their roles in invertebrates and in humans, as well as downstream signaling pathways. The assembly of chapters is written by experts and underscores commonalities between and among the RTKs. It is an ideal companion volume to The Receptor Tyrosine Kinase: Families and Subfamilies, which proceeds, family by family through all of the specific subfamilies of RTKs, along with their unique landmarks.
The Escrt Complexes
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Author : Emmanuel Culetto
language : en
Publisher: Springer Nature
Release Date : 2019-06-27
The Escrt Complexes written by Emmanuel Culetto and has been published by Springer Nature this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019-06-27 with Science categories.
This detailed collection gathers both established and recent technical procedures to study the Endosomal Sorting Complex Required for Transport (ESCRT) complexes in a wide range of biological systems: Archaea, A. thaliana, U. maydis, S. cerevisiae, S. pombe, C. elegans, D. melanogaster, and mammalian cells. Opening with a section on imaging techniques, the book continues with chapters covering biochemical approaches presenting strategies for production and characterization of recombinant ESCRT proteins, or of specific ESCRT protein domains, as well as genetic and proteomic experimental approaches. Written for the highly successful Methods in Molecular Biology series, chapters include introduction to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, The ESCRT Complexes: Methods and Protocols serves as a compact guide for researchers interested in establishing an integrated approach to investigate the ESCRT machinery functions in cell biology.
Current Frontiers And Perspectives In Cell Biology
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Author : Stevo Najman
language : en
Publisher: BoD – Books on Demand
Release Date : 2012-04-25
Current Frontiers And Perspectives In Cell Biology written by Stevo Najman and has been published by BoD – Books on Demand this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-04-25 with Science categories.
A numerous internationally renowned authors in the pages of this book present the views of the fields of cell biology and their own research results or review of current knowledge. Chapters are divided into five sections that are dedicated to cell structures and functions, genetic material, regulatory mechanisms, cellular biomedicine and new methods in cell biology. Multidisciplinary and often quite versatile approach by many authors have imposed restrictions of this classification, so it is certain that many chapters could belong to the other sections of this book. The current frontiers, on the manner in which they described in the book, can be a good inspiration to many readers for further improving, and perspectives which are highlighted can be seen in many areas of fundamental biology, biomedicine, biotechnology and other applications of knowledge of cell biology. The book will be very useful for beginners to gain insight into new area, as well as experts to find new facts and expanding horizons.
The Role Of The Igf Insulin Igfbp Axis In Normal Physiology And Disease
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Author : Claire Perks
language : en
Publisher: Frontiers Media SA
Release Date : 2022-05-17
The Role Of The Igf Insulin Igfbp Axis In Normal Physiology And Disease written by Claire Perks and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022-05-17 with Medical categories.