scholarly journals Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites

2006 ◽  
Vol 172 (6) ◽  
pp. 937-948 ◽  
Author(s):  
Katarina Trajkovic ◽  
Ajit Singh Dhaunchak ◽  
José T. Goncalves ◽  
Dirk Wenzel ◽  
Anja Schneider ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Proteolipid Protein ◽  
Myelin Membrane ◽  
Vertebrate Brain ◽  
Late Endosomes ◽  
Membrane Growth ◽  
Neuronal Signal ◽  
Endocytosis Pathway ◽  
Guanosine Triphosphatase

During vertebrate brain development, axons are enwrapped by myelin, an insulating membrane produced by oligodendrocytes. Neuron-derived signaling molecules are temporally and spatially required to coordinate oligodendrocyte differentiation. In this study, we show that neurons regulate myelin membrane trafficking in oligodendrocytes. In the absence of neurons, the major myelin membrane protein, the proteolipid protein (PLP), is internalized and stored in late endosomes/lysosomes (LEs/Ls) by a cholesterol-dependent and clathrin-independent endocytosis pathway that requires actin and the RhoA guanosine triphosphatase. Upon maturation, the rate of endocytosis is reduced, and a cAMP-dependent neuronal signal triggers the transport of PLP from LEs/Ls to the plasma membrane. These findings reveal a fundamental and novel role of LEs/Ls in oligodendrocytes: to store and release PLP in a regulated fashion. The release of myelin membrane from LEs/Ls by neuronal signals may represent a mechanism to control myelin membrane growth.

scholarly journals Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1096 ◽  
Author(s):  
Guerra ◽  
Bucci
Keyword(s):  
Cancer Progression ◽  
Extracellular Vesicle ◽  
Endocytic Pathway ◽  
Cellular Processes ◽  
Molecular Events ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Cellular Context ◽  
Guanosine Triphosphatase

RAB7 is a small guanosine triphosphatase (GTPase) extensively studied as regulator of vesicular trafficking. Indeed, its role is fundamental in several steps of the late endocytic pathway, including endosome maturation, transport from early endosomes to late endosomes and lysosomes, clustering and fusion of late endosomes and lysosomes in the perinuclear region and lysosomal biogenesis. Besides endocytosis, RAB7 is important for a number of other cellular processes among which, autophagy, apoptosis, signaling, and cell migration. Given the importance of RAB7 in these cellular processes, the interest to study the role of RAB7 in cancer progression is widely grown. Here, we describe the current understanding of oncogenic and oncosuppressor functions of RAB7 analyzing cellular context and other environmental factors in which it elicits pro and/or antitumorigenic effects. We also discuss the role of RAB7 in cisplatin resistance associated with its ability to regulate the late endosomal pathway, lysosomal biogenesis and extracellular vesicle secretion. Finally, we examined the potential cancer therapeutic strategies targeting the different molecular events in which RAB7 is involved.

scholarly journals Comparable affinity of RabGDIα for GTP- and GDP-bound forms of Rab7 supports a four-state transition model for Rab7 subcellular localization

2018 ◽  
Author(s):  
Akane Kanemitsu-Fujita ◽  
So Morishita ◽  
Svend Kjaer ◽  
Mitsunori Fukuda ◽  
Giampietro Schiavo ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
State Transition ◽  
Transition Model ◽  
Late Endosomes ◽  
Cell Life ◽  
Inactive Form ◽  
State Transition Model ◽  
Almost All

AbstractEndolysosomal system is linked to almost all aspects of cell life and diseases, and Rab7 occupies a critical node in this crucial pathway. However, there have been conflicting views about the exact role of Rab7 in membrane trafficking, since some studies have reported that Rab7 regulates the trafficking from early to late endosomes, while others highlighted its role in late endosomes to lysosomes progression. In the present study, we have revisited this issue from a new viewpoint. In COS-7 cells, a GDP-bound Rab7 mutant, T22N, was located to vesicular membranes as well as in cytoplasm. Similarly, the GTPase-deficient Q67L mutant of Rab7 resided in cytoplasm as well as on membranes. Additionally, we found that RabGDI interacted with both GTP- and GDP-bound forms of Rab7 in vitro. These results have prompted us to propose a four-state transition model for Rab7. This four-state model matches with our recent findings that Rab7 was initially recruited to macropinosomes in a GDP-bound inactive form and subsequently became activated during endocytic maturation in EGF-stimulated COS-7 cells.

scholarly journals Small GTPases of the Rab and Arf Families: Key Regulators of Intracellular Trafficking in Neurodegeneration

2021 ◽  
Vol 22 (9) ◽  
pp. 4425
Author(s):  
Alazne Arrazola Arrazola Sastre ◽  
Miriam Luque Luque Montoro ◽  
Hadriano M. Lacerda ◽  
Francisco Llavero ◽  
José L. Zugaza
Keyword(s):  
Membrane Trafficking ◽  
Neurodegenerative Disorders ◽  
Synaptic Vesicles ◽  
Intracellular Trafficking ◽  
Small Gtpases ◽  
Constant Flow ◽  
Parkinson’S Diseases ◽  
The Central Nervous System ◽  
Arf Gtpases

Small guanosine triphosphatases (GTPases) of the Rab and Arf families are key regulators of vesicle formation and membrane trafficking. Membrane transport plays an important role in the central nervous system. In this regard, neurons require a constant flow of membranes for the correct distribution of receptors, for the precise composition of proteins and organelles in dendrites and axons, for the continuous exocytosis/endocytosis of synaptic vesicles and for the elimination of dysfunctional proteins. Thus, it is not surprising that Rab and Arf GTPases have been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Both pathologies share characteristics such as the presence of protein aggregates and/or the fragmentation of the Golgi apparatus, hallmarks that have been related to both Rab and Arf GTPases functions. Despite their relationship with neurodegenerative disorders, very few studies have focused on the role of these GTPases in the pathogenesis of neurodegeneration. In this review, we summarize their importance in the onset and progression of Alzheimer’s and Parkinson’s diseases, as well as their emergence as potential therapeutical targets for neurodegeneration.

scholarly journals Role of the V1G1 subunit of V-ATPase in breast cancer cell migration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria De Luca ◽  
Roberta Romano ◽  
Cecilia Bucci
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Downstream Signaling ◽  
Late Endosomes ◽  
Intracellular Compartments

AbstractV-ATPase is a large multi-subunit complex that regulates acidity of intracellular compartments and of extracellular environment. V-ATPase consists of several subunits that drive specific regulatory mechanisms. The V1G1 subunit, a component of the peripheral stalk of the pump, controls localization and activation of the pump on late endosomes and lysosomes by interacting with RILP and RAB7. Deregulation of some subunits of the pump has been related to tumor invasion and metastasis formation in breast cancer. We observed a decrease of V1G1 and RAB7 in highly invasive breast cancer cells, suggesting a key role of these proteins in controlling cancer progression. Moreover, in MDA-MB-231 cells, modulation of V1G1 affected cell migration and matrix metalloproteinase activation in vitro, processes important for tumor formation and dissemination. In these cells, characterized by high expression of EGFR, we demonstrated that V1G1 modulates EGFR stability and the EGFR downstream signaling pathways that control several factors required for cell motility, among which RAC1 and cofilin. In addition, we showed a key role of V1G1 in the biogenesis of endosomes and lysosomes. Altogether, our data describe a new molecular mechanism, controlled by V1G1, required for cell motility and that promotes breast cancer tumorigenesis.

scholarly journals AP-3 Mediates Tyrosinase but Not TRP-1 Trafficking in Human Melanocytes

2001 ◽  
Vol 12 (7) ◽  
pp. 2075-2085 ◽  
Author(s):  
Marjan Huizing ◽  
Rangaprasad Sarangarajan ◽  
Erin Strovel ◽  
Yang Zhao ◽  
William A. Gahl ◽  
...  
Keyword(s):  
Dense Body ◽  
Multivesicular Bodies ◽  
Normal Pattern ◽  
Late Endosomes ◽  
Human Melanocytes ◽  
Hermansky Pudlak Syndrome ◽  
Functional Deficiency ◽  
Tyrosinase Related Protein

Patients with Hermansky-Pudlak syndrome type 2 (HPS-2) have mutations in the β3A subunit of adaptor complex-3 (AP-3) and functional deficiency of this complex. AP-3 serves as a coat protein in the formation of new vesicles, including, apparently, the platelet's dense body and the melanocyte's melanosome. We used HPS-2 melanocytes in culture to determine the role of AP-3 in the trafficking of the melanogenic proteins tyrosinase and tyrosinase-related protein-1 (TRP-1). TRP-1 displayed a typical melanosomal pattern in both normal and HPS-2 melanocytes. In contrast, tyrosinase exhibited a melanosomal (i.e., perinuclear and dendritic) pattern in normal cells but only a perinuclear pattern in the HPS-2 melanocytes. In addition, tyrosinase exhibited a normal pattern of expression in HPS-2 melanocytes transfected with a cDNA encoding the β3A subunit of the AP-3 complex. This suggests a role for AP-3 in the normal trafficking of tyrosinase to premelanosomes, consistent with the presence of a dileucine recognition signal in the C-terminal portion of the tyrosinase molecule. In the AP-3–deficient cells, tyrosinase was also present in structures resembling late endosomes or multivesicular bodies; these vesicles contained exvaginations devoid of tyrosinase. This suggests that, under normal circumstances, AP-3 may act on multivesicular bodies to form tyrosinase-containing vesicles destined to fuse with premelanosomes. Finally, our studies demonstrate that tyrosinase and TRP-1 use different mechanisms to reach their premelanosomal destination.

scholarly journals Role of Fgf signalling in positioning neurogenic regions in the early embryonic vertebrate brain

2017 ◽  
Vol 145 ◽  
pp. S124
Author(s):  
Charlotte Smith ◽  
Emily Trebert ◽  
Marina Pradoz Uhle ◽  
Frank R. Schubert
Keyword(s):  
Vertebrate Brain ◽  
Fgf Signalling

scholarly journals Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER

2021 ◽  
Vol 7 (21) ◽  
pp. eabg0942
Author(s):  
Jae Ho Lee ◽  
Ahmad Jomaa ◽  
SangYoon Chung ◽  
Yu-Hsien Hwang Fu ◽  
Ruilin Qian ◽  
...  
Keyword(s):  
Single Molecule ◽  
Protein Translocation ◽  
Molecular Model ◽  
Genetic Diseases ◽  
Signal Recognition Particle ◽  
Biological Regulation ◽  
Single Molecule Studies ◽  
Guanosine Triphosphatase ◽  
Gtpase Cycle

The conserved signal recognition particle (SRP) cotranslationally delivers ~30% of the proteome to the eukaryotic endoplasmic reticulum (ER). The molecular mechanism by which eukaryotic SRP transitions from cargo recognition in the cytosol to protein translocation at the ER is not understood. Here, structural, biochemical, and single-molecule studies show that this transition requires multiple sequential conformational rearrangements in the targeting complex initiated by guanosine triphosphatase (GTPase)–driven compaction of the SRP receptor (SR). Disruption of these rearrangements, particularly in mutant SRP54G226E linked to severe congenital neutropenia, uncouples the SRP/SR GTPase cycle from protein translocation. Structures of targeting intermediates reveal the molecular basis of early SRP-SR recognition and emphasize the role of eukaryote-specific elements in regulating targeting. Our results provide a molecular model for the structural and functional transitions of SRP throughout the targeting cycle and show that these transitions provide important points for biological regulation that can be perturbed in genetic diseases.

Evolution of the diverse biological roles of inositols

2007 ◽  
Vol 74 ◽  
pp. 223-246 ◽  
Author(s):  
Robert H. Michell
Keyword(s):  
Membrane Trafficking ◽  
Cell Signalling ◽  
Compatible Solutes ◽  
Mirror Image ◽  
Membrane Phospholipids ◽  
Functional Diversification ◽  
Redox Reagent ◽  
Ca2 Channels ◽  
Mycobacterium Spp

Several of the nine hexahydroxycylohexanes (inositols) have functions in Biology, with myo-inositol (Ins) in most of the starring roles; and Ins polyphosphates are amongst the most abundant organic phosphate constituents on Earth. Many Archaea make Ins and use it as a component of diphytanyl membrane phospholipids and the thermoprotective solute di-L-Ins-1,1′-phosphate. Few bacteria make Ins or use it, other than as a carbon source. Those that do include hyperthermophilic Thermotogales (which also employ di-l-Ins-1,1′-phosphate) and actinomycetes such as Mycobacterium spp. (which use mycothiol, an inositol-containing thiol, as an intracellular redox reagent and have characteristic phosphatidylinositol-linked surface oligosaccharides). Bacteria acquired their Ins3P synthases by lateral gene transfer from Archaea. Many eukaryotes, including stressed plants, insects, deep-sea animals and kidney tubule cells, adapt to environmental variation by making or accumulating diverse inositol derivatives as ‘compatible’ solutes. Eukaryotes use phosphatidylinositol derivatives for numerous roles in cell signalling and regulation and in protein anchoring at the cell surface. Remarkably, the diradylglycerol cores of archaeal and eukaryote/bacterial glycerophospholipids have mirror image configurations: sn-2,3 and sn-1,2 respectively. Multicellular animals and amoebozoans exhibit the greatest variety of functions for PtdIns derivatives, including the use of PtdIns(3,4,5)P3 as a signal. Evolutionarily, it seems likely that (i) early archaeons first made myo-inositol approx. 3500 Ma (million years) ago; (ii) archeons brought inositol derivatives into early eukaryotes (approx. 2000 Ma?); (iii) soon thereafter, eukaryotes established ubiquitous functions for phosphoinositides in membrane trafficking and Ins polyphosphate synthesis; and (iv) since approx. 1000 Ma, further waves of functional diversification in amoebozoans and metazoans have introduced Ins(1,4,5)P3 receptor Ca2+ channels and the messenger role of PtdIns(3,4,5)P3.

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