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Characteristics, Events, and Stages in Tumorigenesis
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Microvesicles are produced from the plasma membrane through direct outward budding (and fission) with subsequent release into the extracellular space [830, 857, 896]. Membrane lipid curvature plays an important role for either inward-budding vesicle formation within the endocytic system (exosomes) or an outward-budding vesicle formation at the plasma membrane (microvesicles) [831]. Some of the biogenetic mechanisms involved include flippase, flippase and scramblase (TMEM16F), amino-phospholipid translocases, ARF6, membrane curvature, cytoskeleton, and asymmetric movement of phosphatidylserine [769, 840, 897–900]. From plasma membranes of prostate and breast cancer cells, the shedding of cancer-derived MVs is attributed to the ADP-ribosylation factor 6 (ARF6) that is enriched in MVs [851, 901]. EVs, (especially exosomes), have been identified as major modes by which cells interact with each other, including stromal cells, within the tumor microenvironment [849].
Reconstituted Membrane Systems for Assaying Membrane Proteins in Controlled Lipid Environments
Published in Qiu-Xing Jiang, New Techniques for Studying Biomembranes, 2020
The challenges the reconstituted vesicles face also come from multiple directions. First, proteoliposomes usually do not harbor asymmetry of native cell membranes. Even for cholesterol, recent imaging with cholesterol-specific binding proteins showed that there is a significantly lower level of cholesterol in the inner leaflet than the outer leaflet in the plasma membrane of a live cell.80 Reconstituted membranes usually lack the lipid transporters that maintain lipid asymmetry. Further, the orientations of different membrane proteins are not easy to control precisely such that the man-made membranes are still not able to reflect the protein-lipid organizations observed in cell membranes. With the strong lipid-dependent gating effects observed on Kv channels, Nav1.8 and Kv4.3 in different cell types,81,82 it is an inevitable necessity to be cautious when the structural and functional insights into particular membrane proteins in nanodiscs or vesicles are applied to the same proteins in native cell membranes, even though we expect that some of the fundamental biophysical and biochemical properties remain the same despite changes in lipid environments. With the structures and functions of scramblases and other lipid transporters being revealed,83,84 it will be feasible to reconstitute them into proteoliposomes and generate asymmetrical distribution of lipid molecules.
Molecular Imaging of Apoptosis
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
Mikko I. Kettunen, Kevin M. Brindle
Exposure of phosphatidylserine (PS) on the cell surface occurs relatively early in the apoptotic process.96 PS is normally resident predominantly on the inner leaflet of the plasma membrane bilayer, and this asymmetry is maintained by an ATP-dependent translocase that transports aminophospholipids from the outer leaflet to the inner leaflet. During apoptosis, PS may be flipped to the outer leaflet, due to inhibition of this translocase and by activation of a Ca2+-dependent scramblase, which transports lipids bidirectionally.97 As a result, the number of surface PS molecules can increase 100- to 1000-fold.98,99 For example, in Jurkat cells, the induction of apoptosis results in the exposure of ~240 μmol of PS/106 cells.100 At the estimated cell densities found in tumors of ~109/ml,101 this corresponds to a local PS concentration of ~200 μM. However, PS exposure can also occur during necrosis due to the leakiness of the plasma membrane under these conditions, and therefore is not specific to apoptosis per se.18
Gene of the issue: ANO6 and Scott Syndrome
Published in Platelets, 2020
Sarah L. Millington-Burgess, Matthew T. Harper
PS is normally restricted to the inner leaflet of the plasma membrane by inward ‘flippase’ activity (Figure 1). Procoagulant platelet stimuli, such as dual stimulation with collagen and thrombin, or a Ca2+ ionophore, trigger a large, sustained increase in cytosolic Ca2+. This inhibits flippase activity and activates a ‘scramblase’ activity – bidirectional, nonselective movement of phospholipids, leading to loss of membrane asymmetry. Flippase activity is unaffected in Scott Syndrome patients but the scramblase activity is defective [15,16]. As a result, PS exposure is almost completely abolished in Scott Syndrome platelets following stimulation [1]. Platelet microparticle release, which requires PS exposure, is also abolished [17]. Procoagulant platelets resemble necrotic cells, with a diluted cytoplasm, few remaining organelles and rapid swelling into large ‘balloon’-like structures [18,19]. Procoagulant ballooning is also diminished in Scott Syndrome platelets [20,21].
Bacteria-induced intracellular signalling in platelets
Published in Platelets, 2015
Bacillus anthracis-derived peptidoglycan activates platelets by binding IgG and subsequently engaging the FcγRIIA pathway, as outlined above, leading to aggregation, αIIbβ3 integrin expression and exposure of the phosphatidylserine-enriched procoaggulant surface [86]. However, although blockade of FcγRIIA inhibited aggregation and αIIbβ3 integrin expression, there was no significant effect on the procoaggulant surface exposure [86]. Furthermore, the B. anthracis-derived peptidoglycan-induced expression of the procoaggulant surface was a consequence of complement binding [86]. Interestingly, complement does not bind to quiescent platelets. Taken together, this suggests that B. anthracis-derived peptidoglycan activates the IgG/FcγRIIA pathway which in turn up-regulates gC1q-R expression, as suggested for S. sanguinis, leading to complement binding [86]. The pathway distal to gC1q-R leading to the exposure of the procoaggulant surface has not been addressed. However, under in vitro conditions, procoaggulant surface expression requires a huge increase in the cytosolic calcium level (as induced by a combination of thrombin and collagen) to induce the activation of scramblase and the expression of the phosphatidylserine-enriched pro-coagulant surface [87]. The precise mechanism has not been elucidated but the calcium store-operated Orai 1 [88] channel and the STIM1 calcium sensors [89] have been implicated, although these are unlikely to be the only processes involved [89]. Thus, it is possible that engagement of gC1q-R leads to an elevation of cytosolic calcium to a level which stimulates scramblase.
Extracellular vesicle cargo of the male reproductive tract and the paternal preconception environment
Published in Systems Biology in Reproductive Medicine, 2021
Ahmet Ayaz, Emily Houle, J. Richard Pilsner
Although exosomes and microvesicles (also referred to ectosomes) are structurally similar, microvesicles differ in their size (100–1000 nm) and biogenesis. While exosomes utilize an endosomal-mediated mechanism, microvesicles are formed from the direct outward budding from the plasma membrane to the extracellular space. Microvesicle biogenesis is the result of two dynamic intracellular processes: phospholipid redistribution and cytoskeletal protein contraction (Figure 1(B)). The phospholipids and proteins are not uniformly distributed within the plasma membrane; as a result, they form microdomains. Aminophospholipid translocases are proteins that regulate the asymmetric distribution of the molecules within the membrane. For instance, flippases and floppases enable lipid movement to the inner and outer membrane, respectively, while scramblases allow bidirectional lipid movement (Hugel et al. 2005). Finally, phosphatidylserine translocation induces membrane budding and actin–myosin interactions to complete the budding process (Akers et al. 2013). Although the molecular content of the microvesicles is dependent upon the cell type of origin, protein content is common to most microvesicles and includes cytoplasmic proteins such as tubulin, cell structure proteins (e.g. actin) as well as signal transduction and transcription proteins (Raposo and Stoorvogel 2013). Although the biogenesis of microvesicles is widely accepted to be endosomal-independent, some overlap of the protein machinery used for exosome formation (e.g., ESCRT complexes and TSG101) may also play a role in microvesicle biogenesis (Nabhan et al. 2012; Raposo and Stoorvogel 2013).