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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].
Mother and Embryo Cross Communication during Conception
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Anna Idelevich, Andrea Peralta, Felipe Vilella
Microvesicles (100–1000 nm) were first described as subcellular material originating from platelets in normal plasma and serum. The molecular markers of microvesicles are ADP-ribosylation factor 6 (ARF6), integrins, selectins, and CD40 ligand. Microvesicles have been studied mainly for their role in blood coagulation and cancer cell-to-cell communication, where they are called oncosomes. Unlike apoptotic bodies and microvesicles, exosomes are small, virus-sized particles (30–150 nm), formed by inward budding of the cytoplasmic membrane. Exosomes are derived from the endolysosomal pathway and represent a more homogeneous population of vesicles than microvesicles. For a long time, they were considered to be nanodust, or dust in electron microscopy. This perception changed dramatically in the past years and their role evolved from debris bins to biologically active particles [89,90]. The immunomodulatory role of exosomes is the most studied [87,91], followed by angiogenesis, thrombosis [92], and pathologies, such as cancer [88]. The molecular markers of exosomes include: CD63, CD9, CD81, ALIX, TSG101, flotillin-1, HSC70, and syntenin-1 [13]. Cargo sorting into exosomes involves the endosomal sorting complex required for transport (ESCRT) and other associated proteins.
TRPML Subfamily of Endolysosomal Channels
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Nicholas E. Karagas, Morgan A. Rousseau, Kartik Venkatachalam
Given the physical interactions between TRPML1 and TRPML2, it stands to reason that the latter protein also localizes to late-endosomes (Venkatachalam et al., 2006). In addition, TRPML2 has been detected in long tubulovesicular compartments associated with GTPase ADP-ribosylation factor-6 (Arf-6) (Karacsonyi et al., 2007; Radhakrishna and Donaldson, 1997). Indeed, activation of Arf-6 has been shown to cause accumulation of TRPML2 in tubulovesicular structures where it colocalizes with major histocompatibility complex I and glycosylphosphatidylinositol-anchored proteins (Karacsonyi et al., 2007). Interactions with TRPML1 drive TRPML3 to the endolysosomal membrane (Venkatachalam et al., 2006). When overexpressed alone in cell culture models, murine TRPML3-YFP was found localized to the endoplasmic reticulum (ER) (Venkatachalam et al., 2006). Only upon coexpression with TRPML1 or TRPML2, which possess endolysosomal targeting motifs, was TRPML3 delivered to the vesicles, yet again pointing to a hierarchical relationship between the channels. TRPML3 does appear to exhibit the greatest diversity in subcellular compartments. In addition to localizing to endolysosomal compartments, TRPML3 has also been shown to reside in the plasma membrane, early endosomes, and autophagosomal membranes (Kim et al., 2009; Martina et al., 2009; Miao et al., 2015).
ADP Ribosylation Factor 6 Relieves Airway Inflammation and Remodeling by Inhibiting Ovalbumin Induced-Epithelial Mesenchymal Transition in Experimental Asthma, Possibly by Regulating of E2F Transcription Factor 8
Published in Immunological Investigations, 2023
Dongdong Dou, Meirong Bi, Xiuyun Li, Nan Zhang, Mi Xu, Aili Guo, Feng Li, Weiwei Zhu
ADP-ribosylation factor 6 (ARF6) belongs to the ARF family of small GTPases and is involved in the regulation of membrane trafficking and structural and cytoskeletal dynamic (Donaldson and Jackson 2011). ARF6 is commonly expressed in various types of normal cells (including lungs) and is involved in the development and progression of various human diseases (Donaldson and Honda 2005; Schweitzer et al. 2011). Studies of AFR6 have focused on its key role in cell motility. AFR6 has been reported to be overexpressed in different cancer types and promotes cell adhesion, invasion, and metastasis (Hashimoto et al. 2004, 2016; Sabe 2003). In addition, ARF6 is involved in the endocytosis of E-cadherin, an intercellular adhesion molecule, which is essential for the acquisition of a mesenchymal phenotype. A previous study has shown that AFR6 is closely related to EMT. ARF6 disrupts cell junctions mediated by E-cadherin and inhibits EMT in head and neck cancer (Matsumoto et al. 2017). In pancreatic cancer, ARF6 up-regulated the expression of E-cadherin to promote fibrosis (Tsutaho et al. 2020). A recent study reported that the inhibition of AFR6 could attenuate ovalbumin (OVA)-induced asthma by inhibiting inflammation (Lee et al. 2021), however, its role in airway remodeling and EMT remains unclear.
Post-translational and transcriptional dynamics – regulating extracellular vesicle biology
Published in Expert Review of Proteomics, 2019
Bethany Claridge, Kenneth Kastaniegaard, Allan Stensballe, David W. Greening
PPIs have provided insights into the release of sMVs from the plasma membrane, including regulation of cytoskeletal dynamics and remodeling. Actin–myosin interactions allow the contraction of the cytoskeleton ending the budding process. RhoA activates ROCK proteins which remodel the cytoskeleton, and inhibition of this pathway has shown it is important in plasma membrane budding [140]. The cytoskeleton is also regulated by ARF6 activity through activation of phospholipase D, recruitment of ERK, activation of MLCK to phosphorylate the myosin required for the actomyosin-centered membrane separation which facilitates budding [79]. Another PPI that influences sMV release is the plasma membrane localized ARRDC1, which recruits and interacts with TSG101 to mediate release [141]. With regards to cargo sorting, the SNARE protein VAMP3 delivers sMV cargo such as MT1-MMP to the nascent sMVs [142]. These PPIs, along with other uncharacterized mechanisms, are vital for the regulatory processes associated with sMV formation and biology.
Microvesicles as promising biological tools for diagnosis and therapy
Published in Expert Review of Proteomics, 2018
Isabella Panfoli, Laura Santucci, Maurizio Bruschi, Andrea Petretto, Daniela Calzia, Luca A. Ramenghi, Gianmarco Ghiggeri, Giovanni Candiano
Evidence is gathering that cancer cell-secreted MVs contribute to disease propagation. Cancer cell MVs cargo transfer to adjacent or remote cells acts as a potent inducer of cell migration, and angiogenesis [33]. Several reports indicate that MVs secreted by tumor cells induce endothelial cells to release MVs that contain VEGF promoting angiogenesis, vital for tumor survival [12]. MVs have been shown to play vital roles also in other cancer hallmark abilities such as escape from immune surveillance, and metastasis [11]. In fact, MVs shed by endothelial cells contain MMP-2, MMP-9 and MT1-MMP metalloproteinases proteases that facilitate invasion, providing a means of matrix degradation. MMPs remodel extracellular matrix, modifying tumor microenvironment and contributing to premetastatic niche formation [reviewed in [11]]. ARF6 activation promotes MVs shedding, whereas dominant inhibition of ARF6 activation attenuates it [31]. MVs are expected to become indicators of the T cell status in leukemia bearing patients [46].