Characteristics, Events, and Stages in Tumorigenesis
Franklyn De Silva, Jane Alcorn in The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
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
Carlos Simón, Carmen Rubio in Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
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.
Endotoxin Effects on Synthesis of Phosphatidic Acid and Phosphatidic Acid–Derived Diacylglyceride Species
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
Both lyso-PA and exogenous PA also act to stimulate endogenous cellular PA levels, possibly through small G-protein stimulation of phosphatidylcholine (PC)-directed and phosphatidylethanolamine (PE)-directed phospholipases D (PLD). Small ras-related G-proteins linked to lyso-PA receptor stimulation include rho, arfl, arf6, and possibly cdc42, which have been implicated to different degrees in activation of intracellular PCPLD (2,14–19). In addition, administration of PA to microsomal systems from rat (RMC) and human mesangial cells (HMC) results in stimulation of lyso-PA acyl-CoA: acyltransferase (LPAAT), with resulting increases in specific sn-2-unsaturated PA species; exogenous administration of PA in these systems to intact cells also results in stimulation of linoleate and arachidonate uptake into cellular PA, with a corresponding increase in PA mass suggestive of intracellular activation of LPAAT (20–23). The amplification effect of exogenous PA is paralleled by exogenous administration of lipid A to RMC and HMC, which results in increases in PA and apparent stimulation of LPAAT activity (discussed in detail later). Tandem activation of LPAAT and PLD has also been described (24), suggesting generation of PA from (most probably) PC and possibly PE, followed by sn-2 remodeling through the sequential activity of PLA2 and LPAAT. Thus, it is probable that exogenous PA acts to modulate calcium currents through both native PA receptors and conversion to lyso-PA and possibly DG; in addition, PA acts as an auto-stimulant or amplification factor to its own intracellular synthesis both through small G-protein stimulation of PLDs and through stimulation of LPAAT, the modulation of which will be discussed below, as well as apparent interactions of LPAAT with endotoxin. Little to no evidence exists to support the original idea of PA as a direct calcium ionophore (1,2).
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.
Small GTPases in platelet membrane trafficking
Published in Platelets, 2019
Tony G. Walsh, Yong Li, Andreas Wersäll, Alastair W. Poole
The ADP-ribosylation factor (Arf) family of small GTPases comprises six founding members that are separated into three classes largely based on sequence homology; Class I (Arfs 1–3), Class II (Arfs 4–5) and Class III (Arf6). It is now recognised that these Arf proteins form part of a larger family containing over 20 proteins consisting of Arf-like (Arl), Arf-related (Arfrp) and the distally related, secretion-associated and Ras-related (Sar) proteins [58]. Figure 3 details the expression profile for this family in platelets, with the founding Arf members being the most highly expressed and a total of 14 Arf family members have been identified. Similar to Rab GTPases, Arfs are under tight spatial and functional control by GEFs and GAPs, but a distinguishing feature is the myristoylation at the N terminus which brings the GTPase in close contact with the membrane allowing for biological activity [59]. Arf effectors, which include coat proteins involved in endocytosis, membrane tethers, lipid enzymes and scaffold proteins, preferentially bind the GTP-bound form of Arfs, but the GDP-bound form can also interact with separate targets to regulate trafficking events [60]. Beyond trafficking-associated functions, the Arf family also plays important roles in cytoskeletal remodelling, cytokinesis and lipid droplet formation [60,61]. Various human diseases with mutations in Arf family proteins have begun to emerge, but to the best of our knowledge there are currently no reports of associated bleeding diathesis.
Related Knowledge Centers
- Adp Ribosylation Factor
- Arrestin
- G Protein
- Pseudogene
- Transmembrane Protein
- Cell Membrane
- Receptor
- Biological Membrane
- Endocytosis
- Ras Superfamily