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Cells & Development Dec 2021Macropinocytosis is a form of endocytosis performed by ruffles and cups of the plasma membrane. These close to entrap droplets of medium into micron-sized vesicles,... (Review)
Review
Macropinocytosis is a form of endocytosis performed by ruffles and cups of the plasma membrane. These close to entrap droplets of medium into micron-sized vesicles, which are trafficked through the endocytic system, their contents digested and useful products absorbed. Macropinocytosis is constitutive in certain immune cells and stimulated in many other cells by growth factors. It occurs across the animal kingdom and in amoebae, implying a deep evolutionary history. Its scientific history goes back 100 years, but increasingly work is focused on its medical importance in the immune system, cancer cell feeding, and as a backdoor into cells for viruses and drugs. Macropinocytosis is driven by the actin cytoskeleton whose dynamics can be appreciated with lattice light sheet microscopy: this reveals a surprising variety of routes for forming macropinosomes. In Dictyostelium amoebae, macropinocytic cups are organized around domains of PIP3 and active Ras and Rac in the plasma membrane. These attract activators of the Arp2/3 complex to their periphery, creating rings of actin polymerization that shape the cups. The size of PIP3 domains is controlled by RasGAPs, such as NF1, and the lipid phosphatase, PTEN. It is likely that domain dynamics determine the shape, evolution and closing of macropinocytic structures.
Topics: Actin Cytoskeleton; Amoeba; Animals; Biology; Dictyostelium; Endocytosis; Pinocytosis
PubMed: 34175511
DOI: 10.1016/j.cdev.2021.203713 -
Cancer Cell May 2021Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that...
Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
Topics: Animals; Autophagy; Carcinoma, Pancreatic Ductal; Mice; NF-E2-Related Factor 2; Oxidative Stress; Pancreatic Neoplasms; Pinocytosis; Sequestosome-1 Protein; Signal Transduction
PubMed: 33740421
DOI: 10.1016/j.ccell.2021.02.016 -
Nature Communications Feb 2022Hepatocellular carcinoma (HCC) invariably exhibits inadequate O (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular events that...
Hepatocellular carcinoma (HCC) invariably exhibits inadequate O (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular events that enable cancer cells to adapt and propagate. Macropinocytosis is an endocytic process initiated by membrane ruffling, causing the engulfment of extracellular fluids (proteins), protein digestion and subsequent incorporation into the biomass. We show that macropinocytosis occurs universally in HCC under hypoxia. HIF-1 activates the transcription of a membrane ruffling protein, EH domain-containing protein 2 (EHD2), to initiate macropinocytosis. Knockout of HIF-1 or EHD2 represses hypoxia-induced macropinocytosis and prevents hypoxic HCC cells from scavenging protein that support cell growth. Germline or somatic deletion of Ehd2 suppresses macropinocytosis and HCC development in mice. Intriguingly, EHD2 is overexpressed in HCC. Consistently, HIF-1 or macropinocytosis inhibitor suppresses macropinocytosis and HCC development. Thus, we show that hypoxia induces macropinocytosis through the HIF/EHD2 pathway in HCC cells, harnessing extracellular protein as a nutrient to survive.
Topics: Animals; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Mice; Mice, Knockout; Pinocytosis; Proof of Concept Study; Tumor Hypoxia; Xenograft Model Antitumor Assays
PubMed: 35177645
DOI: 10.1038/s41467-022-28618-9 -
Cell May 2017Macropinocytosis is the bulk ingestion of extracellular fluids via large endocytic vacuoles. This SnapShot provides an overview of physiological macropinocytosis in...
Macropinocytosis is the bulk ingestion of extracellular fluids via large endocytic vacuoles. This SnapShot provides an overview of physiological macropinocytosis in immune surveillance and its pathogenic contribution during infection and cancer proliferation.
Topics: Animals; Endocytosis; Humans; Immunologic Surveillance; Infections; Pinocytosis; Vacuoles
PubMed: 28475901
DOI: 10.1016/j.cell.2017.04.031 -
Current Opinion in Virology Feb 2022Endocytosis is used by eukaryotic cells for ingesting external objects. Importantly, endocytosis is a major process that determines phage pharmacokinetics in vivo.... (Review)
Review
Endocytosis is used by eukaryotic cells for ingesting external objects. Importantly, endocytosis is a major process that determines phage pharmacokinetics in vivo. Either dissemination of phages throughout the system or phage clearance engages cellular uptake of phage particles. Here we discuss phage uptake by mammalian cells, focusing on mechanisms and pathways involved. Of note, cellular uptake of phage virions was first observed in professional phagocytes, such as macrophages or granulocytes. For this reason, it was historically referred to as 'phagocytosis'. The modern definition of phagocytosis, however, identifies this process as a type of endocytosis within a larger repertoire of endocytic pathways, such as macropinocytosis, clathrin-mediated endocytosis, and caveolar endocytosis, which have all been included in the scope of this review.
Topics: Animals; Bacteriophages; Caveolae; Endocytosis; Mammals; Phagocytosis; Pinocytosis
PubMed: 34968792
DOI: 10.1016/j.coviro.2021.12.009 -
Molecular Aspects of Medicine Feb 2022Endocytosis mechanisms are one of the methods that cells use to interact with their environments. Endocytosis mechanisms vary from the clathrin-mediated endocytosis to... (Review)
Review
Endocytosis mechanisms are one of the methods that cells use to interact with their environments. Endocytosis mechanisms vary from the clathrin-mediated endocytosis to the receptor independent macropinocytosis. Macropinocytosis is a niche of endocytosis that is quickly becoming more relevant in various fields of research since its discovery in the 1930s. Macropinocytosis has several distinguishing factors from other receptor-mediated forms of endocytosis, including: types of extracellular material for uptake, signaling cascade, and niche uses between cell types. Nanoparticles (NPs) are an important tool for various applications, including drug delivery and disease treatment. However, surface engineering of NPs could be tailored to target them inside the cells exploiting different endocytosis pathways, such as endocytosis versus macropinocytosis. Such surface engineering of NPs mainly, size, charge, shape and the core material will allow identification of new adapter molecules regulating different endocytosis process and provide further insight into how cells tweak these pathways to meet their physiological need. In this review, we focus on the description of macropinocytosis, a lesser studied endocytosis mechanism than the conventional receptor mediated endocytosis. Additionally, we will discuss nanoparticle endocytosis (including macropinocytosis), and how the physio-chemical properties of the NP (size, charge, and surface coating) affect their intracellular uptake and exploiting them as tools to identify new adapter molecules regulating these processes.
Topics: Biological Transport; Clathrin; Endocytosis; Humans; Nanoparticles; Pinocytosis
PubMed: 34281720
DOI: 10.1016/j.mam.2021.100993 -
Philosophical Transactions of the Royal... Feb 2019Macropinocytosis is an evolutionarily conserved form of endocytosis that mediates non-selective uptake of extracellular fluid and the solutes contained therein. In... (Review)
Review
Macropinocytosis is an evolutionarily conserved form of endocytosis that mediates non-selective uptake of extracellular fluid and the solutes contained therein. In mammalian cells, macropinocytosis is initiated by growth factor-mediated activation of the Ras and PI3-kinase signalling pathways. In malignant cells, oncogenic activation of growth factor signalling sustains macropinocytosis cell autonomously. Recent studies of cancer metabolism, discussed here, have begun to define a role for macropinocytosis as a nutrient uptake route. Macropinocytic cancer cells ingest macromolecules in bulk and break them down in the lysosome to support metabolism and macromolecular synthesis. Thereby, macropinocytosis allows cells to tap into the copious nutrient stores of extracellular macromolecules when canonical nutrients are scarce. These findings demonstrate that macropinocytosis promotes metabolic flexibility and resilience, which enables cancer cells to survive and grow in nutrient-poor environments. Implications for physiological roles of growth factor-stimulated macropinocytosis in cell metabolism and its relationship with other nutrient uptake pathways are considered. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.
Topics: Animals; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Pinocytosis; Signal Transduction
PubMed: 30967008
DOI: 10.1098/rstb.2018.0285 -
Philosophical Transactions of the Royal... Feb 2019In macropinocytosis, cells take up micrometre-sized droplets of medium into internal vesicles. These vesicles are acidified and fused to lysosomes, their contents... (Review)
Review
In macropinocytosis, cells take up micrometre-sized droplets of medium into internal vesicles. These vesicles are acidified and fused to lysosomes, their contents digested and useful compounds extracted. Indigestible contents can be exocytosed. Macropinocytosis has been known for approaching 100 years and is described in both metazoa and amoebae, but not in plants or fungi. Its evolutionary origin goes back to at least the common ancestor of the amoebozoa and opisthokonts, with apparent secondary loss from fungi. The primary function of macropinocytosis in amoebae and some cancer cells is feeding, but the conserved processing pathway for macropinosomes, which involves shrinkage and the retrieval of membrane to the cell surface, has been adapted in immune cells for antigen presentation. Macropinocytic cups are large actin-driven processes, closely related to phagocytic cups and pseudopods and appear to be organized around a conserved signalling patch of PIP3, active Ras and active Rac that directs actin polymerization to its periphery. Patches can form spontaneously and must be sustained by excitable kinetics with strong cooperation from the actin cytoskeleton. Growth-factor signalling shares core components with macropinocytosis, based around phosphatidylinositol 3-kinase (PI3-kinase), and we suggest that it evolved to take control of ancient feeding structures through a coupled growth factor receptor. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.
Topics: Amoebozoa; Animals; Biological Evolution; Humans; Pinocytosis; Signal Transduction
PubMed: 30967007
DOI: 10.1098/rstb.2018.0158 -
The International Journal of... 2019The formation and processing of vesicles from the cell surface serves many important cellular functions ranging from nutrient acquisition to regulating the turnover of... (Review)
Review
The formation and processing of vesicles from the cell surface serves many important cellular functions ranging from nutrient acquisition to regulating the turnover of membrane components and signalling. In this article, we summarise the endocytic pathways of the social amoeba Dictyostelium from the clathrin-dependent and independent internalisation of surface components to the engulfment of bacteria or fluid by phagocytosis and macropinocytosis respectively. Due to similarities with the professional phagocytes of the mammalian immune system Dictyostelium has been extensively used to investigate the complex remodelling and trafficking events that occur as phagosomes and macropinosomes transit through the cell. Here we discuss what is known about this maturation process in order to kill any potential pathogens and obtain nutrients for growth. Finally, we aim to put these studies in evolutionary context and highlight some of the many questions that remain in our understanding of these complex and important pathways.
Topics: Cell Membrane; Cell Movement; Clathrin; Dictyostelium; Endocytosis; Exocytosis; Immune System; Lysosomes; Phagocytosis; Phagosomes; Pinocytosis; Signal Transduction
PubMed: 31840784
DOI: 10.1387/ijdb.190236jk -
Traffic (Copenhagen, Denmark) Apr 2009Macropinocytosis represents a distinct pathway of endocytosis in mammalian cells. This actin-driven endocytic process is not directly co-ordinated by the presence of... (Review)
Review
Macropinocytosis represents a distinct pathway of endocytosis in mammalian cells. This actin-driven endocytic process is not directly co-ordinated by the presence of cargo but can be induced upon activation of growth factor signalling pathways. The capacity to dissect the contribution of macropinocytosis to cellular processes has been hampered by a lack of unique molecular markers and defining features. While aspects of macropinosome formation and maturation are common to those shared by the other endocytic pathways, a number of key differences have recently begun to emerge and will be discussed in this study. It is now well established that macropinocytosis significantly contributes to antigen presentation by the immune system and is exploited by a range of pathogens for cellular invasion and avoidance of immune surveillance.
Topics: Animals; Antigen Presentation; Bacteria; Drug Delivery Systems; Endocytosis; Endosomes; Pinocytosis; Signal Transduction; Viruses
PubMed: 19192253
DOI: 10.1111/j.1600-0854.2009.00878.x