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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 -
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 -
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 -
Cancer Discovery Jan 2020Allele-specific signaling by different KRAS alleles remains poorly understood. The mutation displays uneven prevalence among cancers that harbor the highest occurrence...
Allele-specific signaling by different KRAS alleles remains poorly understood. The mutation displays uneven prevalence among cancers that harbor the highest occurrence of mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRAS is functionally distinct from the more common KRAS- or KRAS-mutant proteins (KRAS). We found that KRAS but not KRAS drives macropinocytosis and that MYC is essential for macropinocytosis in KRAS- but not KRAS-mutant PDAC. Surprisingly, we found that KRAS is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRAS-mutant PDAC. Finally, we determined that KRAS-mutant PDAC displayed a distinct drug sensitivity profile compared with KRAS-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRAS is impaired in activating a key effector, p110α PI3K. As such, KRAS is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers...
Topics: Animals; Apoptosis; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Pancreatic Neoplasms; Pinocytosis; Proto-Oncogene Proteins p21(ras); Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 31649109
DOI: 10.1158/2159-8290.CD-19-1006 -
Frontiers in Cell and Developmental... 2020Endocytosis is the process of actively transporting materials into a cell by membrane engulfment. Traditionally, endocytosis was divided into three forms: phagocytosis... (Review)
Review
Endocytosis is the process of actively transporting materials into a cell by membrane engulfment. Traditionally, endocytosis was divided into three forms: phagocytosis (cell eating), pinocytosis (cell drinking), and the more selective receptor-mediated endocytosis (clathrin-mediated endocytosis); however, other important endocytic pathways (e.g., caveolin-dependent endocytosis) contribute to the uptake of extracellular substances. In each, the plasma membrane changes shape to allow the ingestion and internalization of materials, resulting in the formation of an intracellular vesicle. While receptor-mediated endocytosis remains the best understood pathway, mammalian cells utilize each form of endocytosis to respond to their environment. Receptor-mediated endocytosis permits the internalization of cell surface receptors and their ligands through a complex membrane invagination process that is facilitated by clathrin and adaptor proteins. Internalized vesicles containing these receptor-ligand cargoes fuse with early endosomes, which can then be recycled back to the plasma membrane, delivered to other cellular compartments, or destined for degradation by fusing with lysosomes. These intracellular fates are largely determined by the interaction of specific cargoes with adaptor proteins, such as the epsins, disabled-homolog 2 (Dab2), the stonin proteins, epidermal growth factor receptor substrate 15, and adaptor protein 2 (AP-2). In this review, we focus on the role of epsins and Dab2 in controlling these sorting processes in the context of cardiovascular disease. In particular, we will focus on the function of epsins and Dab2 in inflammation, cholesterol metabolism, and their fundamental contribution to atherogenicity.
PubMed: 33363178
DOI: 10.3389/fcell.2020.624159 -
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 -
Cold Spring Harbor Perspectives in... Mar 2020The autophagy lysosomal pathway (ALP) is a major mechanism for degrading intracellular macromolecules. The catabolic products can then be used by the cell for energy or... (Review)
Review
The autophagy lysosomal pathway (ALP) is a major mechanism for degrading intracellular macromolecules. The catabolic products can then be used by the cell for energy or as building blocks to make other macromolecules. Since its discovery, a variety of cellular pathways have emerged that target components with varying specificity for lysosomal degradation. Under some circumstances, lysosomes may release their contents into the extracellular space where they may serve signaling or pathogenic functions. The ALP is active in healthy cells, and the level of activity can be regulated by nutrient-sensing and metabolic signaling pathways. The ALP is the primary pathway by which lipids and damaged organelles are degraded and may be the only pathway capable of degrading aggregated proteins. As such, there has been intense interest in understanding the role of the ALP in the accumulation of aggregated misfolded proteins characteristic of many of the major adult-onset neurodegenerative diseases. This review focuses on recent advances in our understanding of the ALP and its potential relationship to the pathogenesis and treatment of neurodegenerative diseases.
Topics: Animals; Autophagy; Humans; Lipids; Lysosomes; Molecular Chaperones; Neurodegenerative Diseases; Parkinson Disease; Pinocytosis; Signal Transduction
PubMed: 30936119
DOI: 10.1101/cshperspect.a033993 -
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 -
Frontiers in Physiology 2017Enamel formation requires consecutive stages of development to achieve its characteristic extreme mineral hardness. Mineralization depends on the initial presence then... (Review)
Review
Enamel formation requires consecutive stages of development to achieve its characteristic extreme mineral hardness. Mineralization depends on the initial presence then removal of degraded enamel proteins from the matrix via endocytosis. The ameloblast membrane resides at the interface between matrix and cell. Enamel formation is controlled by ameloblasts that produce enamel in stages to build the enamel layer (secretory stage) and to reach final mineralization (maturation stage). Each stage has specific functional requirements for the ameloblasts. Ameloblasts adopt different cell morphologies during each stage. Protein trafficking including the secretion and endocytosis of enamel proteins is a fundamental task in ameloblasts. The sites of internalization of enamel proteins on the ameloblast membrane are specific for every stage. In this review, an overview of endocytosis and trafficking of vesicles in ameloblasts is presented. The pathways for internalization and routing of vesicles are described. Endocytosis is proposed as a mechanism to remove debris of degraded enamel protein and to obtain feedback from the matrix on the status of the maturing enamel.
PubMed: 28824442
DOI: 10.3389/fphys.2017.00529