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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 -
Sub-cellular Biochemistry 2022Macropinocytosis is a critical route of nutrient acquisition in pancreatic cancer cells. Constitutive macropinocytosis is promoted by mutant KRAS, which activates the... (Review)
Review
Macropinocytosis is a critical route of nutrient acquisition in pancreatic cancer cells. Constitutive macropinocytosis is promoted by mutant KRAS, which activates the PI3Kα lipid kinase and RAC1, to drive membrane ruffling, macropinosome uptake and processing. However, our recent study on the KRAS mutant indicated the presence of a KRAS-independent mode of macropinocytosis in pancreatic cancer cell lines, thereby increasing the complexity of this process. We found that KRAS-mutant cell lines promote macropinocytosis independent of KRAS activity using PI3Kγ and RAC1, highlighting the convergence of regulation on RAC signaling. While macropinocytosis has been proposed to be a therapeutic target for the treatment of pancreatic cancer, our studies have underscored how little we understand about the activation and regulation of this metabolic process. Therefore, this review seeks to highlight the differences in macropinocytosis regulation in the two cellular subtypes while also highlighting the features that make the KRAS mutant atypical.
Topics: Humans; Pancreatic Neoplasms; Pinocytosis; Proto-Oncogene Proteins p21(ras); Signal Transduction
PubMed: 35378710
DOI: 10.1007/978-3-030-94004-1_11 -
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 -
Proceedings of the National Academy of... May 2022Mammalian target of rapamycin complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Some amino acids signal to mTORC1 through the Rag...
Mammalian target of rapamycin complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Some amino acids signal to mTORC1 through the Rag GTPase, whereas glutamine and asparagine activate mTORC1 through a Rag GTPase-independent pathway. Here, we show that the lysosomal glutamine and asparagine transporter SNAT7 activates mTORC1 after extracellular protein, such as albumin, is macropinocytosed. The N terminus of SNAT7 forms nutrient-sensitive interaction with mTORC1 and regulates mTORC1 activation independently of the Rag GTPases. Depletion of SNAT7 inhibits albumin-induced mTORC1 lysosomal localization and subsequent activation. Moreover, SNAT7 is essential to sustain KRAS-driven pancreatic cancer cell growth through mTORC1. Thus, SNAT7 links glutamine and asparagine signaling from extracellular protein to mTORC1 independently of the Rag GTPases and is required for macropinocytosis-mediated mTORC1 activation and pancreatic cancer cell growth.
Topics: Amino Acid Transport Systems, Neutral; Asparagine; Glutamine; Humans; Lysosomes; Mechanistic Target of Rapamycin Complex 1; Pancreatic Neoplasms; Pinocytosis; Signal Transduction
PubMed: 35561222
DOI: 10.1073/pnas.2123261119 -
Biochimica Et Biophysica Acta Jun 2015Professional phagocytes provide immunoprotection and aid in the maintenance of tissue homeostasis. They perform these tasks by recognizing, engulfing and eliminating... (Review)
Review
Professional phagocytes provide immunoprotection and aid in the maintenance of tissue homeostasis. They perform these tasks by recognizing, engulfing and eliminating pathogens and endogenous cell debris. Here, we examine the paramount role played by phosphoinositides in phagocytosis and macropinocytosis, two major endocytic routes that mediate the uptake of particulate and fluid matter, respectively. We analyze accumulating literature describing the molecular mechanisms whereby phosphoinositides translate environmental cues into the complex, sophisticated responses that underlie the phagocytic and macropinocytic responses. In addition, we exemplify virulence strategies involving modulation of host cell phosphoinositide signaling that are employed by bacteria to undermine immunity. This article is part of a Special Issue entitled Phosphoinositides.
Topics: Bacteria; Gene Expression Regulation; Humans; Immune Evasion; Immunity, Cellular; Macrophages; Opsonin Proteins; Phagocytosis; Phagosomes; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Pinocytosis; Receptors, IgG; Signal Transduction
PubMed: 25238964
DOI: 10.1016/j.bbalip.2014.09.005 -
Nature Jun 2017Mammalian cells are surrounded by diverse nutrients, such as glucose, amino acids, various macromolecules and micronutrients, which they can import through transmembrane... (Review)
Review
Mammalian cells are surrounded by diverse nutrients, such as glucose, amino acids, various macromolecules and micronutrients, which they can import through transmembrane transporters and endolysosomal pathways. By using different nutrient sources, cells gain metabolic flexibility to survive periods of starvation. Quiescent cells take up sufficient nutrients to sustain homeostasis. However, proliferating cells depend on growth-factor-induced increases in nutrient uptake to support biomass formation. Here, we review cellular nutrient acquisition strategies and their regulation by growth factors and cell-intrinsic nutrient sensors. We also discuss how oncogenes and tumour suppressors promote nutrient uptake and thereby support the survival and growth of cancer cells.
Topics: Animals; Cell Proliferation; Cells; Endocytosis; Glucose; Glutamine; Intercellular Signaling Peptides and Proteins; Lysosomes; Neoplasms; Pinocytosis; Proteins; Tumor Microenvironment
PubMed: 28593971
DOI: 10.1038/nature22379 -
Journal of Cell Science Jul 2016Macropinocytosis is a means by which eukaryotic cells ingest extracellular liquid and dissolved molecules. It is widely conserved amongst cells that can take on amoeboid... (Review)
Review
Macropinocytosis is a means by which eukaryotic cells ingest extracellular liquid and dissolved molecules. It is widely conserved amongst cells that can take on amoeboid form and, therefore, appears to be an ancient feature that can be traced back to an early stage of evolution. Recent advances have highlighted how this endocytic process can be subverted during pathology - certain cancer cells use macropinocytosis to feed on extracellular protein, and many viruses and bacteria use it to enter host cells. Prion and prion-like proteins can also spread and propagate from cell to cell through macropinocytosis. Progress is being made towards using macropinocytosis therapeutically, either to deliver drugs to or cause cell death by inducing catastrophically rapid fluid uptake. Mechanistically, the Ras signalling pathway plays a prominent and conserved activating role in amoebae and in mammals; mutant amoebae with abnormally high Ras activity resemble tumour cells in their increased capacity for growth using nutrients ingested through macropinocytosis. This Commentary takes a functional and evolutionary perspective to highlight progress in understanding and use of macropinocytosis, which is an ancient feeding process used by single-celled phagotrophs that has now been put to varied uses by metazoan cells and is abused in disease states, including infection and cancer.
Topics: Animals; Cell Death; Communicable Diseases; Humans; Immunity; Macromolecular Substances; Pinocytosis; Prions
PubMed: 27352861
DOI: 10.1242/jcs.176149 -
Sub-cellular Biochemistry 2022Macropinocytosis is a relatively unexplored form of large-scale endocytosis driven by the actin cytoskeleton. Dictyostelium amoebae form macropinosomes from cups...
Macropinocytosis is a relatively unexplored form of large-scale endocytosis driven by the actin cytoskeleton. Dictyostelium amoebae form macropinosomes from cups extended from the plasma membrane, then digest their contents and absorb the nutrients in the endo-lysosomal system. They use macropinocytosis for feeding, maintaining a high rate of fluid uptake that makes assay and experimentation easy. Mutants collected over the years identify cytoskeletal and signalling proteins required for macropinocytosis. Cups are organized around plasma membrane domains of intense PIP3, Ras and Rac signalling, proper formation of which also depends on the RasGAPs NF1 and RGBARG, PTEN, the PIP3-regulated protein kinases Akt and SGK and their activators PDK1 and TORC2, Rho proteins, plus other components yet to be identified. This PIP3 domain directs dendritic actin polymerization to the extending lip of macropinocytic cups by recruiting a ring of the SCAR/WAVE complex around itself and thus activating the Arp2/3 complex. The dynamics of PIP3 domains are proposed to shape macropinocytic cups from start to finish. The role of the Ras-PI3-kinase module in organizing feeding structures in unicellular organisms most likely predates its adoption into growth factor signalling, suggesting an evolutionary origin for growth factor signalling.
Topics: Actin Cytoskeleton; Amoeba; Dictyostelium; Phosphatidylinositol 3-Kinases; Pinocytosis
PubMed: 35378702
DOI: 10.1007/978-3-030-94004-1_3 -
Sub-cellular Biochemistry 2022Eukaryotic cells are capable of internalizing different types of cargo by plasma membrane ruffling and forming vesicles in a process known as endocytosis. The most...
Eukaryotic cells are capable of internalizing different types of cargo by plasma membrane ruffling and forming vesicles in a process known as endocytosis. The most extensively characterized endocytic pathways are clathrin-coated pits, lipid raft/caveolae-mediated endocytosis, phagocytosis, and macropinocytosis. Macropinocytosis is unique among all the endocytic processes due to its nonselective internalization of extracellular fluid, solutes, and membrane in large endocytic vesicles known as macropinosomes with unique susceptibility toward Na+/H+ exchanger inhibitors. Range of cell types capable of macropinocytosis and known to play important role in different physiological processes, which include antigen presentation, nutrient sensing, migration, and signaling. Understanding the physiological function of macropinocytosis will be helpful in filling the gaps in our knowledge and which can be exploited to develop novel therapeutic targets. In this chapter, we discuss the different molecular mechanisms that initiate the process of macropinocytosis with special emphasis on proteins involved and their diversified role in different cell types.
Topics: Endocytosis; Endosomes; Membrane Microdomains; Phagocytosis; Pinocytosis
PubMed: 35378700
DOI: 10.1007/978-3-030-94004-1_1