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Cellular Microbiology Oct 2014Cellular engulfment of particles, cells or solutes displaces large domains of plasma membrane into intracellular membranous vacuoles. This transfer of membrane is... (Review)
Review
Cellular engulfment of particles, cells or solutes displaces large domains of plasma membrane into intracellular membranous vacuoles. This transfer of membrane is accompanied by major transitions of the phosphoinositide (PI) species that comprise the cytoplasmic face of membrane bilayers. Mapping of membrane PIs during engulfment reveals distinct patterns of protein and PI distributions associated with each stage of engulfment, which correspond with activities that regulate the actin cytoskeleton, membrane movements and vesicle secretion. Experimental manipulation of PI chemistry during engulfment indicates that PIs integrate organelle identity and orient signal transduction cascades within confined subdomains of membrane. These pathways are exploited by microbial pathogens to direct or redirect the engulfment process.
Topics: Actin Cytoskeleton; Bacteria; Biological Transport; Cell Membrane; Phagocytosis; Phosphatidylinositols; Pinocytosis; Signal Transduction; Vacuoles
PubMed: 25073505
DOI: 10.1111/cmi.12334 -
Philosophical Transactions of the Royal... Feb 2019Macropinosome formation occurs as a localized sequence of biochemical activities and associated morphological changes, which may be considered a form of signal... (Review)
Review
Macropinosome formation occurs as a localized sequence of biochemical activities and associated morphological changes, which may be considered a form of signal transduction leading to the construction of an organelle. Macropinocytosis may also convey information about the availability of extracellular nutrients to intracellular regulators of metabolism. Consistent with this idea, activation of the metabolic regulator mechanistic target of rapamycin complex-1 (mTORC1) in response to acute stimulation by growth factors and extracellular amino acids requires internalization of amino acids by macropinocytosis. This suggests that macropinocytosis is necessary for mTORC1-dependent growth of metazoan cells, both as a route for delivery of amino acids to sensors associated with lysosomes and as a platform for growth factor-dependent signalling to mTORC1 via phosphatidylinositol 3-kinase (PI3K) and the Akt pathway. Because the biochemical signals required for the construction of macropinosomes are also required for cell growth, and inhibition of macropinocytosis inhibits growth factor signalling to mTORC1, we propose that signalling by growth factor receptors is organized into stochastic, structure-dependent cascades of chemical reactions that both build a macropinosome and stimulate mTORC1. More generally, as discrete units of signal transduction, macropinosomes may be subject to feedback regulation by metabolism and cell dimensions. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.
Topics: Animals; Cell Proliferation; Endosomes; Humans; Pinocytosis; Signal Transduction
PubMed: 30967006
DOI: 10.1098/rstb.2018.0157 -
Cellular and Molecular Life Sciences :... Apr 2018The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces... (Review)
Review
The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth factor receptor signaling and the overall metabolic status of the cell are coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1 (mTORC1), which positively regulates protein synthesis and negatively regulates molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly binds to and activates mTORC1. Rag is activated by both lysosomal luminal and cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt, and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb converge at the lysosomal membrane, and several lines of evidence support the idea that growth factor-dependent endocytosis facilitates amino acid transfer into the lysosome leading to the activation of Rag. This review summarizes evidence that growth factor-stimulated macropinocytosis is essential for amino acid-dependent activation of mTORC1, and that increased solute accumulation by macropinocytosis in transformed cells supports unchecked cell growth.
Topics: Amino Acids; Animals; Cell Proliferation; Humans; Intercellular Signaling Peptides and Proteins; Mechanistic Target of Rapamycin Complex 1; Pinocytosis; Signal Transduction
PubMed: 29119228
DOI: 10.1007/s00018-017-2710-y -
Investigative Ophthalmology & Visual... Jan 2017Autophagy and macropinocytosis are processes that are vital for cellular homeostasis, and help cells respond to stress and take up large amounts of material,... (Review)
Review
Autophagy and macropinocytosis are processes that are vital for cellular homeostasis, and help cells respond to stress and take up large amounts of material, respectively. The limbal and corneal epithelia have the machinery necessary to carry out both processes; however, autophagy and macropinocytosis are relatively understudied in these two epithelia. In this Perspectives, we describe the basic principles behind macropinocytosis and autophagy, discuss how these two processes are regulated in the limbal and corneal epithelia, consider how these two processes impact on the physiology of limbal and corneal epithelia, and elaborate on areas of future research in autophagy and macropinocytosis as related to the limbal/corneal epithelia.
Topics: Animals; Autophagy; Epithelium, Corneal; Humans; Limbus Corneae; Pinocytosis
PubMed: 28118670
DOI: 10.1167/iovs.16-21111 -
The FEBS Journal Nov 2017Macropinocytosis is a mechanism for the nonspecific bulk uptake and internalisation of extracellular fluid. This plays specific and distinct roles in diverse cell types... (Review)
Review
Macropinocytosis is a mechanism for the nonspecific bulk uptake and internalisation of extracellular fluid. This plays specific and distinct roles in diverse cell types such as macrophages, dendritic cells and neurons, by allowing cells to sample their environment, extract extracellular nutrients and regulate plasma membrane turnover. Macropinocytosis has recently been implicated in several diseases including cancer, neurodegenerative diseases and atherosclerosis. Uptake by macropinocytosis is also exploited by several intracellular pathogens to gain entry into host cells. Both capturing and subsequently processing large volumes of extracellular fluid poses a number of unique challenges for the cell. Macropinosome formation requires coordinated three-dimensional manipulation of the cytoskeleton to form shaped protrusions able to entrap extracellular fluid. The following maturation of these large vesicles then involves a complex series of membrane rearrangements to shrink and concentrate their contents, while delivering components required for digestion and recycling. Recognition of the diverse importance of macropinocytosis in physiology and disease has prompted a number of recent studies. In this article, we summarise advances in our understanding of both macropinosome formation and maturation, and seek to highlight the important unanswered questions.
Topics: Animals; Carrier Proteins; Cell Surface Extensions; Endosomes; Humans; Pinocytosis
PubMed: 28544479
DOI: 10.1111/febs.14115 -
Philosophical Transactions of the Royal... Feb 2019Macropinocytosis-the large-scale, non-specific uptake of fluid by cells-is used by Dictyostelium discoideum amoebae to obtain nutrients. These cells form circular... (Review)
Review
Macropinocytosis-the large-scale, non-specific uptake of fluid by cells-is used by Dictyostelium discoideum amoebae to obtain nutrients. These cells form circular ruffles around regions of membrane defined by a patch of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the activated forms of the small G-proteins Ras and Rac. When this ruffle closes, a vesicle of the medium is delivered to the cell interior for further processing. It is accepted that PIP3 is required for efficient macropinocytosis. Here, we assess the roles of Ras and Rac in Dictyostelium macropinocytosis. Gain-of-function experiments show that macropinocytosis is stimulated by persistent Ras activation and genetic analysis suggests that RasG and RasS are the key Ras proteins involved. Among the activating guanine exchange factors (GEFs), GefF is implicated in macropinocytosis by an insertional mutant. The individual roles of Rho family proteins are little understood but activation of at least some may be independent of PIP3. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.
Topics: Dictyostelium; Monomeric GTP-Binding Proteins; Pinocytosis
PubMed: 30967009
DOI: 10.1098/rstb.2018.0150 -
Autophagy May 2017Macroautophagy/autophagy is vital for cellular homeostasis and helps cells respond to various stress situations. Macropinocytosis enables cells to nonselectively engulf... (Review)
Review
Macroautophagy/autophagy is vital for cellular homeostasis and helps cells respond to various stress situations. Macropinocytosis enables cells to nonselectively engulf and take up large volumes of fluid and is known to supply amino acids to cells. The stem cell-enriched limbal epithelium has the machinery necessary to carry out both autophagy and macropinocytosis; however, both processes are relatively understudied in this tissue. We have demonstrated that these processes are linked via MIR103-MIR107, a microRNA family that is limbal epithelial-preferred. Loss of MIR103-MIR107 causes the accumulation of large vacuoles that originate, in part, from a dysregulation in macropinocytosis via activation of SRC-RAS signaling. We found that these vacuoles were autophagic in nature and retained in cells due to inappropriate regulation of end-stage autophagy. Specifically, MIR103-MIR107 regulates diacylglycerol-PRKC/protein kinase C and CDK5 (cyclin dependent kinase 5) signaling, which enables DNM1 (dynamin 1) to function in vacuole clearance.
Topics: Animals; Autophagy; Epithelial Cells; Humans; MicroRNAs; Pinocytosis; Stem Cells; Vacuoles
PubMed: 28402214
DOI: 10.1080/15548627.2017.1287658 -
The Journal of Cell Biology Jul 2021Actin organization underpins conserved functions at the leading edge of cells. In this issue, Yang et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202010096)...
Actin organization underpins conserved functions at the leading edge of cells. In this issue, Yang et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202010096) characterize Leep1 as a bi-functional regulator of migration and macropinocytosis through PIP3 and the Scar/WAVE complex.
Topics: Actins; Pinocytosis
PubMed: 34128957
DOI: 10.1083/jcb.202105141 -
Prion Mar 2016Temporal and spatial patterns of pathological changes such as loss of neurons and presence of pathological protein aggregates are characteristic of neurodegenerative... (Review)
Review
Temporal and spatial patterns of pathological changes such as loss of neurons and presence of pathological protein aggregates are characteristic of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Alzheimer's disease and Parkinson's disease. These patterns are consistent with the propagation of protein misfolding and aggregation reminiscent of the prion diseases. There is a surge of evidence that suggests that large protein aggregates of a range of proteins are able to enter cells via macropinocytosis. Our recent work suggests that this process is activated by the binding of aggregates to the neuron cell surface. The current review considers the potential role of cell surface receptors in the triggering of macropinocytosis by protein aggregates and the possibility of utilizing macropinocytosis pathways as a therapeutic target.
Topics: Animals; Humans; Neurodegenerative Diseases; Neurons; Pinocytosis; Protein Aggregation, Pathological; Protein Folding
PubMed: 26963158
DOI: 10.1080/19336896.2016.1141860 -
Endocrine-related Cancer Dec 2019Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves... (Review)
Review
Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves differential DNA methylation patterns and levels that change in response to the tumor and systemic therapeutic intervention. Epigenetic reprogramming in carcinoma-associated fibroblasts are robust biomarkers for cancer progression and have a transcriptional impact that support cancer epithelial progression in a paracrine manner. For prostate cancer, promoter hypermethylation and silencing of the RasGAP, RASAL3 that resulted in the activation of Ras signaling in carcinoma-associated fibroblasts. Stromal Ras activity initiated a process of macropinocytosis that provided prostate cancer epithelia with abundant glutamine for metabolic conversion to fuel its proliferation and a signal to transdifferentiate into a neuroendocrine phenotype. This epigenetic oncogenic metabolic/signaling axis seemed to be further potentiated by androgen receptor signaling antagonists and contributed to therapeutic resistance. Intervention of stromal signaling may complement conventional therapies targeting the cancer cell.
Topics: Animals; Cancer-Associated Fibroblasts; Cell Differentiation; Chromatin; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Neoplasms; Pinocytosis
PubMed: 31627186
DOI: 10.1530/ERC-19-0347