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The Biochemical Journal Mar 2023Macropinocytosis is defined as an actin-dependent but coat- and dynamin-independent endocytic uptake process, which generates large intracellular vesicles... (Review)
Review
Macropinocytosis is defined as an actin-dependent but coat- and dynamin-independent endocytic uptake process, which generates large intracellular vesicles (macropinosomes) containing a non-selective sampling of extracellular fluid. Macropinocytosis provides an important mechanism of immune surveillance by dendritic cells and macrophages, but also serves as an essential nutrient uptake pathway for unicellular organisms and tumor cells. This review examines the cell biological mechanisms that drive macropinocytosis, as well as the complex signaling pathways - GTPases, lipid and protein kinases and phosphatases, and actin regulatory proteins - that regulate macropinosome formation, internalization, and disposition.
Topics: Actins; Pinocytosis; Endocytosis; Signal Transduction; Macrophages
PubMed: 36920093
DOI: 10.1042/BCJ20210584 -
International Review of Cytology 1959
Topics: Cell Biology; Cytodiagnosis; Pinocytosis
PubMed: 14402865
DOI: 10.1016/s0074-7696(08)62738-2 -
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 -
Current Opinion in Lipidology Oct 2011Because early findings indicated that native low-density lipoprotein (LDL) did not substantially increase macrophage cholesterol content during in-vitro incubations,... (Review)
Review
PURPOSE OF REVIEW
Because early findings indicated that native low-density lipoprotein (LDL) did not substantially increase macrophage cholesterol content during in-vitro incubations, investigators presumed that LDL must be modified in some way to trigger its uptake by the macrophage. The purpose of this review is to discuss recent findings showing that native unmodified LDL can induce massive macrophage cholesterol accumulation mimicking macrophage foam cell formation that occurs within atherosclerotic plaques.
RECENT FINDINGS
Macrophages that show high rates of fluid-phase pinocytosis also show similar high rates of uptake of native unmodified LDL through nonreceptor mediated uptake within both macropinosomes and micropinosomes. Nonsaturable fluid-phase uptake of LDL by macrophages converts the macrophages into foam cells. Different macrophage phenotypes demonstrate either constitutive fluid-phase pinocytosis or inducible fluid-phase pinocytosis. Fluid-phase pinocytosis has been demonstrated by macrophages within mouse atherosclerotic plaques indicating that this pathway contributes to plaque macrophage cholesterol accumulation.
SUMMARY
Contrary to what has been believed previously, macrophages can take up large amounts of native unmodified LDL by receptor-independent, fluid-phase pinocytosis converting these macrophages into foam cells. Thus, targeting macrophage fluid-phase pinocytosis should be considered when investigating strategies to limit macrophage cholesterol accumulation in atherosclerotic plaques.
Topics: Animals; Cholesterol; Foam Cells; Humans; Lipoproteins, LDL; Macrophages; Pinocytosis
PubMed: 21881499
DOI: 10.1097/MOL.0b013e32834adadb -
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 -
Current Pharmaceutical Design 2013Circulating low-density lipoprotein (LDL) that enters the blood vessel wall is the main source of cholesterol that accumulates within atherosclerotic plaques. Much of... (Review)
Review
Circulating low-density lipoprotein (LDL) that enters the blood vessel wall is the main source of cholesterol that accumulates within atherosclerotic plaques. Much of the deposited cholesterol accumulates within plaque macrophages converting these macrophages into cholesterol-rich foamy looking cells. Cholesterol accumulation in macrophages contributes to cholesterol retention within the vessel wall, and promotes vessel wall inflammation and thrombogenicity. Thus, how macrophages accumulate cholesterol and become foam cells has been the subject of intense investigation. It is generally believed that macrophages accumulate cholesterol only through scavenger receptor-mediated uptake of modified LDL. However, an alternative mechanism for macrophage foam cell formation that does not depend on LDL modification or macrophage receptors has been elucidated. By this alternative mechanism, macrophages show receptor-independent uptake of unmodified native LDL that is mediated by fluid-phase pinocytosis. In receptor-independent, fluid-phase pinocytosis, macrophages take up LDL as part of the fluid that they ingest during micropinocytosis within small vesicles called micropinosomes, and by macropinocytosis within larger vacuoles called macropinosomes. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques. Fluid-phase pinocytosis of LDL is a plausible mechanism that can explain how macrophages accumulate cholesterol and become disease-causing foam cells. Fluid-phase pinocytosis of LDL is a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis. Recent studies show that phosphoinositide 3-kinase (PI3K), liver X receptors (LXRs), the macrophage colony-stimulating factor (M-CSF) receptor, and protein kinase C (PKC) mediate macrophage macropinocytosis of LDL, and thus, these may be relevant targets to inhibit macrophage cholesterol accumulation in atherosclerosis.
Topics: Animals; Cholesterol; Foam Cells; Humans; Lipoproteins, LDL; Macrophages; Molecular Targeted Therapy; Pinocytosis; Plaque, Atherosclerotic
PubMed: 23438954
DOI: 10.2174/1381612811319330005 -
Taiwan Yi Xue Hui Za Zhi. Journal of... Jun 1967
Topics: Culture Techniques; Pinocytosis
PubMed: 5238908
DOI: No ID Found -
Scientific American Apr 1961
Topics: Cell Biology; Metabolism; Pinocytosis
PubMed: 13744905
DOI: No ID Found -
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 -
Uspekhi Sovremennoi Biologii 1962
Topics: Cell Biology; Cytodiagnosis; Pinocytosis
PubMed: 14010062
DOI: No ID Found