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British Journal of Cancer Jan 2021A potentially important aspect in the regulation of tumour metastasis is endocytosis. This process consists of internalisation of cell-surface receptors via pinocytosis,... (Review)
Review
A potentially important aspect in the regulation of tumour metastasis is endocytosis. This process consists of internalisation of cell-surface receptors via pinocytosis, phagocytosis or receptor-mediated endocytosis, the latter of which includes clathrin-, caveolae- and non-clathrin or caveolae-mediated mechanisms. Endocytosis then progresses through several intracellular compartments for sorting and routing of cargo, ending in lysosomal degradation, recycling back to the cell surface or secretion. Multiple endocytic proteins are dysregulated in cancer and regulate tumour metastasis, particularly migration and invasion. Importantly, four metastasis suppressor genes function in part by regulating endocytosis, namely, the NME, KAI, MTSS1 and KISS1 pathways. Data on metastasis suppressors identify a new point of dysregulation operative in tumour metastasis, alterations in signalling through endocytosis. This review will focus on the multicomponent process of endocytosis affecting different steps of metastasis and how metastatic-suppressor genes use endocytosis to suppress metastasis.
Topics: Cell Movement; Endocytosis; Humans; Neoplasm Invasiveness; Neoplasms
PubMed: 33262521
DOI: 10.1038/s41416-020-01179-8 -
Nature Communications Sep 2020Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36...
Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.
Topics: 3T3-L1 Cells; Acyltransferases; Adipocytes; Animals; CD36 Antigens; Caveolae; Cells, Cultured; Diet, High-Fat; Endocytosis; Fatty Acids; Humans; Lipid Droplets; Lipoylation; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Obesity; Phosphorylation; Signal Transduction; Syk Kinase; Weight Gain; src-Family Kinases
PubMed: 32958780
DOI: 10.1038/s41467-020-18565-8 -
Current Biology : CB Apr 2018Caveolae are one of the most abundant and striking features of the plasma membrane of many mammalian cell types. These surface pits have fascinated biologists since... (Review)
Review
Caveolae are one of the most abundant and striking features of the plasma membrane of many mammalian cell types. These surface pits have fascinated biologists since their discovery by the pioneers of electron microscopy in the middle of the last century, but we are only just starting to understand their multiple functions. Molecular understanding of caveolar formation is advancing rapidly and we now know that sculpting the membrane to generate the characteristic bulb-shaped caveolar pit involves the coordinated action of integral membrane proteins and peripheral membrane coat proteins in a process dependent on their multiple interactions with membrane lipids. The resulting structure is further stabilised by protein complexes at the caveolar neck. Caveolae can bud to generate an endocytic carrier but can also be disassembled in response to specific stimuli to function as a mechanoprotective device. These structures have also been linked to numerous signalling pathways. Here, we will briefly summarise the current molecular and structural understanding of caveolar formation and dynamics, discuss how the crucial structural components of caveolae work together to generate a dynamic sensing domain, and discuss the implications of recent studies on the diverse roles proposed for caveolae in different cells and tissues.
Topics: Animals; Caveolae; Caveolins; Cell Membrane; Cell Membrane Structures; Humans; Mammals; Membrane Lipids; Membrane Proteins; Signal Transduction
PubMed: 29689223
DOI: 10.1016/j.cub.2017.11.075 -
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 -
Comprehensive Physiology Mar 2020Transcytosis of macromolecules through lung endothelial cells is the primary route of transport from the vascular compartment into the interstitial space. Endothelial... (Review)
Review
Transcytosis of macromolecules through lung endothelial cells is the primary route of transport from the vascular compartment into the interstitial space. Endothelial transcytosis is mostly a caveolae-dependent process that combines receptor-mediated endocytosis, vesicle trafficking via actin-cytoskeletal remodeling, and SNARE protein directed vesicle fusion and exocytosis. Herein, we review the current literature on caveolae-mediated endocytosis, the role of actin cytoskeleton in caveolae stabilization at the plasma membrane, actin remodeling during vesicle trafficking, and exocytosis of caveolar vesicles. Next, we provide a concise summary of experimental methods employed to assess transcytosis. Finally, we review evidence that transcytosis contributes to the pathogenesis of acute lung injury. © 2020 American Physiological Society. Compr Physiol 10:491-508, 2020.
Topics: Actin Cytoskeleton; Animals; Biological Transport; Capillary Permeability; Caveolae; Endothelial Cells; Humans; Lung; Transcytosis
PubMed: 32163197
DOI: 10.1002/cphy.c190012 -
ELife Jun 2023Ring-like structures made up of caveolae appear to drive the development of membrane invaginations called T-tubules which are important for muscle contraction.
Ring-like structures made up of caveolae appear to drive the development of membrane invaginations called T-tubules which are important for muscle contraction.
Topics: Caveolin 1; Caveolae; Endocytosis
PubMed: 37339063
DOI: 10.7554/eLife.88954 -
Neuron May 2017The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular...
The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition specifically inhibits the caveolae-mediated transcytotic route readily used in the periphery. An unbiased lipidomic analysis reveals significant differences in endothelial cell lipid signatures from the CNS and periphery, which underlie a suppression of caveolae vesicle formation and trafficking in brain endothelial cells. Furthermore, lipids transported by Mfsd2a establish a unique lipid environment that inhibits caveolae vesicle formation in CNS endothelial cells to suppress transcytosis and ensure BBB integrity.
Topics: Animals; Blood-Brain Barrier; Blotting, Western; Caveolae; Endothelial Cells; HEK293 Cells; Humans; Immunohistochemistry; Lipid Metabolism; Membrane Transport Proteins; Mice; Mice, Knockout; Microscopy, Confocal; Microscopy, Electron, Transmission; Permeability; Symporters; Transcytosis
PubMed: 28416077
DOI: 10.1016/j.neuron.2017.03.043 -
Frontiers in Cell and Developmental... 2020Caveolae are 70-100 nm diameter plasma membrane invaginations found in abundance in adipocytes, endothelial cells, myocytes, and fibroblasts. Their bulb-shaped membrane... (Review)
Review
Caveolae are 70-100 nm diameter plasma membrane invaginations found in abundance in adipocytes, endothelial cells, myocytes, and fibroblasts. Their bulb-shaped membrane domain is characterized and formed by specific lipid binding proteins including Caveolins, Cavins, Pacsin2, and EHD2. Likewise, an enrichment of cholesterol and other lipids makes caveolae a distinct membrane environment that supports proteins involved in cell-type specific signaling pathways. Their ability to detach from the plasma membrane and move through the cytosol has been shown to be important for lipid trafficking and metabolism. Here, we review recent concepts in caveolae trafficking and dynamics. Second, we discuss how ATP and GTP-regulated proteins including dynamin and EHD2 control caveolae behavior. Throughout, we summarize the potential physiological and cell biological roles of caveolae internalization and trafficking and highlight open questions in the field and future directions for study.
PubMed: 33692993
DOI: 10.3389/fcell.2020.614472 -
Biochemical Society Transactions Feb 2020Caveolae have been implicated in a wide range of critical physiological functions. In the past decade, the dominant role of cavin-1 in caveolae formation has been... (Review)
Review
Caveolae have been implicated in a wide range of critical physiological functions. In the past decade, the dominant role of cavin-1 in caveolae formation has been established, and it has been recognized as another master regulator for caveolae biology. Human patients with cavin-1 mutations develop lipodystrophy and muscular dystrophy and have some major pathological dysfunctions in fat tissue, skeleton muscle, heart, lung and other organs. Cavin-1 deficiency animal models consistently show similar phenotypes. However, the underlying molecular mechanisms remain to be elucidated. Recent studies have suggested many possible pathways, including mechanosensing, stress response, signal transduction, exosome secretion, and potential functions in the nucleus. Many excellent and comprehensive review articles already exist on the topics of caveolae structure formation, caveolins, and their pathophysiological functions. We will focus on recent studies using cavin-1 deficiency models, to summarize the pathophysiological changes in adipose, muscle, and other organs, followed by a summary of mechanistic studies about the roles of cavin-1, which includes caveolae formation, ribosomal RNA transcription, mechanical sensing, stress response, and exosome secretion. Further studies may help to elucidate the exact underlying molecular mechanism to explain the pathological changes observed in cavin-1 deficient human patients and animal models, so potential new therapeutic strategies can be developed.
Topics: Animals; Caveolae; Exosomes; Gene Knockdown Techniques; Humans; Lipodystrophy; Membrane Proteins; Mice; Muscular Dystrophies; Mutation; RNA, Ribosomal; RNA-Binding Proteins; Ribosomes; Transcription, Genetic; Tumor Suppressor Protein p53
PubMed: 31922193
DOI: 10.1042/BST20190380 -
Frontiers in Pharmacology 2017Fibrosis is a process of dysfunctional wound repair, described by a failure of tissue regeneration and excessive deposition of extracellular matrix, resulting in tissue... (Review)
Review
Fibrosis is a process of dysfunctional wound repair, described by a failure of tissue regeneration and excessive deposition of extracellular matrix, resulting in tissue scarring and subsequent organ deterioration. There are a broad range of stimuli that may trigger, and exacerbate the process of fibrosis, which can contribute to the growing rates of morbidity and mortality. Whilst the process of fibrosis is widely described and understood, there are no current standard treatments that can reduce or reverse the process effectively, likely due to the continuing knowledge gaps surrounding the cellular mechanisms involved. Several cellular targets have been implicated in the regulation of the fibrotic process including membrane domains, ion channels and more recently mechanosensors, specifically caveolae, particularly since these latter contain various signaling components, such as members of the TGFβ and MAPK/ERK signaling pathways, all of which are key players in the process of fibrosis. This review explores the anti-fibrotic influences of the caveola, and in particular the key underpinning protein, caveolin-1, and its potential as a novel therapeutic target.
PubMed: 28970796
DOI: 10.3389/fphar.2017.00567