scholarly journals Control of ADAM17 activity by regulation of its cellular localisation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Inken Lorenzen ◽  
Juliane Lokau ◽  
Yvonne Korpys ◽  
Mirja Oldefest ◽  
Charlotte M. Flynn ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cancer Progression ◽  
Phorbol Ester ◽  
Signalling Pathways ◽  
Coated Pits ◽  
Cellular Localisation ◽  
Subsequent Degradation ◽  
A Disintegrin And Metalloproteinase ◽  
Mature Protease

Abstract An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. This central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation. Most mature ADAM17 is localised intracellularly, with only a small amount at the cell surface. We found that ADAM17 is constitutively internalised by clathrin-coated pits and that physiological stimulators such as GPCR ligands induce ADAM17-mediated shedding, but do not alter the cell-surface abundance of the protease. In contrast, the PKC-activating phorbol ester PMA, often used as a strong inducer of ADAM17, causes not only proteolysis by ADAM17 but also a rapid increase of the mature protease at the cell surface. This is followed by internalisation and subsequent degradation of the protease. Eventually, this leads to a substantial downregulation of mature ADAM17. Our results therefore imply that physiological activation of ADAM17 does not rely on its relocalisation, but that PMA-induced PKC activity drastically dysregulates the localisation of ADAM17.

What do nanometer molecular trajectories tell us about heterogeneous cell surface domaines?

1995 ◽  
Vol 53 ◽  
pp. 786-787
Author(s):  
Watt W. Webb
Keyword(s):  
Cell Surface ◽  
Lipid Membranes ◽  
Surface Proteins ◽  
Protein Diffusion ◽  
Coated Pits ◽  
Cell Surface Proteins ◽  
Membrane Heterogeneity ◽  
Fluorescence Photobleaching Recovery ◽  
Photobleaching Recovery ◽  
Plasma Membrane Heterogeneity

Plasma membrane heterogeneity is implicit in the existence of specialized cell surface organelles which are necessary for cellular function; coated pits, post and pre-synaptic terminals, microvillae, caveolae, tight junctions, focal contacts and endothelial polarization are examples. The persistence of these discrete molecular aggregates depends on localized restraint of the constituent molecules within specific domaines in the cell surface by strong intermolecular bonds and/or anchorage to extended cytoskeleton. The observed plasticity of many of organelles and the dynamical modulation of domaines induced by cellular signaling evidence evanescent intermolecular interactions even in conspicuous aggregates. There is also strong evidence that universal restraints on the mobility of cell surface proteins persist virtually everywhere in cell surfaces, not only in the discrete organelles. Diffusion of cell surface proteins is slowed by several orders of magnitude relative to corresponding protein diffusion coefficients in isolated lipid membranes as has been determined by various ensemble average methods of measurement such as fluorescence photobleaching recovery(FPR).

scholarly journals Receptor-mediated endocytosis of alpha 2-macroglobulin in cultured fibroblasts.

1980 ◽  
Vol 28 (8) ◽  
pp. 818-823 ◽  
Author(s):  
M C Willingham ◽  
F R Maxfield ◽  
I Pastan
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Coated Pits ◽  
Cultured Fibroblasts ◽  
Receptor Mediated Endocytosis ◽  
Cytoplasmic Vesicles

Alpha 2-macroglobulin is internalized into cultured fibroblasts by receptor-mediated endocytosis. This ligand binds initially to diffusely distributed receptors on the cell surface which cluster rapidly into bristle-coated pits. Within a few minutes at 37 degrees C, these complexes are internalized into uncoated cytoplasmic vesicles, called receptosomes, which move about in the cell by saltatory motion. These vesicles interact with the Golgi-endoplasmic reticulum-lysosome system in the cell to deliver the ligand to newly formed lysosomes within 30--60 min.

scholarly journals Surface charge distribution on the endothelial cell of liver sinusoids.

1984 ◽  
Vol 99 (2) ◽  
pp. 639-647 ◽  
Author(s):  
L Ghitescu ◽  
A Fixman
Keyword(s):  
Endothelial Cell ◽  
Cell Surface ◽  
Liver Sinusoid ◽  
Electron Microscopic ◽  
Coated Pits ◽  
Endothelial Cell Surface ◽  
Liver Sinusoids ◽  
Surface Charge Distribution ◽  
Cationic Residues

The topography of the charged residues on the endothelial cell surface of liver sinusoid capillaries was investigated by using electron microscopic tracers of different size and charge. The tracers used were native ferritin (pl 4.2-4.7) and its cationized (pl 8.4) and anionized (pl 3.7) derivatives, BSA coupled to colloidal gold (pl of the complex 5.1), hemeundecapeptide (pl 4.85), and alcian blue (pl greater than 10). The tracers were either injected in vivo or perfused in situ through the portal vein of the mouse liver. In some experiments, two tracers of opposite charge were sequentially perfused with extensive washing in between. The liver was processed for electron microscopy and the binding pattern of the injected markers was recorded. The electrostatic nature of the tracer binding was assessed by perfusion with high ionic strength solutions, by aldehyde quenching of the plasma membrane basic residues, and by substituting the cell surface acidic moieties with positively charged groups. Results indicate that the endothelial cells of the liver sinusoids expose on their surface both cationic and anionic residues. The density distribution of these charged groups on the cell surface is different. While the negative charge is randomly and patchily scattered all over the membrane, the cationic residues seem to be accumulated in coated pits. The charged groups co-exist in the same coated pit and bind the opposite charged macromolecule. It appears that the fixed positive and negative charges of the coated pit glycocalyx are mainly segregated in space. The layer of basic residues is located at 20-30-nm distance of the membrane, while most of the negative charges lie close to the external leaflet of the plasmalemma.

DLX6-AS1: a putative lncRNA candidate in multiple human cancers

2021 ◽  
Vol 23 ◽  
Author(s):  
Mohsen Sheykhhasan ◽  
Yaghoub Ahmadyousefi ◽  
Reihaneh Seyedebrahimi ◽  
Hamid Tanzadehpanah ◽  
Hamed Manoochehri ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Critical Analysis ◽  
Molecular Mechanisms ◽  
Signalling Pathways ◽  
Biological Functions ◽  
Initial Development ◽  
Human Cancers ◽  
Expression Of Genes ◽  
Non Coding Rnas ◽  
Research Studies

Abstract Long non-coding RNAs (lncRNAs) have important roles in regulating the expression of genes and act as biomarkers in the initial development of different cancers. Increasing research studies have verified that dysregulation of lncRNAs occurs in various pathological processes including tumorigenesis and cancer progression. Among the different lncRNAs, DLX6-AS1 has been reported to act as an oncogene in the development and prognoses of different cancers, by affecting many different signalling pathways. This review summarises and analyses the recent research studies describing the biological functions of DLX6-AS1, its overall effect on signalling pathways and the molecular mechanisms underlying its action on the expression of genes in multiple human cancers. Our critical analysis suggests that different signalling pathways associated to this lncRNA may be used as a biomarker for diagnosis, or targets of treatment in cancers.

scholarly journals Phorbol ester treatment increases the exocytic rate of the transferrin receptor recycling pathway independent of serine-24 phosphorylation.

1988 ◽  
Vol 106 (4) ◽  
pp. 1061-1066 ◽  
Author(s):  
T E McGraw ◽  
K W Dunn ◽  
F R Maxfield
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Surface ◽  
Phorbol Ester ◽  
Cho Cells ◽  
Transferrin Receptor ◽  
Phosphorylation Site ◽  
Major Protein ◽  
Kinase C ◽  
Recycling Pathway

In Chinese hamster ovary (CHO) fibroblast cells the protein kinase C activating phorbol ester, phorbol myristate acetate (PMA), stimulates an increase in cell surface transferrin receptor (TR) expression by increasing the exocytic rate of the recycling pathway. The human TR expressed in CHO cells is similarly affected by PMA treatment. A mutant human TR in which the major protein kinase C phosphorylation site, serine 24, has been replaced with the non-phosphorylatable amino acid glycine has been constructed to investigate the role of receptor phosphorylation in the PMA induced up-regulation. The Gly-24-substituted receptor binds, internalizes, and recycles Tf. Furthermore, the altered receptor mediates cellular Fe accumulation from diferric-Tf, thereby fulfilling the receptor's major biological role. The Gly-24 TR behaves identically to the wild-type TR when cells are treated with PMA. Therefore, Ser-24 phosphorylation is not required for the PMA-induced redistribution of the human TR expressed in CHO cells. The increased TR expression on the cell surface after PMA treatment results from an increase in the rate of exocytosis of the recycling receptors. No change in the endocytic rate or the size of the recycling receptor pool was observed. These results indicate that the PMA effect on the TR surface expression may result from a more general perturbation of membrane trafficking rather than a specific modulation of the TR.

The effects of cytochalasin D and phorbol myristate acetate on the apical endocytosis of ricin in polarised Caco-2 cells

1996 ◽  
Vol 109 (12) ◽  
pp. 2927-2935 ◽  
Author(s):  
W. Shurety ◽  
N.A. Bright ◽  
J.P. Luzio
Keyword(s):  
Cell Surface ◽  
Apical Cell ◽  
Microscopic Investigation ◽  
Electron Microscopic Investigation ◽  
Cytochalasin D ◽  
Apical Surface ◽  
Electron Microscopic ◽  
Coated Pits ◽  
Acid Media ◽  
Kinase C

Apical endocytosis of 125I-ricin in Caco-2 cells was inhibited > 95% by hypertonic and/or acid media, consistent with the major uptake route being clathrin-mediated. The presence of apical cell surface bound ricin-gold in clathrin coated pits and vesicles was observed by electron microscopy. An electron microscopic investigation in which ricin-gold bound to the apical surface was quantitated, showed that cytochalasin D, which inhibits apical but not basolateral endocytosis, prevented movement of ricin-gold along the microvillar surface. This was consistent with an actin bound mechanochemical motor within microvilli driving the movement of membranous components towards the cell body. Cytochalasin D also caused an increase in the number of coated pits observed at the apical cell surface relative to the number observed in untreated cells. Stimulation of apical endocytosis of ricin by phorbol 12-myristate 13-acetate showed the characteristics of being mediated by protein kinase C, was not due to an effect on ricin movement along the microvillar surface, and may be explained by increases in formation and pinching off of clathrin coated pits at the apical cell surface.

Intracellular signalling

2020 ◽  
pp. 256-265
Author(s):  
R. Andres Floto
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
Cell Surface ◽  
Intracellular Signalling ◽  
Signalling Pathways ◽  
Molecular Processes ◽  
Surface Receptors ◽  
Intracellular Signalling Pathways ◽  
Transmission Of Information ◽  
Effective Transmission

This chapter outlines the general principles of intracellular signalling. Focusing on cell surface receptors, the requirements for effective transmission of information across the plasma membrane are outlined. The principal mechanisms utilized in mammalian signal transduction are described. For each, the pathological consequences of aberrant signalling and means by which pathways can be pharmacologically targeted are described in molecular terms. Intracellular signalling pathways permit the transmission and integration of information within cells. Mammalian receptor signalling relies on only a small number of distinct molecular processes which interact to determine cellular responses. Rapid advances in our knowledge of the mechanisms of intracellular signalling has greatly increased understanding of how cells function physiologically, how they malfunction pathologically, and how their behaviour might be manipulated therapeutically.

scholarly journals A myosin-7B–dependent endocytosis pathway mediates cellular entry of α-synuclein fibrils and polycation-bearing cargos

2020 ◽  
Vol 117 (20) ◽  
pp. 10865-10875 ◽  
Author(s):  
Qi Zhang ◽  
Yue Xu ◽  
Juhyung Lee ◽  
Michal Jarnik ◽  
Xufeng Wu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Actin Filaments ◽  
Membrane Dynamics ◽  
Cell Entry ◽  
Sulfate Proteoglycan ◽  
Actin Network ◽  
Coated Pits ◽  
Endocytosis Pathway ◽  
Underlying Mechanisms ◽  
Pathological Event

Cell-to-cell transmission of misfolding-prone α-synuclein (α-Syn) has emerged as a key pathological event in Parkinson’s disease. This process is initiated when α-Syn–bearing fibrils enter cells via clathrin-mediated endocytosis, but the underlying mechanisms are unclear. Using a CRISPR-mediated knockout screen, we identify SLC35B2 and myosin-7B (MYO7B) as critical endocytosis regulators for α-Syn preformed fibrils (PFFs). We show that SLC35B2, as a key regulator of heparan sulfate proteoglycan (HSPG) biosynthesis, is essential for recruiting α-Syn PFFs to the cell surface because this process is mediated by interactions between negatively charged sugar moieties of HSPGs and clustered K-T-K motifs in α-Syn PFFs. By contrast, MYO7B regulates α-Syn PFF cell entry by maintaining a plasma membrane-associated actin network that controls membrane dynamics. Without MYO7B or actin filaments, many clathrin-coated pits fail to be severed from the membrane, causing accumulation of large clathrin-containing “scars” on the cell surface. Intriguingly, the requirement for MYO7B in endocytosis is restricted to α-Syn PFFs and other polycation-bearing cargos that enter cells via HSPGs. Thus, our study not only defines regulatory factors for α-Syn PFF endocytosis, but also reveals a previously unknown endocytosis mechanism for HSPG-binding cargos in general, which requires forces generated by MYO7B and actin filaments.

scholarly journals Heparan Sulfate Proteoglycans May Promote or Inhibit Cancer Progression by Interacting with Integrins and Affecting Cell Migration

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Mariana A. Soares ◽  
Felipe C. O. B. Teixeira ◽  
Miguel Fontes ◽  
Ana Lúcia Arêas ◽  
Marcelo G. Leal ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Cancer Progression ◽  
Heparan Sulfate Proteoglycans ◽  
Transmembrane Receptors ◽  
Surface Molecules ◽  
Cell Matrix ◽  
Cell Organization ◽  
The Relationship

The metastatic disease is one of the main consequences of tumor progression, being responsible for most cancer-related deaths worldwide. This review intends to present and discuss data on the relationship between integrins and heparan sulfate proteoglycans in health and cancer progression. Integrins are a family of cell surface transmembrane receptors, responsible for cell-matrix and cell-cell adhesion. Integrins’ main functions include cell adhesion, migration, and survival. Heparan sulfate proteoglycans (HSPGs) are cell surface molecules that play important roles as cell receptors, cofactors, and overall direct or indirect contributors to cell organization. Both molecules can act in conjunction to modulate cell behavior and affect malignancy. In this review, we will discuss the different contexts in which various integrins, such asα5,αV,β1, andβ3, interact with HSPGs species, such as syndecans and perlecans, affecting tissue homeostasis.

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