scholarly journals Inhibition of Asparagine-linked Glycosylation Participates in Hypoxia-induced Down-regulation of Cell-surface MICA Expression

2018 ◽  
Vol 38 (3) ◽  
Keyword(s):  
Cell Surface ◽  
Down Regulation ◽  
Mica Expression

Both proteasomes and lysosomes degrade the activated erythropoietin receptor

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 600-608 ◽  
Author(s):  
Pierre Walrafen ◽  
Frédérique Verdier ◽  
Zahra Kadri ◽  
Stany Chrétien ◽  
Catherine Lacombe ◽  
...  
Keyword(s):  
Cell Surface ◽  
Intracellular Signaling ◽  
Erythropoietin Receptor ◽  
Janus Kinase ◽  
Receptor Internalization ◽  
Down Regulation ◽  
Epo Receptor ◽  
Receptor Complexes ◽  
Regulation Mechanisms ◽  
Rapid Activation

AbstractActivation of the erythropoietin receptor (EpoR) after Epo binding is very transient because of the rapid activation of strong down-regulation mechanisms that quickly decrease Epo sensitivity of the cells. Among these down-regulation mechanisms, receptor internalization and degradation are probably the most efficient. Here, we show that the Epo receptor was rapidly ubiquitinated after ligand stimulation and that the C-terminal part of the Epo receptor was degraded by the proteasomes. Both ubiquitination and receptor degradation by the proteasomes occurred at the cell surface and required Janus kinase 2 (Jak2) activation. Moreover, Epo-EpoR complexes were rapidly internalized and targeted to the lysosomes for degradation. Neither Jak2 nor proteasome activities were required for internalization. In contrast, Jak2 activation was necessary for lysosome targeting of the Epo-EpoR complexes. Blocking Jak2 with the tyrphostin AG490 led to some recycling of internalized Epo-Epo receptor complexes to the cell surface. Thus, activated Epo receptors appear to be quickly degraded after ubiquitination by 2 proteolytic systems that proceed successively: the proteasomes remove part of the intracellular domain at the cell surface, and the lysosomes degrade the remaining part of the receptor-hormone complex. The efficiency of these processes probably explains the short duration of intracellular signaling activated by Epo.

scholarly journals HHV-8 reduces dendritic cell migration through down-regulation of cell-surface CCR6 and CCR7 and cytoskeleton reorganization

2012 ◽  
Vol 9 (1) ◽  
Author(s):  
Mara Cirone ◽  
Valeria Conte ◽  
Antonella Farina ◽  
Sandro Valia ◽  
Pankaj Trivedi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Dendritic Cell ◽  
Cell Surface ◽  
Down Regulation ◽  
Cytoskeleton Reorganization ◽  
Dendritic Cell Migration

scholarly journals Down-Regulation of Cell Surface Receptors Is Modulated by Polar Residues within the Transmembrane Domain

2000 ◽  
Vol 11 (8) ◽  
pp. 2643-2655 ◽  
Author(s):  
Lolita Zaliauskiene ◽  
Sunghyun Kang ◽  
Christie G. Brouillette ◽  
Jacob Lebowitz ◽  
Ramin B. Arani ◽  
...  
Keyword(s):  
Cell Surface ◽  
Transmembrane Domain ◽  
Gradient Centrifugation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Surface Proteins ◽  
Down Regulation ◽  
Surface Receptors ◽  
Receptor Complexes ◽  
Polar Residues

How recycling receptors are segregated from down-regulated receptors in the endosome is unknown. In previous studies, we demonstrated that substitutions in the transferrin receptor (TR) transmembrane domain (TM) convert the protein from an efficiently recycling receptor to one that is rapidly down regulated. In this study, we demonstrate that the “signal” within the TM necessary and sufficient for down-regulation is Thr11Gln17Thr19 (numbering in TM). Transplantation of these polar residues into the wild-type TR promotes receptor down-regulation that can be demonstrated by changes in protein half-life and in receptor recycling. Surprisingly, this modification dramatically increases the TR internalization rate as well (∼79% increase). Sucrose gradient centrifugation and cross-linking studies reveal that propensity of the receptors to self-associate correlates with down-regulation. Interestingly, a number of cell surface proteins that contain TM polar residues are known to be efficiently down-regulated, whereas recycling receptors for low-density lipoprotein and transferrin conspicuously lack these residues. Our data, therefore, suggest a simple model in which specific residues within the TM sequences dramatically influence the fate of membrane proteins after endocytosis, providing an alternative signal for down-regulation of receptor complexes to the well-characterized cytoplasmic tail targeting signals.

scholarly journals Intradialytic modulation of granulocyte C5a receptors.

1991 ◽  
Vol 2 (4) ◽  
pp. 920-926
Author(s):  
J Himmelfarb ◽  
N P Gerard ◽  
R M Hakim
Keyword(s):  
Cell Surface ◽  
Sampling Time ◽  
Down Regulation ◽  
Cellulose Acetate Electrophoresis ◽  
C5a Receptor ◽  
Initiation Of Dialysis ◽  
C5a Receptors ◽  
Rapid Reversal ◽  
Maximum Decrease ◽  
Cation Exchange Hplc

Hemodialysis with new cellulosic membranes is associated with profound granulocytopenia, with a nadir 15 min after initiation, followed by a rebound leukocytosis seen 1 h after initiation and persisting up to the termination of dialysis. The rapid reversal of granulocytopenia during hemodialysis has previously been ascribed to down-regulation of granulocyte C5a receptors. In this report, a method of characterizing C5a receptors by using a novel probe consisting of C5a attached to biotin via a six-carbon spacer chain is described. Cellulose acetate electrophoresis and cation exchange HPLC demonstrated a biotin-to-C5a ratio of 1:1. Analysis of granulocyte cell surface C5a receptors were performed with the probe with a fluorescein-avidin conjugate and by using fluorescence flow cytometry. The maximum decrease in C5a receptors was measured at the 15-min sampling time, when the number of C5a receptor decreased from 189,240 +/- 24,500 predialysis to 160,740 +/- 19,380 receptors (P was not significant) at the nadir of granulocytopenia. However, during recovery from neutropenia, granulocyte cell surface C5a receptors increased to 172,140 +/- 19,380 at 30 min and 193,800 +/- 24,510 at the end of dialysis. Concentrations of C3a and C5a peaked at 15 min and declined rapidly thereafter, but both remained significantly above baseline at all times. These studies suggest that down-regulation of C5a receptors, which is seen maximally at 15 min after initiation of dialysis, does not sufficiently account for the reversal of granulocytopenia during hemodialysis.

scholarly journals Kinetic analysis of internalization, recycling and redistribution of atrial natriuretic factor-receptor complex in cultured vascular smooth-muscle cells. Ligand-dependent receptor down-regulation

1992 ◽  
Vol 288 (1) ◽  
pp. 55-61 ◽  
Author(s):  
K N Pandey
Keyword(s):  
Smooth Muscle ◽  
Cell Surface ◽  
Atrial Natriuretic Factor ◽  
Dependent Manner ◽  
Receptor Complex ◽  
Down Regulation ◽  
Surface Receptors ◽  
Natriuretic Factor ◽  
Metabolic Degradation ◽  
Atrial Natriuretic

The kinetics of internalization, sequestration and metabolic degradation of atrial natriuretic factor (ANF)-receptor complex were studied in rat thoracic aortic smooth-muscle (RTASM) cells. These parameters were directly determined by measuring 125I-ANF binding to total, intracellular and cell-surface receptors. Pretreatment of cells with the lysosomotropic agent chloroquine and the energy depleter dinitrophenol led to an increase in the intracellular 125I-ANF radioactivity. After 60 min incubation at 37 degrees C, cell-associated 125I-ANF radioactivity fell rapidly in chloroquine-treated cells (> 85%) compared with the controls (< 45%). 125I-ANF radioactivity increased to a peak of 65% of the initial level within 15 min in chloroquine-treated cells compared with only 22% in the control cells. During the initial incubation period at 37 degrees C, chloroquine inhibited the release of both intact and degraded 125I-ANF in a time-dependent manner. However, at later incubation times, the effect of chloroquine was diminished and release of both degraded and intact ligand was resumed. Extracellular unlabelled ANF did not affect the release of degraded 125I-ANF but it accelerated the release of intact ANF by a retroendocytotic mechanism. After the endocytosis, about 30-40% of ANF receptors were restored to the cell surface from the internalized pool of receptors. The restoration was blocked by chloroquine or dinitrophenol but not by cycloheximide. Exposure of RTASM cells to unlabelled ANF resulted in a time- and concentration-dependent loss of ANF receptors. Unlabelled ANF (10 nM) induced a loss of more than 52% of 125I-ANF binding, and a complete loss occurred at micromolar concentrations. It is inferred that ANF-induced down-regulation of its receptor resulted primarily from an increased rate in internalization and metabolic degradation of ligand-receptor complex by receptor-mediated endocytotic mechanisms.

scholarly journals Proteasomes Regulate the Duration of Erythropoietin Receptor Activation by Controlling Down-regulation of Cell Surface Receptors

2000 ◽  
Vol 275 (24) ◽  
pp. 18375-18381 ◽  
Author(s):  
Frédérique Verdier ◽  
Pierre Walrafen ◽  
Nathalie Hubert ◽  
Stany Chrétien ◽  
Sylvie Gisselbrecht ◽  
...  
Keyword(s):  
Cell Surface ◽  
Receptor Activation ◽  
Erythropoietin Receptor ◽  
Cell Surface Receptors ◽  
Down Regulation ◽  
Surface Receptors

Bryostatin-5 Blocks Stromal Cell–Derived Factor-1 Induced Chemotaxis via Desensitization and Down-regulation of Cell Surface CXCR4 Receptors

2008 ◽  
Vol 68 (21) ◽  
pp. 8678-8686 ◽  
Author(s):  
Xing He ◽  
Liyan Fang ◽  
Jue Wang ◽  
Yanghua Yi ◽  
Shuyu Zhang ◽  
...  
Keyword(s):  
Cell Surface ◽  
Stromal Cell ◽  
Down Regulation ◽  
Stromal Cell Derived Factor

Soluble and Membrane Bound MICA in Myeloma Do Not Adversely Effect Regulation of Natural Killer Cell Function Via NKG2D..

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2462-2462
Author(s):  
Jumei Shi ◽  
Susann Szmania ◽  
Fenghuang Zhan ◽  
John Shaughnessy ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Elevated Serum ◽  
Serum Levels ◽  
Down Regulation ◽  
Nkg2d Expression ◽  
Mica Gene ◽  
Membrane Bound

Abstract The human MHC class I -related chain gene A (MICA), a highly polymorphic MHC-encoded cell-surface glycoprotein, is a stress-induced and transformation related molecule absent from most normal tissues. Expression of MICA has been reported on a variety of mostly epithelial tumors. MICA can activate Natural Killer (NK) cells via interacting with the immunoreceptor NKG2D. Soluble MICA (sMICA), when shedded from tumor by the action of matrix-metalloproteinases (MMPs), can be detected at high levels in the sera of cancer patients. High levels of sMICA can down-regulate NKG2D expression and lead to functional impairment of NK cells thus providing for a mechanism of tumor escape. Gene array expression profiling of bone marrow biopsies revealed high levels of MMP2 and MMP9 in the bone marrow microenvironment, but not in the purified myeloma cells of the same patients. Since we are developing allogeneic NK cell therapy as a novel treatment for high-risk myeloma we decided to study whether the high activity of MMP2 and MMP9 resulted in 1) elevated sMICA levels in myeloma, and 2) affected NKG2D expression by NK cells. We found by ELISA assays that 28% (13/46) of patients with MM at diagnosis contained elevated serum levels of sMICA (median: 265.2 pg/ml; range: 125.9 – 806.5 pg/ml). sMICA levels were low in 16 control healthy donors tested (median: 0.8 pg/ml; range: 0 – 91 pg/ml). Next, we correlated sMICA levels with indicators of tumor burden and prognosticators of outcome in MM. We observed that sMICA levels in the serum of MM patients was not associated with Ras associated oncogene (RAN) expression, presence of abnormal cytogenetics, elevated CRP, elevated b2-microglobulin or elevated serum M-protein levels. There was also no correlation between MICA gene expression in purified MM cells and increased sMICA levels in the serum. We therefore examined several myeloma cell lines and found that high MICA gene expression does not always correlate with MICA expression at the cell surface as detected by flow cytometry. We hypothesize that the lack of correlation between MICA RNA expression and sMICA may be due to variation in translation of the MICA mRNA or failure to transport the MICA protein to the cell surface. Further, we tested the expression of NKG2D on CD3−/CD56+ cells of 5 MM patients with elevated sMICA serum levels and detected no down-regulation of NKG2D on NK cells compared to controls comprising MM patients with normal sMICA levels (n=3) or normal donors (n=5). Recent studies have suggested that tumor-membrane bound MICA may also play a role in the down-regulation of NKG2D on NK cells. We next incubated normal donor NK cells with a) the high membrane bound MICA expressing MM cell line U266 or b) serum from MM patients containing high MICA levels neither of which resulted in down-regulation of NKG2D. We conclude that despite the high expression of MMP2 and MMP9 both soluble or membrane bound MICA do not down-regulate NKG2D on NK cells and hence do not adversely affect NK cell function in MM. One explanation may be that the sMICA levels we found in myeloma patients were in the order of pg/ml, whilst the levels reported in epithelial tumors are 2–3 logs higher.

Down-Regulation of HLA-G1 Cell Surface Expression in Human Cytomegalovirus Infected Cells

2003 ◽  
Vol 50 (4) ◽  
pp. 328-333 ◽  
Author(s):  
Nathalie Pizzato ◽  
Barbara Garmy-Susini ◽  
Philippe Le Bouteiller ◽  
Francoise Lenfant
Keyword(s):  
Cell Surface ◽  
Human Cytomegalovirus ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Down Regulation ◽  
Infected Cells
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