Receptor downregulation and multivesicular-body sorting

Katzmann, David J.; Odorizzi, Greg; Emr, Scott D.

doi:10.1038/nrm973

Cited by 1,112 publications

(1,199 citation statements)

References 115 publications

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“…The formation of the MVB, and the sorting of cargo, is controlled by a large collection of proteins that was originally identified in yeast as the Class E vacuolar sorting proteins (Vps; reviewed in [51]). The mammalian homologs of the Vps proteins include TSG101, which serves to recognize ubiquitylated proteins for MVB internalization.…”

Section: Discussionmentioning

confidence: 99%

ROCK I-mediated activation of NF-κB by RhoB

Rodrı́guez

Sahay

Olabisi

et al. 2007

Cellular Signalling

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RhoB is a short-lived protein whose expression is increased by a variety of extra-cellular stimuli including UV irradiation, epidermal growth factor (EGF) and transforming growth factor β (TGF-β). Whereas most Rho proteins are modified by the covalent attachment of a geranylgeranyl group, RhoB is unique in that it can exist in either a geranylgeranylated (RhoB-GG) or a farnesylated (RhoB-F) form. Although each form is proposed to have different cellular functions, the signaling events that underlie these differences are poorly understood. Here we show that RhoB can activate NF-κB signaling in multiple cell types. Whereas RhoB-F is a potent activator of NF-κB, much weaker activation is observed for RhoB-GG, RhoA, and RhoC. NF-κB activation by RhoB is not associated with increased nuclear translocation of RelA/p65, but rather, by modification of the RelA/p65 transactivation domain. Activation of NF-κB by RhoB is dependent upon ROCK I but not PRK I. Thus, ROCK I cooperates with RhoB to activate NF-κB, and suppression of ROCK I activity by genetic or pharmacological inhibitors blocks NF-κB activation. Suppression of RhoB activity by dominant-inhibitory mutants, or siRNA, blocks NF-κB activation by Bcr, and TSG101, but not by TNFα or oncogenic Ras. Collectively, these observations suggest the existence of an endosomeassociated pathway for NF-κB activation that is preferentially regulated by the farnesylated form of RhoB.

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Section: Discussionmentioning

confidence: 99%

ROCK I-mediated activation of NF-κB by RhoB

Rodrı́guez

Sahay

Olabisi

et al. 2007

Cellular Signalling

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“…The ESCRT machinery is transiently recruited to the cytosolic side of the endosomal membrane for sorting of selected protein to ILV and for ILV formation [11]. The ESCRT machinery is constituted of three separate protein complexes called ESCRT -I, ESCRT-II, ESCRT -III .…”

Section: Sorting Via the Endosomal Sorting Complex Required For Transmentioning

confidence: 99%

Exosomes as intercellular signalosomes and pharmacological effectors

Record

Subra

Silvente-Poirot

et al. 2011

Biochemical Pharmacology

481

336

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International audienceCell secretion is a general process involved in various biological responses. Exosomes are part of this process and have gained considerable scientific interest in the past five years. Several steps through investigations across the last 20years can explain this interest. First characterized during reticulocyte maturation, they were next characterized as a key player in the immune response and cancer immunotherapy. More recently they were characterized as vectors of mRNAs, miRNAs and also lipid mediators able to act on target cells. They are the only type of vesicles released from an intracellular compartment from cells in viable conditions. They appear as a vectorized signaling system operating from inside a donor cell towards either the periphery, the cytosol, or possibly to the nucleus of target cells. Exosomes from normal cells trigger positive effects, whereas those from pathological ones, such as tumor cells or infected ones may trigger non-positive health effects. Therefore regulating the biogenesis and secretion of exosomes appear as a pharmacological challenge to intervene in various pathophysiologies. Exosome biogenesis and molecular content, interaction with target cells, utilisation as biomarkers, and functional effects in various pathophysiologies are considered in this review

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“…For PfCRT to be functional it should be in the limiting lysosomal membrane and not inside the lysosomes where it may be destined for sequestration or degradation, for example by incorporation in multivesicular bodies within the lysosome [32]. The optical resolution of immunofluorescence is insufficient to distinguish between localization in the membrane vs. inside the lysosome.…”

Section: Subcellular Localization Of Pfcrt In Hek293 Cellsmentioning

confidence: 99%

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

Reeves

Liebelt

Lakshmanan

et al. 2006

Molecular and Biochemical Parasitology

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The emergence of chloroquine-resistant Plasmodium falciparum malaria imperils the lives of millions of people in Africa, Southeast Asia and South America. Chloroquine resistance is associated with mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT). We expressed chloroquine sensitive (HB3) and resistant (Dd2) pfcrt alleles in HEK293 human embryonic kidney cells. PfCRT localized to the lysosomal limiting membrane and was not detected in the plasma membrane. We observed significant acidification of lysosomes containing PfCRT HB3 and Dd2, with Dd2 acidifying significantly more than HB3. A mutant HB3 allele expressing the K76T mutation (earlier found to be key for chloroquine resistance) acidified to the same extent as Dd2, whereas the acidification of a Dd2 allele expressing the T76K "back mutation" was significantly less than Dd2. Thus, the amino acid at position 76 is both an important determinant of chloroquine resistance in parasites and of lysosomal acidification following heterologous expression. PfCRT may be capable of modulating the pH of the parasite digestive vacuole, and thus chloroquine availability. Chloroquine accumulation and glycyl-phenylalanine-2-naphthylamide-induced release of lysosomal Ca 2+ stores were unaffected by PfCRT expression. Cytoplasmic domain mutations did not alter PfCRT sorting to the lysosomal membrane. This heterologous expression system will be useful to characterize PfCRT protein structure and function, and elucidate its molecular role in chloroquine resistance.

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Receptor downregulation and multivesicular-body sorting

Cited by 1,112 publications

References 115 publications

ROCK I-mediated activation of NF-κB by RhoB

ROCK I-mediated activation of NF-κB by RhoB

Exosomes as intercellular signalosomes and pharmacological effectors

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

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