Re-localization of activated EGF receptor and its signal transducers to multivesicular compartments downstream of early endosomes in response to EGF

Oksvold, Morten P.; Skarpen, Ellen; Wierød, Lene; Paulsen, Ragnhild E.; Huitfeldt, Henrik S.

doi:10.1078/0171-9335-00160

Cited by 59 publications

(38 citation statements)

References 52 publications

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“…Beside the morphologic similarities, the identity of the VP40-positive MVBs is further elucidated by the finding that these membrane structures contained Lamp-1 and the TfR. Both proteins are known to accumulate in MVBs which belong to the late endosomal compartment (30,41,51).…”

Section: Discussionmentioning

confidence: 99%

VP40, the Matrix Protein of Marburg Virus, Is Associated with Membranes of the Late Endosomal Compartment

Kolesnikova

Bugany

Klenk

et al. 2002

J Virol

130

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Localization of VP40 in Marburg virus (MBGV)-infected cells was studied by using immunofluorescence and immunoelectron microscopic analysis. VP40 was detected in association with nucleocapsid structures, present in viral inclusions and at sites of virus budding. Additionally, VP40 was identified in the foci of virus-induced membrane proliferation and in intracellular membrane clusters which had the appearance of multivesicular bodies (MVBs). VP40-containing MVBs were free of nucleocapsids. When analyzed by immunogold labeling, the concentration of VP40 in MVBs was six times higher than in nucleocapsid structures. Biochemical studies showed that recombinant VP40 represented a peripheral membrane protein that was stably associated with membranes by hydrophobic interaction. Recombinant VP40 was also found in association with membranes of MVBs and in filopodia-or lamellipodia-like protrusions at the cell surface. Antibodies against marker proteins of various cellular compartments showed that VP40-positive membranes contained Lamp-1 and the transferrin receptor, confirming that they belong to the late endosomal compartment. VP40-positive membranes were also associated with actin. Western blot analysis of purified MBGV structural proteins demonstrated trace amounts of actin, Lamp-1, and Rab11 (markers of recycling endosomes), while markers for other cellular compartments were absent. Our data indicate that MBGV VP40 was able to interact with membranes of late endosomes in the course of viral infection. This capability was independent of other MBGV proteins. The family of Filoviridae comprises Marburg virus (MBGV)and Ebola virus (EBOV), which cause a severe and often fatal hemorrhagic disease in human and nonhuman primates. During the reported outbreaks, up to 80% of the cases had a fatal outcome. The recent outbreak of MBGV hemorrhagic fever in the Democratic Republic of the Congo underlines the emerging potential of this pathogen (68). Filoviral infections are pantropic, affecting almost every organ of the infected host. However, the major and primary targets are cells of the mononuclear phagocytic system (55).The enveloped MBGV particles are composed of seven structural proteins and the nonsegmented negative-strand RNA genome (7,15). The viral envelope is spiked with homotrimers of the glycoprotein GP (1,16,60). Four proteins are components of the nucleocapsid: the nucleoprotein NP (2,36,40,57), the L protein (46), VP35 (45), and VP30 (2). NP, VP35, and L are essential for viral replication and transcription (45); the function of VP30, an NP-binding phosphoprotein, is still unclear (44).Between the nucleocapsid and the viral envelope, MBGV particles contain two proteins, VP24 and the highly abundant VP40, whose function is not yet elucidated (2, 13). However, the position of VP40 in the genome (third gene), its hydrophobicity, and its abundance within the virions suggest that VP40 represents a homologue of the matrix proteins of other nonsegmented negative-strand RNA viruses.It is currently believed that matrix prot...

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Section: Discussionmentioning

confidence: 99%

VP40, the Matrix Protein of Marburg Virus, Is Associated with Membranes of the Late Endosomal Compartment

Kolesnikova

Bugany

Klenk

et al. 2002

J Virol

130

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“…BAD1 enters M rapidly, appearing in cells within 10 min of its introduction to cells. Particles can be taken up by cells via multiple routes (30). Pinocytosis, for example, involves the nonspecific "drinking" of extracellular elements.…”

Section: Discussionmentioning

confidence: 99%

“…These latter two proteins are markers for early and late endosomes, respectively (30). Within 10 min of incubation, BAD1 colocalized with the transferrin receptor in early endosomes, and by 60 min of incubation, BAD1 colocalized with LAMP-1 in late endosomes or phagolysosomes (Fig.…”

Section: Internalization Of Sbad1 By Mmentioning

confidence: 99%

Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

Brandhorst

Wüthrich

Finkel-Jimenez

et al. 2004

The Journal of Immunology

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TNF-α is crucial in defense against intracellular microbes. Host immune cells use type 3 complement receptors (CR3) to regulate excess TNF-α production during physiological clearance of apoptotic cells. BAD1, a virulence factor of Blastomyces dermatitidis, is displayed on yeast and released during infection. BAD1 binds yeast to macrophages (Mφ) via CR3 and CD14 and suppresses TNF-α, which is required for resistance. We investigated whether blastomyces adhesin 1 (BAD1) exploits host receptors for immune deviation and pathogen survival. Soluble BAD1 rapidly entered Mφ, accumulated intracellularly by 10 min after introduction to cells, and trafficked to early and late endosomes. Inhibition of receptor recycling by monodansyl cadaverine blocked association of BAD1 with Mφ and reversed TNF-α suppression in vitro. Inhibition of BAD1 uptake with cytochalasin D and FcR-redirected delivery of soluble BAD1 as Ag-Ab complexes or of wild-type yeast opsonized with IgG similarly reversed TNF-α suppression. Hence, receptor-mediated entry of BAD1 is requisite in TNF-α suppression, and the route of entry is critical. Binding of soluble BAD1 to Mφ of CR3−/− and CD14−/− mice was reduced to 50 and 33%, respectively, of that in wild-type mice. Mφ of CR3−/− and CD14−/− mice resisted soluble BAD1 TNF-α suppression in vitro, but, in contrast to CR3−/− cells, CD14−/− cells were still subject to suppression mediated by surface BAD1 on wild-type yeast. CR3−/− mice resisted both infection and TNF-α suppression in vivo, in contrast to wild-type and CD14−/− mice. BAD1 of B. dermatitidis thus co-opts normal host cell physiology by exploiting CR3 to subdue TNF-α production and foster pathogen survival.

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“…This has been clearly demonstrated in studies of a prototype RTK, the epidermal growth factor receptor (EGFR): while an absence of EGFR signaling is lethal, excessive EGFR signaling is associated with the development of a broad range of human cancers. Research aimed at identifying the mechanisms used by normal cells to regulate EGFR suggests that the modulation of receptor trafficking and degradation is essential for appropriate EGFR signaling (8,14,15,22,39,40).…”

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confidence: 99%

Epidermal Growth Factor Receptor Fate Is Controlled by Hrs Tyrosine Phosphorylation Sites That Regulate Hrs Degradation

Stern¹,

Smit²,

Place³

et al. 2007

Molecular and Cellular Biology

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Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is an endosomal protein essential for the efficient sorting of activated growth factor receptors into the lysosomal degradation pathway. Hrs undergoes ligand-induced tyrosine phosphorylation on residues Y329 and Y334 downstream of epidermal growth factor receptor (EGFR) activation. It has been difficult to investigate the functional roles of phosphoHrs, as only a small proportion of the cellular Hrs pool is detectably phosphorylated. Using an HEK 293 model system, we found that ectopic expression of the protein Cbl enhances Hrs ubiquitination and increases Hrs phosphorylation following cell stimulation with EGF. We exploited Cbl's expansion of the phosphoHrs pool to determine whether Hrs tyrosine phosphorylation controls EGFR fate. In structure-function studies of Cbl and EGFR mutants, the level of Hrs phosphorylation and rapidity of apparent Hrs dephosphorylation correlated directly with EGFR degradation. Differential expression of wild-type versus Y329,334F mutant Hrs in Hrs-depleted cells revealed that one or both tyrosines regulate ligand-dependent Hrs degradation, as well as EGFR degradation. By modulating Hrs ubiquitination, phosphorylation, and protein levels, Cbl may control the composition of the endosomal sorting machinery and its ability to target EGFR for lysosomal degradation.

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Re-localization of activated EGF receptor and its signal transducers to multivesicular compartments downstream of early endosomes in response to EGF

Cited by 59 publications

References 52 publications

VP40, the Matrix Protein of Marburg Virus, Is Associated with Membranes of the Late Endosomal Compartment

VP40, the Matrix Protein of Marburg Virus, Is Associated with Membranes of the Late Endosomal Compartment

Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

Epidermal Growth Factor Receptor Fate Is Controlled by Hrs Tyrosine Phosphorylation Sites That Regulate Hrs Degradation

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