The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments

Cortese, Katia; Howes, Mark T.; Lundmark, Richard; Tagliatti, Erica; Bagnato, Paola; Petrelli, Annalisa; Bono, Marı́a Rosa; McMahon, Harvey T.; Parton, Robert G.; Tacchetti, Carlo

doi:10.1091/mbc.e12-04-0282

Cited by 45 publications

(74 citation statements)

References 71 publications

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“…8 illustrates our main concept, demonstrating that the HBV infection promotes the formation of an interconnecting reticular network between MVBs, autophagosomes and lysosomes driven by the activation of Rab7. Although tubules extending from MVBs and autophagosomes have been reported previously (Cooney et al, 2002;Cortese et al, 2013;Gao et al, 2010), those induced by HBV in the current study are much more prominent.…”

Section: Discussionsupporting

confidence: 42%

HBV secretion is regulated through the activation of endocytic and autophagic compartments via Rab7 stimulation

Inoue

Krueger

Chen

et al. 2015

Journal of Cell Science

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The cellular mechanisms by which hepatitis B virus (HBV) is assembled and exported are largely undefined. Recently, it has been suggested that these steps require the multivesicular body (MVB) and the autophagic machinery. However, the mechanisms by which HBV might regulate these compartments are unclear. In this study, we have found that by activating Rab7a, HBV alters its own secretion by inducing dramatic changes in the morphology of MVB and autophagic compartments. These changes are characterized by the formation of numerous tubules that are dependent upon the increase in Rab7 activity observed in the HBV-expressing HepG2.2.15 cells compared to HepG2 cells. Interestingly, transfection-based expression of the five individual viral proteins indicated that the precore protein, which is a precursor of HBeAg, was largely responsible for the increased Rab7 activity. Finally, small interfering RNA (siRNA)-mediated depletion of Rab7 significantly increased the secretion of virions, suggesting that reduced delivery of the virus to the lysosome facilitates viral secretion. These findings provide novel evidence indicating that HBV can regulate its own secretion through an activation of the endo-lysosomal and autophagic pathway mediated by Rab7 activation.

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Section: Discussionsupporting

confidence: 42%

HBV secretion is regulated through the activation of endocytic and autophagic compartments via Rab7 stimulation

Inoue

Krueger

Chen

et al. 2015

Journal of Cell Science

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“…Although HER2 internalization was found in geldanamycin‐treated cells and is a clathrin‐dependent process (Lerdrup et al ., 2007; Pedersen et al ., 2008), many studies indicated that HER2‐containing heterodimers is internalization resistant in response to ligand stimulation (Lenferink et al ., 1998; Worthylake et al ., 1999) probably due to the lack of an internalization motif in the cytoplasmic domain of HER2 (Sorkin et al ., 1993). Moreover, HER2 inhibits EGF‐induced EGFR internalization by forming EGFR/ErbB2 heterodimerization without affecting the phosphorylation or ubiquitination of EGFR (Haslekas et al ., 2005; Wang et al ., 1999), and by having a negative effect on the formation of CCP (Cortese et al ., 2013). Consistently, our data showed that EGF induced downregulation of membrane EGFR but not HER2 level.…”

Section: Discussionmentioning

confidence: 99%

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

et al. 2017

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Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.

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“…7A). Because the number of cells with internalized aggregates is the same as in untreated cells, the reduction in the number of endolysosomes can only be explained by a role of Hsp90 in endosomal trafficking between early endosomes and lysosomes (54). Geldanamycin also affected the endosomal trafficking of PepS.…”

Section: Pepl But Not Peps Internalization Requires Hsp70 and Ismentioning

confidence: 99%

Sequence-dependent Internalization of Aggregating Peptides

Couceiro

Gallardo

Smet

et al. 2015

Journal of Biological Chemistry

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Background: Prionoid propagation requires cell internalization of aggregated polypeptides. Results: Aggregates of different sequence are internalized through different endocytic pathways. Only phagocytosed aggregates (Ͼ1 m) elicit an HSF1-dependent proteostatic response. Conclusion: Proteostatic response upon aggregate internalization differs markedly depending on the sequence. Significance: The characterization of mechanisms of cell penetration is fundamental for the understanding of aggregate transmission in disease.

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The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments

Cited by 45 publications

References 71 publications

HBV secretion is regulated through the activation of endocytic and autophagic compartments via Rab7 stimulation

HBV secretion is regulated through the activation of endocytic and autophagic compartments via Rab7 stimulation

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

Sequence-dependent Internalization of Aggregating Peptides

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