Geldanamycin-Induced Down-Regulation of ErbB2 from the Plasma Membrane Is Clathrin Dependent but Proteasomal Activity Independent

Pedersen, Nina Marie; Madshus, Inger Helene; Haslekås, Camilla; Stang, Espen

doi:10.1158/1541-7786.mcr-07-0191

Cited by 51 publications

(76 citation statements)

References 49 publications

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“…S4). This is consistent with the notion that full-length ErbB2 was endocytosed (36,37). ErbB2 was eventually degraded on incubation of the cells with geldanamycin as shown by Western blots using antibody to an intracellular epitope (Fig.…”

Section: Erbb2 Is Endocytosed On Incubation With Geldanamycin In Cellsupporting

confidence: 90%

“…1B). Previous studies have shown that incubation with geldanamycin induces clathrin-dependent endocytosis of ErbB2 (37) and that ErbB2 in cells incubated with geldanamycin localizes to early as well as to late endosomes (36,37). Geldanamycin-induced endocytosis of ErbB2 was confirmed by immunoelectron microscopy experiments.…”

Section: Erbb2 Is Endocytosed On Incubation With Geldanamycin In Cellmentioning

confidence: 59%

“…This reportedly leads to polyubiquitination and proteasomal degradation (35). However, recent observations show that ErbB2 is internalized intact in a clathrin-dependent manner and eventually degraded in lysosomes on exposure to geldanamycin (36,37).…”

Section: Introductionmentioning

confidence: 99%

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Expression of Epidermal Growth Factor Receptor or ErbB3 Facilitates Geldanamycin-Induced Down-Regulation of ErbB2

Pedersen

Breen

Rødland

et al. 2009

Molecular Cancer Research

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Overexpression of the epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 promotes growth and antiapoptotic signaling. Overexpression of ErbB2 in breast cancer is associated with poor clinical outcome, and ways of down-regulating ErbB2 are important as therapeutic approaches. In contrast to EGFR, ErbB2 has been shown to be endocytosis deficient. However, down-regulation of ErbB2 can be induced by incubation of cells with geldanamycin and geldanamycin derivatives, counteracting the stabilizing function of heat shock protein 90 on ErbB2. In the present study, we have made use of stably transfected isogenic cell lines expressing ErbB2 only or ErbB2 together with EGFR and/or ErbB3. We now show that whereas ErbB2 can be down-regulated by incubation with geldanamycin in cells expressing ErbB2 only, the rate of geldanamycininduced down-regulation increases significantly when the cells additionally express EGFR and/or ErbB3. This increase does, however, not correlate with activation/ phosphorylation of ErbB2. The potential of heterodimer formation in ErbB2-positive breast cancer cells could thus turn out to be prognostically predictive with respect to outcome of treatment with geldanamycin derivatives. (Mol Cancer Res 2009;7(2):275 -84)

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Section: Erbb2 Is Endocytosed On Incubation With Geldanamycin In Cellsupporting

confidence: 90%

Section: Erbb2 Is Endocytosed On Incubation With Geldanamycin In Cellmentioning

confidence: 59%

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Expression of Epidermal Growth Factor Receptor or ErbB3 Facilitates Geldanamycin-Induced Down-Regulation of ErbB2

Pedersen

Breen

Rødland

et al. 2009

Molecular Cancer Research

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“…It is however controversial how this takes place. Some studies have suggested that Hsp90 inhibitors enhance the clathrin-dependent or clathrin-independent endocytosis of ErbB2 (54,55). Other studies suggest that ErbB2 is constitutively internalized, and that HSP90 inhibitors do not influence this rate but instead promote sorting of ErbB2 away from the recycling pathway and into lysosomes (46,51).…”

mentioning

confidence: 99%

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

Bailey

Luan

Tom

et al. 2014

Journal of Biological Chemistry

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ErbB2 overexpression drives oncogenesis in 20–30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca2+-dependent PKCs (α, β1, βII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.

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“…Because it relies on Hsp90 for stable expression, exposure of ErbB2/HER2-expressing cells to an Hsp90 inhibitor such as geldanamycin leads to rapid internalization, ubiquitination, and degradation of the protein (Mimnaugh et al 1996;Lerdrup et al 2006). Pedersen et al (2008) have argued that ubiquitination of ErbB2/HER2 following inhibition of Hsp90 is essential for presentation of the internalized protein to the lysosomes for degradation. Concurrent treatment of ErbB2/HER2-expressing cells with geldanamycin and lactacystin, a well known proteasomal inhibitor, rescues ErbB2/HER2 from degradation and results in the accumulation of internalized, ubiquitinated protein (Lerdrup et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

Papathanassiu

MacDonald

Emlet

et al. 2011

Cell Stress and Chaperones

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Efrapeptins (EF), a family of fungal peptides, inhibit proteasomal enzymatic activities and the in vitro and in vivo growth of HT-29 cells. They are also known inhibitors of F 1 F 0 -ATPase, a mitochondrial enzyme that functions as an Hsp90 co-chaperone. We have previously shown that treatment of cancer cells with EF results in disruption of the Hsp90:F 1 F 0 -ATPase complex and inhibition of Hsp90 chaperone activity. The present study examines the effect of EF on breast cancer growth in vitro and in vivo. As a monotherapy, EF inhibited cell proliferation in vitro with an IC 50 value ranging from 6 nM to 3.4 μM. Inhibition of Hsp90 chaperone function appeared to be the dominant mechanism of action and the factor determining cellular sensitivity to EF. In vitro inhibition of proteasome became prominent in the absence of adequate levels of Hsp90 and F 1 F 0 -ATPase as in the case of the relatively EF-resistant MDA-MB-231 cell line. In vivo, EF inhibited MCF-7 and MDA-MB-231 xenograft growth with a maximal inhibition of 60% after administration of 0.15 and 0.3 mg/kg EF, respectively. 2-Deoxyglucose (2DG), a known inhibitor of glycolysis, acted synergistically with EF in vitro and antagonistically in vivo. In vitro, the synergistic effect was attributed to a prolonged endoplasmic reticulum (ER) stress. In vivo, the antagonistic effect was ascribed to the downregulation of tumoral and/or stromal F 1 F 0 -ATPase by 2DG.

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Geldanamycin-Induced Down-Regulation of ErbB2 from the Plasma Membrane Is Clathrin Dependent but Proteasomal Activity Independent

Cited by 51 publications

References 49 publications

Expression of Epidermal Growth Factor Receptor or ErbB3 Facilitates Geldanamycin-Induced Down-Regulation of ErbB2

Expression of Epidermal Growth Factor Receptor or ErbB3 Facilitates Geldanamycin-Induced Down-Regulation of ErbB2

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

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