ErbB2 Trafficking and Degradation Associated with K48 and K63 Polyubiquitination

Marx, Corina; Held, Jason M.; Gibson, Bradford W.; Benz, Christopher C.

doi:10.1158/0008-5472.can-09-3768

Cited by 94 publications

(85 citation statements)

References 36 publications

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“…USP9X, a ubiquitin-specific protease family member, is shown to regulate ubiquitination of different signal transduction pathway proteins, including AMPK (48), TGFb (8), ErbB2/HER2 (49), and ASK1 (7). It has been reported that deubiquitinase USP9X stabilizes Mcl-1 and promotes tumor cell survival.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Zhang

Cai

Zhu

et al. 2011

Molecular Cancer Therapeutics

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The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL, but not Mcl-1, which may confer resistance to this agent in various cancers with high levels of Mcl-1. Here, we showed that the combination of gemcitabine and ABT-737 exhibited synergistic cytotoxicity and induced significant apoptosis in multiple cancer types, including lung, renal, bladder, and prostate cancers. The enhanced apoptosis induced by gemcitabine plus ABT-737 was accompanied by the greater extent of mitochondrial depolarization, caspases-3 activation, and PARP cleavage in 95-D and 5637 cell lines. Importantly, in ABT-737-resistant cancer cells, the interaction between USP9X and Mcl-1, which was increased by ABT-737 treatment, could be disrupted by gemcitabine, thus resulting in enhanced ubiquitination and the subsequent degradation of Mcl-1 and ultimately in the synergism of these two drugs. Moreover, the increased anticancer efficacy of gemcitabine combined with ABT-737 was further validated in a human lung cancer 95-D xenograft model in nude mice. Taken together, our data first showed the synergistic anticancer capabilities achieved by combining gemcitabine and ABT-737 and, second, opened new opportunities to use antiapoptotic Bcl-2 family members, which drive tumor cell resistance in current anticancer therapies, therapeutically. Mol Cancer Ther; 10(7); 1264-75. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Zhang

Cai

Zhu

et al. 2011

Molecular Cancer Therapeutics

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“…Internalization and degradation of HER2 can occur after its polyubiquitination by the E3 ubiquitin ligase, c-Cbl (21)(22)(23). In control cells, c-Cbl and HER2 do not colocalize after stimulation with EGF or NRG1, but in PMCA2KD cells, c-Cbl becomes colocalized with HER2 at the cell surface and within the cytoplasm after receptor stimulation (Fig.…”

Section: Pmca2 Regulates Breast Cancer Cell Growth and Tumor Formationmentioning

confidence: 99%

PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

Jeong

VanHouten

Dann

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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In the lactating mammary gland, the plasma membrane calcium ATPase2 (PMCA2) transports milk calcium. Its expression is activated in breast cancers, where high tumor levels predict increased mortality. We find that PMCA2 expression correlates with HER2 levels in breast cancers and that PMCA2 interacts with HER2 in specific actin-rich membrane domains. Knocking down PMCA2 increases intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and results in internalization and degradation of HER2. Manipulating PMCA2 levels regulates the growth of breast cancer cells, and knocking out PMCA2 inhibits the formation of tumors in mouse mammary tumor virus (MMTV)-Neu mice. These data reveal previously unappreciated molecular interactions regulating HER2 localization, membrane retention, and signaling, as well as the ability of HER2 to generate breast tumors, suggesting that interactions between PMCA2 and HER2 may represent therapeutic targets for breast cancer.calcium pumps | ErbB2 | receptor internalization | HSP-90 | epidermal growth factor receptor P lasma membrane calcium ATPases (PMCAs) are a family of ion pumps that transport calcium out of cells and maintain low resting intracellular calcium levels (1-3). PMCA2 (gene symbol Atp2b2) is highly expressed in the apical membrane of mammary epithelial cells only during lactation, where it has been shown to transport calcium into milk (4-6). After weaning, PMCA2 expression rapidly decreases, contributing to the initiation of programmed cell death and mammary gland involution (7,8). PMCA2 is also expressed in breast cancers (8-10), and high levels of tumor PMCA2 expression predict increased mortality in patients (8).Approximately 25-30% of invasive breast cancers overexpress human epidermal growth factor receptor 2 (HER2) as a result of amplification of the ERBB2 kinase gene (11-13), and overexpression of HER2 causes breast tumors in mouse mammary tumor virus (MMTV)-Neu transgenic mice (14). HER2 functions as a heterodimer with other ERBB family members, most commonly pairing with EGFR or human epidermal growth factor receptor 3 (HER3) in breast cancers (11, 13). For reasons that remain poorly understood, in contrast to other ERBB family members, which are internalized and degraded after stimulation, HER2 remains on the cell surface and continues to signal for prolonged periods (12,15).In this study, we describe a previously unrecognized function for PMCA2: supporting active HER2 signaling and HER2-mediated tumor formation. Our data suggest that PMCA2 interacts with HER2 within specific membrane domains and is required for HER2 expression, membrane retention, and signaling.Results PMCA2 and HER2 Are Coexpressed in Breast Cancers. PMCA2 levels correlate with HER2 in breast tumors (8). To further explore potential interactions between PMCA2 and HER2, we analyzed their expression in a previously reported tissue microarray consisting of 652 breast cancers with a median 9 y of clinical follow-up (8, 16). Patients with the highest quartiles of ...

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“…This result indicates that CD137 endocytosis and K63 polyubiquitination are tightly linked events, similar to what has been previously described for other surface receptors. Indeed, K63-linked polyubiquitination has been associated with clathrin-dependent endocytosis of several surface receptors (44)(45)(46).…”

Section: Internalized Cd137 Codistributes With K63-polyubiquitin Chainsmentioning

confidence: 99%

T Cell Costimulation with Anti-CD137 Monoclonal Antibodies Is Mediated by K63–Polyubiquitin-Dependent Signals from Endosomes

Martínez-Forero

Azpilikueta

Bolaños

et al. 2013

The Journal of Immunology

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Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. Agonist anti-human CD137 mAbs binding to four distinct epitopes on the CD137 glycoprotein costimulated T cell activation irrespective of the engaged epitope or its interference with CD137L binding. CD137 perturbation with all these agonist mAbs resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed in activated T lymphocytes from humans and mice, not only in culture but also in Ab-injected living animals. These in vivo experiments were carried out upon systemic i.v. injections with anti-CD137 mAbs and showed CD137 internalization in tumor-infiltrating lymphocytes and in activated human T cells transferred to immunodeficient mice. Efficient CD137 internalization required K63 polyubiquitination and endocytosed CD137-containing vesicles recruited TNFR-associated factor (TRAF) 2 and were decorated with K63 polyubiquitins. CD137 stimulation activates NF-κB through a K63-linked polyubiquitination-dependent route, and CD137-associated TRAF2 becomes K63 polyubiquitinated. Consistent with a role for TRAF2 in CD137 signaling, transgenic mice functionally deficient in TRAF2 showed delayed immunotherapeutic activity of anti-CD137 mAbs. As a whole, these findings advance our knowledge of the mechanisms of action of anti-CD137 immunostimulatory mAbs such as those currently undergoing clinical trials in cancer patients.

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ErbB2 Trafficking and Degradation Associated with K48 and K63 Polyubiquitination

Cited by 94 publications

References 36 publications

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

T Cell Costimulation with Anti-CD137 Monoclonal Antibodies Is Mediated by K63–Polyubiquitin-Dependent Signals from Endosomes

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