Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Theodoraki, Maria A.; Kunjappu, Mary J; Sternberg, David; Caplan, Avrom J.

doi:10.1016/j.yexcr.2007.06.022

Cited by 21 publications

(21 citation statements)

References 28 publications

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“…In addition, total-Akt expression was reduced by Hsp90 blockade in HepG2 and Hep3B cells, but not in Huh-7 cells, a variable effect reported previously. 25 Otherwise, the effects of this dual-inhibition in terms of pathway inhibition were similar to 17-DMAG treatment alone (Fig. 1C).…”

Section: Impact Of Combining Hsp90 and Mtormentioning

confidence: 65%

Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice #

et al. 2009

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Section: Impact Of Combining Hsp90 and Mtormentioning

confidence: 65%

Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice #

et al. 2009

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“…Differential TrkAI and TrkAIII transfectant sensitivity to GA resulted in GA selection of TrkAIII transfectants from co-culture with TrkAI transfectants, confirming TrkAIII negative impact on GA-induced NB cell eradication and adding TrkAIII to other oncogenes, including ERGFR, which decrease tumour cell GA sensitivity (Theodoraki et al, 2007;Puyo et al, 2008). This, combined with TrkAIII re-phosphorylation after GA removal, provides a potential mechanism for post GA therapeutic relapse.…”

Section: Hsp90 Interacts With Trkai and Trkaiii In Neuroblastoma Cellsmentioning

confidence: 78%

The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells

et al. 2009

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Hsp90 chaperones stabilize many tyrosine kinases including several oncogenes, which are inhibited or induced to degrade by the Hsp90 inhibitor geldanamycin (GA). As a consequence, GA has been developed for future chemotherapeutic use in several tumour types including neuroblastoma (NB). Alternative splicing of the neurotrophin receptor tyrosine kinase TrkA may have a pivotal function in regulating NB behaviour, with reports suggesting that tumour-suppressing signals from TrkA may be converted to oncogenic signals by stress-regulated alternative TrkAIII splicing. Within this context, it is important to know whether Hsp90 interacts with TrkA variants in NB cells and how GA influences this. Here, we report that both TrkAI and TrkAIII are Hsp90 clients in human NB cells. TrkAI exhibits GA-sensitive interaction with Hsp90 required for receptor endoplasmic reticulum export, maturation, cell surface stabilization and ligandmediated activation, whereas TrkAIII exhibits GAsensitive interactions with Hsp90 required for spontaneous activity and to a lesser extent stability. We show that GA inhibits proliferation and induces apoptosis of TrkAI expressing NB cells, whereas TrkAIII reduces the sensitivity of NB cells to GA-induced elimination. Our data suggest that GA-sensitive interactions with Hsp90 are critical for both TrkAI tumour suppressor and TrkAIII oncogenic function in NB and that TrkAIII expression exerts a negative impact on GA-induced NB cell eradication, which can be counteracted by a novel TrkAIII-specific peptide nucleic acid inhibitor.

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“…In the oncogenic tyrosine kinase fusion nucleophosmin-anaplastic lymphoma receptor tyrosine kinase (NPM-ALK) model, downstream kinase AKT displayed increased activity as well as an increased dependency on HSP90 for its stability (8). This model suggests that attributes of AKT associated with its activity are recognized by the chaperone complex and is consistent with previous and striking observations that numerous cancer-promoting kinases, whether activated through mutation, aberrant upstream activation, or gene upregulation, are more dependent on HSP90 activities than their counterparts in normal cells (9).…”

mentioning

confidence: 99%

Mutational Analysis of Glycogen Synthase Kinase 3β Protein Kinase Together with Kinome-Wide Binding and Stability Studies Suggests Context-Dependent Recognition of Kinases by the Chaperone Heat Shock Protein 90

Jin

Tian

Pasculescu

et al. 2016

Molecular and Cellular Biology

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The heat shock protein 90 (HSP90) and cell division cycle 37 (CDC37) chaperones are key regulators of protein kinase folding and maturation. Recent evidence suggests that thermodynamic properties of kinases, rather than primary sequences, are recognized by the chaperones. In concordance, we observed a striking difference in HSP90 binding between wild-type (WT) and kinase-dead (KD) glycogen synthase kinase 3␤ (GSK3␤) forms. Using model cell lines stably expressing these two GSK3␤ forms, we observed no interaction between WT GSK3␤ and HSP90, in stark contrast to KD GSK3␤ forming a stable complex with HSP90 at a 1:1 ratio. In a survey of 91 ectopically expressed kinases in DLD-1 cells, we compared two parameters to measure HSP90 dependency: static binding and kinase stability following HSP90 inhibition. We observed no correlation between HSP90 binding and reduced stability of a kinase after pharmacological inhibition of HSP90. We expanded our stability study to >50 endogenous kinases across four cell lines and demonstrated that HSP90 dependency is context dependent. These observations suggest that HSP90 binds to its kinase client in a particular conformation that we hypothesize to be associated with the nucleotide-processing cycle. Lastly, we performed proteomics profiling of kinases and phosphopeptides in DLD-1 cells to globally define the impact of HSP90 inhibition on the kinome. As protein kinases regulate a multitude of cellular functions, it is imperative that their activity be highly regulated. This meticulous control is achieved through a variety of mechanisms, including phosphorylation, proteolytic processing, and direct engagement with other molecules, including chaperones. The heat shock protein 90 (HSP90) chaperone, in particular, is recruited to kinase clients to assist in their nascent folding and, depending on the kinase, to further contribute to its stability and function (1). A recent kinome-wide study of pairwise HSP90-kinase interactions observed various strengths of binding affinities between protein kinases and HSP90 (2), consistent with HSP90 assuming different roles depending on the client. HSP90 typically requires its cochaperone cell division cycle 37 (CDC37) to engage a kinase client, but the mechanism for kinase selection is not fully understood. There is no particular kinase class that forms stronger interactions with HSP90 (2), and there are even distinct binding specificities for closely related kinases. For example, epidermal growth factor receptor (EGFR) does not associate with HSP90, but close family member Erb-b2 receptor tyrosine kinase 2 (ERBB2) forms strong interactions with HSP90, and inhibition of HSP90 by geldanamycin induces rapid proteasome-mediated degradation of ERBB2 (3-5). Thus, amino acid sequences or structural features conserved in close family members are unlikely to be primary determinants for chaperone recognition, which is not surprising given that protein kinases represent a fraction of HSP90 clients (6). Instead, it appears that HSP90 recognizes kinases in a par...

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Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Cited by 21 publications

References 28 publications

Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice #

Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice #

The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells

Mutational Analysis of Glycogen Synthase Kinase 3β Protein Kinase Together with Kinome-Wide Binding and Stability Studies Suggests Context-Dependent Recognition of Kinases by the Chaperone Heat Shock Protein 90

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