Systematic Identification of the HSP90 Regulated Proteome

Wu, Zhixiang; Moghaddas Gholami, Amin; Kuster, Bernhard

doi:10.1074/mcp.m111.016675

Cited by 94Heat shock proteins researchAdvanced Proteomics Techniques and ApplicationsUbiquitin and proteasome pathways

Systematic Identification of the HSP90 Regulated Proteome

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Wu, Zhixiang, Moghaddas Gholami, Amin, Kuster, Bernhard·2012·Molecular & Cellular Proteomics

DOI 10.1074/mcp.m111.016675PMC PMC3433914

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Abstract

HSP90 is a central player in the folding and maturation of many proteins. More than two hundred HSP90 clients have been identified by classical biochemical techniques including important signaling proteins with high relevance to human cancer pathways. HSP90 inhibition has thus become an attractive therapeutic concept and multiple molecules are currently in clinical trials. It is therefore of fundamental biological and medical importance to identify, ideally, all HSP90 clients and HSP90 regulated proteins. To this end, we have taken a global and a chemical proteomic approach in geldanamycin treated cancer cell lines using stable isotope labeling with amino acids in cell culture and quantitative mass spectrometry. We identified >6200 proteins in four different human cell lines and ~1600 proteins showed significant regulation upon drug treatment. Gene ontology and pathway/network analysis revealed common and cell-type specific regulatory effects with strong connections to unfolded protein binding and protein kinase activity. Of the 288 identified protein kinases, 98 were geldanamycin treatment including >50 kinases not formerly known to be regulated by HSP90. Protein turn-over measurements using pulsed stable isotope labeling with amino acids in cell culture showed that protein down-regulation by HSP90 inhibition correlates with protein half-life in many cases. Protein kinases show significantly shorter half lives than other proteins highlighting both challenges and opportunities for HSP90 inhibition in cancer therapy. The proteomic responses of the HSP90 drugs geldanamycin and PU-H71 were highly similar suggesting that both drugs work by similar molecular mechanisms. Using HSP90 immunoprecipitation, we validated several kinases (AXL, DDR1, TRIO) and other signaling proteins (BIRC6, ISG15, FLII), as novel clients of HSP90. Taken together, our study broadly defines the cellular proteome response to HSP90 inhibition and provides a rich resource for further investigation relevant for the treatment of cancer.

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The fungal Hsp90 interactome includes numerous client proteins such as receptors, protein kinases and transcription factors.
“The fungal Hsp90 interactome, which includes numerous client proteins such as receptors, protein kinases and transcription factors, displays a surprisingly high degree of plasticity that depends on environmental conditions.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [93]
Many features of the Hsp90 interactome are highly conserved from yeast to humans despite substantial network rewiring over evolutionary time.
“Also, many features of the Hsp90 interactome are highly conserved from yeast to humans despite substantial network rewiring over evolutionary time.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [93]
Conserved features of the Hsp90 interactome include a preponderance of protein kinases and transcription factors as client proteins.
“These conserved features include a preponderance of protein kinases and transcription factors as client proteins67,78,91-93.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [93]

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Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS
Varjosalo, M. T., Sacco, R., Stukalov, A., van Drogen, A., Planyavsky, M., Hauri, S., Aebersold, R. H., Bennett, K. L., Colinge, J., Gstaiger, M., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2400 · Cited by 202 · see citing works
TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models
Ohkubo, S., Kodama, Y., Muraoka, H., Hitotsumachi, H., Yoshimura, C., Kitade, M., Hashimoto, A., Ito, K., Gomori, A., Takahashi, K., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0219 · Cited by 148 · see citing works
Nitration of Hsp90 induces cell death
Franco, M. C., Ye, Y., Refakis, C. A., Feldman, J. L., Stokes, A. L., Basso, M., de Mera, R. M. M.-F., Sparrow, N. A., Calingasan, N. Y., Kiaei, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215177110 · Cited by 146 · see citing works
Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies
Schoumacher, M., & Burbridge, M. F. (2017) · Current Oncology Reports · doi:10.1007/s11912-017-0579-4 · Cited by 132 · see citing works
ALK inhibitor resistance in ALKF1174L-driven neuroblastoma is associated with AXL activation and induction of EMT
Debruyne, D. N., Bhatnagar, N., Sharma, B., Luther, W., Moore, N. F., Cheung, N., Gray, N. S., & George, R. E. (2015) · Oncogene · doi:10.1038/onc.2015.434 · Cited by 119 · see citing works
Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs
Leach, M. D., Klipp, E., Cowen, L. E., & Brown, A. J. P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2875 · Cited by 107 · see citing works
Proteomics-Based Methods for Discovery, Quantification, and Validation of Protein–Protein Interactions
Miteva, Y. V., Budayeva, H. G., & Cristea, I. M. (2013) · Analytical Chemistry · doi:10.1021/ac3033257 · Cited by 105 · see citing works
HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy
Condelli, V., Crispo, F., Pietrafesa, M., Lettini, G., Matassa, D. S., Esposito, F., Landriscina, M., & Maddalena, F. (2019) · Cells · doi:10.3390/cells8060532 · Cited by 105 · see citing works
“Approximately two hundred HSP90 client proteins have been described, and, among these, there are proteins involved in several cell functions, some of them extremely relevant in human carcinogenesis [32].”
Background
The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
Joshi, A., Dai, L., Liu, Y. X., Lee, J., Ghahhari, N. M., Segala, G., Beebe, K. E., Jenkins, L. M. M., Lyons, G. C., Bernasconi, L., et al. (2020) · BMC Biology · doi:10.1186/s12915-020-0740-7 · Cited by 85 · see citing works
Quantitative proteomics of heat-treated human cells show an across-the-board mild depletion of housekeeping proteins to massively accumulate few HSPs
Finka, A., Sood, V., Quadroni, M., Rios, P. D. L., & Goloubinoff, P. (2015) · Cell Stress and Chaperones · doi:10.1007/s12192-015-0583-2 · Cited by 78 · see citing works
“…addition to the generally annotated GO categories, four ad hoc categories were added: the cytosolic small ribosomal subunit proteins (RPS), the human chaperome (Finka and Goloubinoff 2013), HSP90-interacting kinases (Wu et al. 2012), and HSP90 interactors (http://www.picard.ch/HSP90Int/index.php).”
A Chemical Proteomics Approach for Global Analysis of Lysine Monomethylome Profiling *
Wu, Z., Cheng, Z., Sun, M., Wan, X., Liu, P., Tie-ming, H., Tan, M., & Zhao, Y. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.044255 · Cited by 76 · see citing works
Self-citation
Hsp90 Heterocomplexes Regulate Steroid Hormone Receptors: From Stress Response to Psychiatric Disease
Baker, J. D., McMillan, I. O., Ospina, S. R., Gulick, D., & Blair, L. J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010079 · Cited by 73 · see citing works
Inhibitors of HSP90 in melanoma
Mielczarek-Lewandowska, A., Hartman, M. L., & Czyż, M. (2019) · APOPTOSIS · doi:10.1007/s10495-019-01577-1 · Cited by 73 · see citing works
A global view of Hsp90 functions
Chiosis, G., Dickey, C. A., & Johnson, J. L. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2481 · Cited by 63 · see citing works
Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours
Infante, J. R., Weiss, G. J., Jones, S. F., Tibes, R., Bauer, T. M., Bendell, J. C., Hinson, J. M., Hoff, D. D. V., Burris, H. A., Orlemans, E. O., et al. (2014) · European Journal of Cancer · doi:10.1016/j.ejca.2014.07.017 · Cited by 54 · see citing works
“Treatment of four different human cell lines with geldanamycin showed significant regulation of approximately 1,600 proteins, including 115 kinases [24].”
Background
Unusual Suspects in the Twilight Zone Between the Hsp90 Interactome and Carcinogenesis
Vartholomaiou, E., Echeverría, P. C., & Picard, D. (2015) · Advances in cancer research · doi:10.1016/bs.acr.2015.08.001 · Cited by 54 · see citing works
Tyrosine nitration as mediator of cell death
Franco, M. C., & Estévez, Á. G. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1662-8 · Cited by 50 · see citing works
A Novel Pulse-Chase SILAC Strategy Measures Changes in Protein Decay and Synthesis Rates Induced by Perturbation of Proteostasis with an Hsp90 Inhibitor
Fierro-Monti, I., Racle, J., Hernandez, C., Waridel, P., Vassily Hatzimanikatis, A., & Quadroni, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080423 · Cited by 49 · see citing works
Human Hsp90 cochaperones: perspectives on tissue-specific expression and identification of cochaperones with similar in vivo functions
Dean, M. E., & Johnson, J. L. (2020) · Cell Stress and Chaperones · doi:10.1007/s12192-020-01167-0 · Cited by 48 · see citing works
“Hsp90 is a complicated molecular chaperone machine that directly or indirectly impacts the function of 10–15% of all proteins in humans (Wu et al. 2012).”
Background
Dynamic Impacts of the Inhibition of the Molecular Chaperone Hsp90 on the T-Cell Proteome Have Implications for Anti-Cancer Therapy
Fierro-Monti, I., Echeverría, P. C., Racle, J., Hernandez, C., Picard, D., & Quadroni, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080425 · Cited by 44 · see citing works
Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer
Al‐Ejeh, F., Miranda, M. S., Shi, W., Simpson, P. T., Song, S., Vargas, A. C., Saunus, J. M., Smart, C. E., Mariasegaram, M., Wiegmans, A. P., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1865 · Cited by 44 · see citing works
“Upon closer examination, we found that many of the activated kinases in our screen are oncoclients of the heat shock protein Hsp90; known to stabilize these proteins [20-22]; thus the elevation of proteins in cluster ii may be due to stabilization rather than elevation of mRNA levels.”
Background
Chaperome heterogeneity and its implications for cancer study and treatment
Wang, T., Rodina, A., Dunphy, M. P., Corben, A. D., Modi, S., Guzmán, M. L., Gewirth, D. T., & Chiosis, G. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.rev118.002811 · Cited by 42 · see citing works
Quantitative proteomics of the yeast Hsp70/Hsp90 interactomes during DNA damage reveal chaperone-dependent regulation of ribonucleotide reductase
Truman, A. W., Kristjánsdóttir, K., Wolfgeher, D. J., Ricco, N., Mayampurath, A. M., Volchenboum, S. L., Clotet, J., & Kron, S. J. (2014) · Journal of Proteomics · doi:10.1016/j.jprot.2014.09.028 · Cited by 41 · see citing works
Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
Pulvino, M. J., Chen, L., Oleksyn, D. W., Li, J., Compitello, G., Rossi, R., Spence, S. A., Balakrishnan, V., Jordan, C. T., Poligone, B., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4193 · Cited by 41 · see citing works
HSP90 affects root growth in Arabidopsis by regulating the polar distribution of PIN1
Samakovli, D., Roka, L., Dimopoulou, A., Plitsi, P. K., Žukauskaitė, A., Georgopoulou, P., Novák, O., Milioni, D., & Hatzopoulos, P. (2021) · New Phytologist · doi:10.1111/nph.17528 · Cited by 41 · see citing works
A Chemical Biology Approach to the Chaperome in Cancer—HSP90 and BeyondPreprint
Taldone, T., Wang, T., Rodina, A., Pillarsetty, N., Digwal, C. S., Sharma, S., Yan, P., Joshi, S., Pagare, P. P., Bolaender, A., et al. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a034116 · Cited by 40 · see citing works
“It should be restated that in tissue culture, under conditions of equilibrium, several of these agents have similar biological activity (Wu et al. 2012; Rodina et al. 2016).”
Background
Differential Modulation of Functional Dynamics and Allosteric Interactions in the Hsp90-Cochaperone Complexes with p23 and Aha1: A Computational Study
Blacklock, K. M., & Verkhivker, G. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071936 · Cited by 38 · see citing works
Allosteric Regulation of the Hsp90 Dynamics and Stability by Client Recruiter Cochaperones: Protein Structure Network Modeling
Blacklock, K. M., & Verkhivker, G. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086547 · Cited by 39 · see citing works
Topically Applied Hsp90 Blocker 17AAG Inhibits Autoantibody-Mediated Blister-Inducing Cutaneous Inflammation
Tukaj, S., Bieber, K., Kleszczyński, K., Witte, M., Cames, R., Kalies, K., Zillikens, D., Ludwig, R. J., Fischer, T. W., & Kasperkiewicz, M. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.08.032 · Cited by 38 · see citing works
“…200 Hsp90-dependent clients have been identified, including those considerably implicated in both cancer and inflammation such as transcription factors of the NFκB protein family and tissue degrading matrix metalloproteinases (MMPs) (Sevin et al., 2015; Tukaj and Węgrzyn, 2016; Wu et al., 2012).”
Background
Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)
Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korben, V. A., Gaponova, A. V., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger‐Nukpezah, T., Somlo, S., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201700909r · Cited by 35 · see citing works
AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations
Falcone, I., Conciatori, F., Bazzichetto, C., Bria, E., Carbognin, L., Malaguti, P., Ferretti, G., Cognetti, F., Milella, M., & Ciuffreda, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228419 · Cited by 35 · see citing works
Identification of Novel Response and Predictive Biomarkers to Hsp90 Inhibitors Through Proteomic Profiling of Patient-derived Prostate Tumor Explants
Nguyen, E. V., Centenera, M. M., Moldovan, M. V., Das, R., Irani, S., Vincent, A. D., Chan, H., Horvath, L. G., Lynn, D. J., Daly, R. J., et al. (2018) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra118.000633 · Cited by 35 · see citing works
Discoidin domain receptors: a proteomic portrait
Iwai, L. K., Luczynski, M. T., & Huang, P. H. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1616-1 · Cited by 33 · see citing works
Proteomics and drug discovery in cancer
Dias, M. H., Kitano, E. S., Zelanis, A., & Iwai, L. K. (2015) · Drug Discovery Today · doi:10.1016/j.drudis.2015.10.004 · Cited by 30 · see citing works
The Hsp90-Dependent Proteome Is Conserved and Enriched for Hub Proteins with High Levels of Protein–Protein Connectivity
Gopinath, R. K., You, S., Chien, K., Swamy, K. B. S., Yu, J., Schuyler, S. C., & Leu, J. (2014) · Genome Biology and Evolution · doi:10.1093/gbe/evu226 · Cited by 29 · see citing works
“GO analyses show that the yeast Hsp90-regulated proteome has a general consensus with its human counterpart, where the major effects are the downregulation of kinases and the upregulation of unfolded response proteins (Sharma et al. 2012; Wu et al. 2012).”
Background
HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling
Walter, R. B., Pan, K., Doebele, C., Comoglio, F., Tomska, K., Bohnenberger, H., Young, R. M., Jacobs, L. A., Keller, U. B., Bonig, H. B., et al. (2016) · Blood · doi:10.1182/blood-2016-06-721423 · Cited by 27 · see citing works
The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity
Echeverría, P. C., Bhattacharya, K., Joshi, A., Wang, T., & Picard, D. (2019) · PLoS ONE · doi:10.1371/journal.pone.0208287 · Cited by 26 · see citing works
The Anticancer Drug AUY922 Generates a Proteomics Fingerprint That Is Highly Conserved among Structurally Diverse Hsp90 Inhibitors
Voruganti, S., LaCroix, J. C., Rogers, C. N., Rogers, J., Matts, R. L., & Hartson, S. D. (2013) · Journal of Proteome Research · doi:10.1021/pr400321x · Cited by 25 · see citing works
Quantitative proteomics analysis provides insight into the biological role of Hsp90 in BmNPV infection in Bombyx mori
Wu, P., Shang, Q., Huang, H., Zhang, S., Zhong, J., Hou, Q., & Guo, X. (2019) · Journal of Proteomics · doi:10.1016/j.jprot.2019.103379 · Cited by 24 · see citing works
Proteomic interrogation of HSP90 and insights for medical research
Weidenauer, L., Wang, T., Joshi, S., Chiosis, G., & Quadroni, M. (2017) · Expert Review of Proteomics · doi:10.1080/14789450.2017.1389649 · Cited by 25 · see citing works
Experimentally Guided Structural Modeling and Dynamics Analysis of Hsp90–p53 Interactions: Allosteric Regulation of the Hsp90 Chaperone by a Client Protein
Blacklock, K. M., & Verkhivker, G. M. (2013) · Journal of Chemical Information and Modeling · doi:10.1021/ci400434g · Cited by 25 · see citing works
Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy
Papanicolaou, K. N., Jung, J., Ashok, D., Zhang, W., Modaressanavi, A., Avila, E., Foster, D. B., Zachara, N. E., & O'Rourke, B. P. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.102907 · Cited by 23 · see citing works
“Finally, geldanamycin, an Hsp90-binding macrocyclic, was found to affect the expression of 288 kinases (115).”
Background
Therapeutic Landscape of AXL Receptor Kinase in Triple-Negative Breast Cancer
Özyurt, R., & Özpolat, B. (2023) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-22-0617 · Cited by 26 · see citing works
New Affinity Probe Targeting VEGF Receptors for Kinase Inhibitor Selectivity Profiling by Chemical Proteomics
Ku, X., Heinzlmeir, S., Helm, D., Médard, G., & Küster, B. (2014) · Journal of Proteome Research · doi:10.1021/pr401247t · Cited by 22 · see citing works
Targeting HSF1 as a Therapeutic Strategy for Multiple Mechanisms of EGFR Inhibitor Resistance in EGFR Mutant Non-Small-Cell Lung Cancer
Lee, S., Jung, J., Lee, Y., Kim, S., Kim, J., Kim, B., Park, K. C., Kwon, B., & Han, D. C. (2021) · Cancers · doi:10.3390/cancers13122987 · Cited by 20 · see citing works
Phosphoproteomics reveals ALK promote cell progress via RAS/JNK pathway in neuroblastoma
Chen, K., Lv, F., Xu, G., Zhang, M., Wu, Y., & Wu, Z. (2016) · Oncotarget · doi:10.18632/oncotarget.12513 · Cited by 20 · see citing works
Self-citation
Evidence for Hsp90 Co-chaperones in Regulating Hsp90 Function and Promoting Client Protein Folding
Cox, M. B., & Johnson, J. L. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7477-1_28 · Cited by 20 · see citing works
Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome
Mansfield, C. R., Quan, B., Chirgwin, M. E., Eduful, B. J., Hughes, P. F., Neveu, G., Sylvester, K., Ryan, D. H., Kafsack, B. F. C., Haystead, T., et al. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.02.008 · Cited by 20 · see citing works
Hsp90 inhibition induces both protein-specific and global changes in the ubiquitinome
Quadroni, M., Potts, A., & Waridel, P. (2015) · Journal of Proteomics · doi:10.1016/j.jprot.2015.02.020 · Cited by 19 · see citing works
Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders
Johnson, J. L. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.787260 · Cited by 19 · see citing works
“Hsp90 inhibition directly or indirectly impacts the function of up to 10–15% of all human proteins (Wu et al., 2012).”
Background
Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone
Stetz, G., Tse, A., & Verkhivker, G. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0186089 · Cited by 18 · see citing works
Mutation of essential Hsp90 co-chaperones SGT1 or CNS1 renders yeast hypersensitive to overexpression of other co-chaperones
Johnson, J. L., Zuehlke, A. D., Tenge, V. R., & Langworthy, J. C. (2014) · Current Genetics · doi:10.1007/s00294-014-0432-3 · Cited by 17 · see citing works
“Established clients include steroid receptors and other transcription factors, a variety of serine/threonine and tyrosine kinases and additional proteins such as telomerase and the hepatitis B virus reverse transcriptase (Zhao et al. 2005; Wu et al. 2012; Wegele et al. 2004).”
Background
Separation methodology to improve proteome coverage depth
Lenz, C., & Urlaub, H. (2014) · Expert Review of Proteomics · doi:10.1586/14789450.2014.919862 · Cited by 16 · see citing works
“Consequently, when peptides derived from various molecular weight regions are then separated with a capillary column packed with RP material of smaller particle size and operated by ultrahigh pressure liquid chromatography pumps [33], the analysis depth of a sample increases dramatically, and up to 8000 proteins from…”
Background
Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β
Peng, Y.-J., Huang, J.-J., Wu, H.-H., Hsieh, H.-Y., Wu, C., Chen, S.-C., Chen, T., & Tang, C. (2016) · Scientific Reports · doi:10.1038/srep32444 · Cited by 17 · see citing works
Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells
ROUHI, A. M., Miller, C. V., Grasedieck, S., Reinhart, S., Stolze, B., Döhner, H., Kuchenbauer, F. C., Bullinger, L., Fröhling, S., & Scholl, C. (2016) · Oncotarget · doi:10.18632/oncotarget.13841 · Cited by 16 · see citing works
“This so-called “oncogenic switch” may be overcome by HSP90 inhibition since EGFR, MET, AXL and BRAF are all HSP90 clients [15].”
Background
Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus
Frinchi, M., Scaduto, P., Cappello, F., Belluardo, N., & Mudò, G. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26454 · Cited by 16 · see citing works
Human Genetic Relevance and Potent Antitumor Activity of Heat Shock Protein 90 Inhibition in Canine Lung Adenocarcinoma Cell Lines
Clemente-Vicario, F., Alvarez, C. E., Rowell, J., Roy, S., London, C. A., Kisseberth, W. C., & Lorch, G. (2015) · PLoS ONE · doi:10.1371/journal.pone.0142007 · Cited by 15 · see citing works
“HSP90 inhibition should lead to the rapid degradation of newly synthesized proteins and those with a longer half-life will show a slower decrease in loss of protein after the HSP90 inhibition [53].”
Background
Heat shock protein 90 inhibition and multi‐target approach to maximize cardioprotection in ischaemic injury
Sarkissian, S. D., Aceros, H., Williams, P., Scalabrini, C., Borie, M., & Noiseux, N. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15075 · Cited by 14 · see citing works
A new chemical probe for quantitative proteomic profiling of fibroblast growth factor receptor and its inhibitors
Ku, X., Heinzlmeir, S., Liu, X., Médard, G., & Küster, B. (2013) · Journal of Proteomics · doi:10.1016/j.jprot.2013.10.031 · Cited by 12 · see citing works
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, J., Tian, R., Pasculescu, A., Dai, A. Y., Williton, K., Taylor, L., Savitski, M. M., Bantscheff, M., Woodgett, J. R., Pawson, T. J., et al. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.01045-15 · Cited by 12 · see citing works
Proteomic Profiling of Hsp90 Inhibitors
Voruganti, S., Kline, J. T., Balch, M., Rogers, J., Matts, R. L., & Hartson, S. D. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7477-1_11 · Cited by 12 · see citing works
Identification of proteins associated with Aha1 in HeLa cells by quantitative proteomics
Sun, L., Hartson, S. D., & Matts, R. L. (2015) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2015.01.002 · Cited by 11 · see citing works
Disrupting progression of the yeast Hsp90 folding pathway at different transition points results in client-specific maturation defects
Hohrman, K., Gonçalves, D. L., Morano, K. A., & Johnson, J. L. (2021) · Genetics · doi:10.1093/genetics/iyab009 · Cited by 11 · see citing works
Cytosolic and Mitochondrial Hsp90 in Cytokinesis, Mitochondrial DNA Replication, and Drug Action in Trypanosoma brucei
Meyer, K. J., & Shapiro, T. A. (2021) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00632-21 · Cited by 11 · see citing works
Hsp90 mutants with distinct defects provide novel insights into cochaperone regulation of the folding cycle
Mercier, R., Yama, D., LaPointe, P., & Johnson, J. L. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010772 · Cited by 11 · see citing works
Protozoan HSP90-Heterocomplex: Molecular Interaction Network and Biological Significance
Figueras, M. J., Echeverría, P. C., & Angel, S. O. (2014) · Current Protein and Peptide Science · doi:10.2174/1389203715666140331114233 · Cited by 10 · see citing works
Efficacy of doxycycline in the treatment of early stages of mycosis fungoides: a randomized controlled trial
Sayed, H. E., Shalaby, S., Abdel‐Halim, M. R. E., Aboelfadl, D. M., & Samir, N. (2019) · Journal of Dermatological Treatment · doi:10.1080/09546634.2019.1667474 · Cited by 10 · see citing works
The Ribosomal Biogenesis Protein Utp21 Interacts with Hsp90 and Has Differing Requirements for Hsp90-Associated Proteins
Tenge, V. R., Jared, K., & Johnson, J. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092569 · Cited by 9 · see citing works
Expanding the Interactome of the Noncanonical NF-κB Signaling Pathway
Willmann, K. L., Sacco, R., Martins, R., Garncarz, W., Krolo, A., Knapp, S., Bennett, K. L., & Boztuǧ, K. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b01004 · Cited by 9 · see citing works
Proteomic Analysis of Hsp90β-Selective Inhibitors Against Triple-Negative Breast Cancer to Gain a Mechanistic Insight
Reynolds, T. S., Hu, D. D., Weaver, S. D., Ronck, E. C., Mishra, S. J., Champion, M. M., & Blagg, B. S. J. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101043 · Cited by 8 · see citing works
“However, many of the identified pathways have been previously associated with Hsp90 inhibition, providing support of on-target effects (24, 25).”
A Global View of the Proteome Perturbations by Hsp90 Inhibitors
Echeverría, P. C., & Picard, D. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1130-1_6 · Cited by 8 · see citing works
FS-93, an Hsp90 inhibitor, induces G2/M arrest and apoptosis via the degradation of client proteins in oncogene addicted and derived resistant cancer cells
Zhang, L., Shen, A., Wang, L., Liu, H., Chen, D., Xiong, B., Shen, J., & Geng, M. (2015) · Oncoscience · doi:10.18632/oncoscience.156 · Cited by 7 · see citing works
Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery
Lawless, N., Blacklock, K. M., Berrigan, E., & Verkhivker, G. M. (2013) · Pharmaceuticals · doi:10.3390/ph6111407 · Cited by 7 · see citing works
Hsp90 regulates the tumorigenic function of tyrosine protein kinase in osteosarcoma
Yao, Z., Zhu, H. F., Shen, F., & Gong, D. (2021) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13613 · Cited by 7 · see citing works
Native Size-Exclusion Chromatography–Based Mass Spectrometry Reveals New Components of the Early Heat Shock Protein 90 Inhibition Response Among Limited Global Changes
Samant, R. S., Batista, S., Larance, M., Özer, B., Milton, C. I., Bludau, I., Wu, E., Biggins, L., Andrews, S., Hervieu, A., et al. (2022) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2022.100485 · Cited by 8 · see citing works
“We discovered that Anillin abundance was significantly altered in previous HSP90 inhibition datasets (21, 23); yet it”
Background
Quantitative proteomic analysis reveals unique Hsp90 cycle-dependent client interactions
Rios, E. I., Gonçalves, D. L., Morano, K. A., & Johnson, J. L. (2024) · Genetics · doi:10.1093/genetics/iyae057 · Cited by 5 · see citing works
PU-H71 effectively induces degradation of IκB kinase β in the presence of TNF-α
Qu, Z., Wang, S., Teng, R., & Yi, X. (2013) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-013-1852-y · Cited by 5 · see citing works
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Jung, L. A., Demir, S., Hotes, A., Hiyama, E., Hishiki, T., Indersie, É., Branchereau, S., Cairo, S., & Kappler, R. (2025) · Cancers · doi:10.3390/cancers17081341 · Cited by 3 · see citing works
“Proteomic studies have revealed more than 6000 HSP90 client proteins, including receptor tyrosine kinases, signaling proteins, transcription factors, and cell cycle regulatory proteins [37].”
Hsp90: A means to an end
Whalen, K. M., & Freeman, B. (2026) · Cell Stress and Chaperones · doi:10.1016/j.cstres.2026.100190 · Cited by 3 · see citing works
“31 A general assessment of all proteins (i.e., clients and non-clients) found that ∼ 1600 of the ∼ 6200 detectable proteins in cancer cell lines were altered following application of GA. 32 Multiplexed proteome dynamics profiling assessed the influence of the synthetic GA-derivative 17-AAG on client-protein stability,…”
Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect
Fu, S.-J., Hu, M., Hsiao, C.-T., Cheng, A.-T., Chen, T., Jeng, C., & Tang, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115859 · Cited by 4 · see citing works
The Interaction Network of the Hsp90 Molecular Chaperone
Rizzolo, K., Wong, P., Tillier, E. R. M., & Houry, W. A. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1130-1_5 · Cited by 3 · see citing works
Oncogenic acidic nuclear phosphoproteins ANP32C/D are novel clients of heat shock protein 90
Yuzefovych, Y., Blasczyk, R., & Huyton, T. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.06.007 · Cited by 3 · see citing works
Proteomics
Budzinski, I. G. F., Regiani, T., Labate, M. T. V., Guidetti‐Gonzalez, S., Silva, D. I. R., Calderan‐Rodrigues, M. J., Borges, J. D. S., Mozol, I. M., & Labate, C. A. (2014) · Omics in Plant Breeding · doi:10.1002/9781118820971.ch4 · Cited by 2 · see citing works
The Role of Chloroplast Localized Molecular Chaperone HSP90 in Arabidopsis thaliana Development
Oh, S. E. (2012) · TSpace (University of Toronto) · Cited by 1 · see citing works
Characterization of Drug–Protein Interactions by Chemoproteomics
Schirle, M., Bantscheff, M., & Küster, B. (2019) · doi:10.1002/9781119081661.ch10 · Cited by 1 · see citing works
Caspase regulation of autophagy in Drosophila melanogaster
DeVorkin, L. (2013) · Summit (Simon Fraser University)
Hsp90 Inhibition on the Western Blot: N‐Terminal Versus C‐Terminal Inhibitors in Breast Cancer
Dernovšek, J., Cingl, J., Fonović, U. P., & Tomašič, T. (2026) · Medicinal Research Reviews · doi:10.1002/med.70079
Ten Non-N-Terminal-Domain Inhibitors of the Hsp90 Chaperone Machine Fail to Elicit Canonical Proteome-wide Responses in Jurkat Leukemia Cells
Gile, S. A., Rogers, J., Balch, M., Voruganti, S., Matts, R. L., & Hartson, S. D. (2026) · Journal of Proteome Research · doi:10.1021/acs.jproteome.6c00387

Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics
Haupt, A., Joberty, G., Bantscheff, M., Fröhlich, H., Stehr, H., Schweiger, M. R., Fischer, A., Kerick, M., Boerno, S. T., Dahl, A., et al. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-38 · Cited by 44 · see citing works
Quantitative Proteomics Reveals That Hsp90 Inhibition Preferentially Targets Kinases and the DNA Damage Response
Sharma, K., Vabulas, R. M., Maček, B., Pinkert, S., Cox, J., Mann, M., & Hartl, F. U. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.014654 · Cited by 114 · see citing works
The expanding proteome of the molecular chaperone HSP90
Samant, R. S., Clarke, P. A., & Workman, P. (2012) · Cell Cycle · doi:10.4161/cc.19722 · Cited by 31 · see citing works
Assays for HSP90 and Inhibitors
Aherne, W., Maloney, A., Prodromou, C., Rowlands, M., Hardcastle, A., Boxall, K. J., Clarke, P. A., Walton, M. I., & Pearl, L. H. (2003) · Humana Press eBooks · doi:10.1385/1-59259-380-1:149 · Cited by 27 · see citing works
Heat-Shock Protein 90 Inhibitors in Cancer Therapy: 17AAG and Beyond
Younes, A., & Georgakis, G. V. (2005) · Future Oncology · doi:10.1517/14796694.1.2.273 · Cited by 51 · see citing works

Authors: Wu, Z., Moghaddas Gholami, A., & Kuster, B.
Affiliations: Technical University of Munich (DE)
ORCID: Wu, Zhixiang
Venue: Molecular & Cellular Proteomics
Publisher: Elsevier BV
Published: 2012-06
Volume: 11
Issue: 6
Pages: M111.016675
ISSN: 1535-9476 (ISSN-L)
DOI: 10.1074/mcp.m111.016675
PMC: PMC3433914
OpenAlex: W2159443208
Cited by: 94
References: 53
Citations by year: 2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 7 · 2020: 4 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 7 · 2015: 10 · 2014: 18 · 2013: 14 · 2012: 4
FWCI: 5.92
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 3019 d)
Locations: Molecular & Cellular Proteomics (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
Funders: China Scholarship Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: HSP90, HSP90 inhibition, geldanamycin, PU-H71, protein kinases, protein half-life, protein turnover, cancer cell lines, chemoproteomics, AXL, DDR1, trios, BIRC6, ISG15, FliI, drug target identification
MeSH terms: Half-Life, Humans, Kinetics, Protein Kinases, Purines, Signal Transduction, Benzoquinones, HSP90 Heat-Shock Proteins, Proteome, Protein Interaction Mapping, Cell Line, Tumor, Lactams, Macrocyclic, Benzodioxoles, Protein Stability, Protein Interaction Maps

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Systematic Identification of the HSP90 Regulated Proteome

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