Heat shock protein 90kDa alpha (cytosolic), member A1

The gene, HSP90AA1, encodes the human stress-inducible 90-kDa heat shock protein alpha (Hsp90A). Complemented by the constitutively expressed paralog Hsp90B which shares over 85% amino acid sequence identity, Hsp90A expression is initiated when a cell experiences proteotoxic stress. Once expressed Hsp90A dimers operate as molecular chaperones that bind and fold other proteins into their functional 3-dimensional structures. This molecular chaperoning ability of Hsp90A is driven by a cycle of structural rearrangements fueled by ATP hydrolysis. Current research on Hsp90A focuses in its role as a drug target due to its interaction with a large number of tumor promoting proteins and its role in cellular stress adaptation.

Human HSP90AA1 is encoded on the complement strand of Chromosome 14q32.33 and spans over 59 kbp. Several pseudogenes of HSP90AA1 exist throughout the human genome located on Chromosomes 3, 4, 11 and 14.{{cite journal | vauthors = Ozawa K, Murakami Y, Eki T, Soeda E, Yokoyama K | title = Mapping of the gene family for human heat-shock protein 90 alpha to chromosomes 1, 4, 11, and 14 | journal = Genomics | volume = 12 | issue = 2 | pages = 214–20 | date = Feb 1992 | pmid = 1740332 | doi=10.1016/0888-7543(92)90368-3}} The HSP90AA1 gene encodes for two distinct mRNA transcripts initiated from separate transcription start sites (TSS). No mRNA splice variants of HSP90AA1 have presently been verified. Transcript variant 1 (TV1, NM_001017963.2) encodes the infrequently observed 854 amino acid isoform 1 of Hsp90A (NP_001017963) from a 3,887 bp mRNA transcript containing 12 exons spanning 59, 012 bp. Transcript variant 1 is located directly next to the WDR20 gene, which is encoded on the opposite coding strand. Transcript variant 2 (TV2, NM_005348.3) encodes the well-studied 732 amino acid isoform 2 (NP_005339) from a 3,366 bp mRNA transcript containing 11 exons spanning 6,438 bp. DYNC1H1 encodes the gene product on the other side of HSP90AA1, which coincidentally has been found to interact with Hsp90A. Hsp90A TV1 and TV2 are identical except for an additional 112 amino acids on the N-terminus of isoform 1 encoded by its first 2 exons. The function of the extended N-terminal domain on isoform 1 is currently not understood. This information was gathered from both NCBI Gene and the UCSC Genome Browser.

Despite sharing similar amino acid sequence, Hsp90A expression is regulated in a different manner than Hsp90B. Hsp90A is the stress inducible isoform while Hsp90B is expressed constitutively. Several heat shock elements (HSE) are located upstream of Hsp90A allowing for its inducible expression. RNA levels measured in cell lines collected from cancer patients as well as normal tissue can be found at The Human Protein Atlas.

Transcription of the HSP90AA1 gene is currently understood to be induced by stress through binding of the master transcription factor (TF) HSF1 to the HSP90AA1 promoter.{{cite journal | vauthors = Ciocca DR, Arrigo AP, Calderwood SK | title = Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update | journal = Archives of Toxicology | volume = 87 | issue = 1 | pages = 19–48 | date = Jan 2013 | pmid = 22885793 | doi = 10.1007/s00204-012-0918-z | pmc=3905791| bibcode = 2013ArTox..87...19C }} However, several focused studies of the HSP90AA1 promoter along with extensive global analysis of the human genome indicate that various other transcription complexes regulate HSP90AA1 gene expression. Mammalian HSP90AA1 along with HSP90AB1 gene expression was first characterized in transformed mouse cells where it was shown that HSP90AB1 is constitutively expressed 2.5-fold higher than HSP90AA1 under normal conditions. However upon heat shock, HSP90AA1 expression increased 7.0-fold while HSP90AB1 increases only 4.5-fold.{{cite journal | vauthors = Ullrich SJ, Moore SK, Appella E | title = Transcriptional and translational analysis of the murine 84- and 86-kDa heat shock proteins | journal = The Journal of Biological Chemistry | volume = 264 | issue = 12 | pages = 6810–6 | date = Apr 1989 | doi = 10.1016/S0021-9258(18)83502-5 | pmid = 2708345 | doi-access = free }} Detailed analysis of the HSP90AA1 promoter shows that there are 2 heat shock elements (HSE) within 1200 bp of the transcription start site.{{cite journal | vauthors = Zhang SL, Yu J, Cheng XK, Ding L, Heng FY, Wu NH, Shen YF | title = Regulation of human hsp90alpha gene expression | journal = FEBS Letters | volume = 444 | issue = 1 | pages = 130–5 | date = Feb 1999 | pmid = 10037161 | doi=10.1016/s0014-5793(99)00044-7| doi-access = free | bibcode = 1999FEBSL.444..130Z }}{{cite journal | vauthors = Sreedhar AS, Kalmár E, Csermely P, Shen YF | title = Hsp90 isoforms: functions, expression and clinical importance | journal = FEBS Letters | volume = 562 | issue = 1–3 | pages = 11–5 | date = Mar 2004 | pmid = 15069952 | doi=10.1016/s0014-5793(04)00229-7| doi-access = free | bibcode = 2004FEBSL.562...11S }} The distal HSE is required for heat shock induction and the proximal HSE functions as a permissive enhancer. This model is supported by ChIP-SEQ analysis of cells under normal conditions where HSF1 is found bound to the proximal HSE and not detected at the distal HSE. The proto-oncogene MYC is also found to induce HSP90AA1 gene expression and binds proximally to the TSS as verified by ChIP-SEQ. Depletion of Hsp90A expression indicates that HSP90AA1 is required for MYC-driven transformation.{{cite journal | vauthors = Teng SC, Chen YY, Su YN, Chou PC, Chiang YC, Tseng SF, Wu KJ | title = Direct activation of HSP90A transcription by c-Myc contributes to c-Myc-induced transformation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 15 | pages = 14649–55 | date = Apr 2004 | pmid = 14724288 | doi = 10.1074/jbc.M308842200 | url = http://ntur.lib.ntu.edu.tw//bitstream/246246/2006111501221911/1/5427.pdf | doi-access = free }} In breast cancer cells the growth hormone prolactin induces HSP90AA1 expression through STAT5.{{cite journal | vauthors = Perotti C, Liu R, Parusel CT, Böcher N, Schultz J, Bork P, Pfitzner E, Groner B, Shemanko CS | title = Heat shock protein-90-alpha, a prolactin-STAT5 target gene identified in breast cancer cells, is involved in apoptosis regulation | journal = Breast Cancer Research | volume = 10 | issue = 6 | pages = R94 | date = 2008 | pmid = 19014541 | doi = 10.1186/bcr2193 | pmc=2656886 | doi-access = free }} NF-κB or RELA also induces HSP90AA1 expression possibly explaining the pro-survival ability of NF-κB-driven transcription.{{cite journal | vauthors = Ammirante M, Rosati A, Gentilella A, Festa M, Petrella A, Marzullo L, Pascale M, Belisario MA, Leone A, Turco MC | title = The activity of hsp90 alpha promoter is regulated by NF-kappa B transcription factors | journal = Oncogene | volume = 27 | issue = 8 | pages = 1175–8 | date = Feb 2008 | pmid = 17724475 | doi = 10.1038/sj.onc.1210716 | doi-access = free }} Conversely, STAT1, the proto-tumor suppressor, is found to inhibit stress induced expression of HSP90AA1.{{cite journal | vauthors = Chen XS, Zhang Y, Wang JS, Li XY, Cheng XK, Zhang Y, Wu NH, Shen YF | title = Diverse effects of Stat1 on the regulation of hsp90alpha gene under heat shock | journal = Journal of Cellular Biochemistry | volume = 102 | issue = 4 | pages = 1059–66 | date = Nov 2007 | pmid = 17427945 | doi = 10.1002/jcb.21342 | s2cid = 84261368 }} In addition to these findings, ChIP-SEQ analysis of the human genome indicates that at least 85 unique TFs bind to the RNA polymerase II (POLR2A) footprints associated with the promoter regions that drive the expression of both HSP90AA1 transcript variants.{{cite journal | vauthors = Wang J, Zhuang J, Iyer S, Lin XY, Greven MC, Kim BH, Moore J, Pierce BG, Dong X, Virgil D, Birney E, Hung JH, Weng Z | title = Factorbook.org: a Wiki-based database for transcription factor-binding data generated by the ENCODE consortium | journal = Nucleic Acids Research | volume = 41 | issue = Database issue | pages = D171–6 | date = Jan 2013 | pmid = 23203885 | doi = 10.1093/nar/gks1221 | pmc=3531197}}{{cite journal | vauthors = Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM, Wong MC, Maddren M, Fang R, Heitner SG, Lee BT, Barber GP, Harte RA, Diekhans M, Long JC, Wilder SP, Zweig AS, Karolchik D, Kuhn RM, Haussler D, Kent WJ | title = ENCODE data in the UCSC Genome Browser: year 5 update | journal = Nucleic Acids Research | volume = 41 | issue = Database issue | pages = D56–63 | date = Jan 2013 | pmid = 23193274 | doi = 10.1093/nar/gks1172 | pmc=3531152}}{{cite journal | vauthors = Euskirchen GM, Rozowsky JS, Wei CL, Lee WH, Zhang ZD, Hartman S, Emanuelsson O, Stolc V, Weissman S, Gerstein MB, Ruan Y, Snyder M | title = Mapping of transcription factor binding regions in mammalian cells by ChIP: comparison of array- and sequencing-based technologies | journal = Genome Research | volume = 17 | issue = 6 | pages = 898–909 | date = Jun 2007 | pmid = 17568005 | doi = 10.1101/gr.5583007 | pmc=1891348}}{{cite journal | vauthors = Hudson ME, Snyder M | title = High-throughput methods of regulatory element discovery | journal = BioTechniques | volume = 41 | issue = 6 | pages = 673–681 | date = Dec 2006 | pmid = 17191608 | doi=10.2144/000112322| doi-access = free }} This indicates that HSP90AA1 gene expression may be highly regulated and complex.

Combined, Hsp90A and Hsp90B are predicted to interact with 10% of the eukaryotic proteome.{{cite journal | vauthors = Zhao R, Davey M, Hsu YC, Kaplanek P, Tong A, Parsons AB, Krogan N, Cagney G, Mai D, Greenblatt J, Boone C, Emili A, Houry WA | title = Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone | journal = Cell | volume = 120 | issue = 5 | pages = 715–27 | date = Mar 2005 | pmid = 15766533 | doi = 10.1016/j.cell.2004.12.024 | doi-access = free }} In humans this represents a network of roughly 2,000 interacting proteins. Presently over 725 interactions have been experimentally documented for both HSP90A and Hsp90B.{{cite journal | vauthors = Echeverría PC, Bernthaler A, Dupuis P, Mayer B, Picard D | title = An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine | journal = PLOS ONE | volume = 6 | issue = 10 | pages = e26044 | date = 2011 | pmid = 22022502 | doi = 10.1371/journal.pone.0026044 | pmc=3195953| bibcode = 2011PLoSO...626044E | doi-access = free }}{{cite web|url=http://www.picard.ch/Hsp90Int/index.php|title=Hsp90 PPI database|last=Dupuis}} This connectivity allows Hsp90 to function as a network hub linking diverse protein interaction networks. Within these networks Hsp90 primarily specializes in maintaining and regulating proteins involved in signal transduction or information processing. These include transcription factors that initiate gene expression, kinases that transmit information by post-translationally modifying other proteins and E3-ligases that target proteins for degradation via the proteosome. Indeed, a recent study utilizing the LUMIER method has shown that human Hsp90B interacts with 7% of all transcription factors, 60% of all kinases and 30% of all E3-ligases.{{cite journal | vauthors = Taipale M, Tucker G, Peng J, Krykbaeva I, Lin ZY, Larsen B, Choi H, Berger B, Gingras AC, Lindquist S | title = A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways | journal = Cell | volume = 158 | issue = 2 | pages = 434–48 | date = Jul 2014 | pmid = 25036637 | doi = 10.1016/j.cell.2014.05.039 | pmc=4104544}} Other studies have shown that Hsp90 interacts with various structural proteins, ribosomal components and metabolic enzymes.{{cite journal | vauthors = Falsone SF, Gesslbauer B, Tirk F, Piccinini AM, Kungl AJ | title = A proteomic snapshot of the human heat shock protein 90 interactome | journal = FEBS Letters | volume = 579 | issue = 28 | pages = 6350–4 | date = Nov 2005 | pmid = 16263121 | doi = 10.1016/j.febslet.2005.10.020 | doi-access = free | bibcode = 2005FEBSL.579.6350F }}{{cite journal | vauthors = Skarra DV, Goudreault M, Choi H, Mullin M, Nesvizhskii AI, Gingras AC, Honkanen RE | title = Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5 | journal = Proteomics | volume = 11 | issue = 8 | pages = 1508–16 | date = Apr 2011 | pmid = 21360678 | doi = 10.1002/pmic.201000770 | pmc=3086140}} Hsp90 has also been found to interact with a large number of viral proteins including those from HIV and EBOLA.{{cite journal | vauthors = Low JS, Fassati A | title = Hsp90: a chaperone for HIV-1 | journal = Parasitology | volume = 141 | issue = 9 | pages = 1192–202 | date = Aug 2014 | pmid = 25004926 | doi = 10.1017/S0031182014000298 | s2cid = 8637871 }}{{cite journal | vauthors = Smith DR, McCarthy S, Chrovian A, Olinger G, Stossel A, Geisbert TW, Hensley LE, Connor JH | title = Inhibition of heat-shock protein 90 reduces Ebola virus replication | journal = Antiviral Research | volume = 87 | issue = 2 | pages = 187–94 | date = Aug 2010 | pmid = 20452380 | doi = 10.1016/j.antiviral.2010.04.015 | pmc=2907434}} This is not to mention the numerous co-chaperones that modulate and direct HSP90 activity.{{cite journal | vauthors = Li J, Soroka J, Buchner J | title = The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1823 | issue = 3 | pages = 624–35 | date = Mar 2012 | pmid = 21951723 | doi = 10.1016/j.bbamcr.2011.09.003 | doi-access = free }} Few studies have focused on discerning the unique protein interactions between Hsp90A and HSP90B.{{cite journal | vauthors = Gano JJ, Simon JA | title = A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein | journal = Molecular & Cellular Proteomics | volume = 9 | issue = 2 | pages = 255–70 | date = Feb 2010 | pmid = 19875381 | doi = 10.1074/mcp.M900261-MCP200 | pmc=2830838 | doi-access = free }}{{cite journal | vauthors = Hartson SD, Matts RL | title = Approaches for defining the Hsp90-dependent proteome | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1823 | issue = 3 | pages = 656–67 | date = Mar 2012 | pmid = 21906632 | doi = 10.1016/j.bbamcr.2011.08.013 | pmc=3276727}} Work done in Xenopus eggs and yeast has shown that Hsp90A and Hsp90B differ in co-chaperone and client interactions.{{cite journal | vauthors = Taherian A, Krone PH, Ovsenek N | title = A comparison of Hsp90alpha and Hsp90beta interactions with cochaperones and substrates | journal = Biochemistry and Cell Biology | volume = 86 | issue = 1 | pages = 37–45 | date = Feb 2008 | pmid = 18364744 | doi = 10.1139/o07-154 }}{{cite journal | vauthors = Gong Y, Kakihara Y, Krogan N, Greenblatt J, Emili A, Zhang Z, Houry WA | title = An atlas of chaperone-protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell | journal = Molecular Systems Biology | volume = 5 | pages = 275 | date = 2009 | pmid = 19536198 | doi = 10.1038/msb.2009.26 | pmc=2710862}} However, little is understood concerning the unique functions delegated to each human paralog. The Picard lab has aggregated all available Hsp90 interaction data into the Hsp90Int.DB website.{{cite web | title = Hsp90Int.db | url = http://www.picard.ch/Hsp90Int/index.php | website = picard.ch/Hsp90Int/index.php }} Gene ontology analysis of both Hsp90A and Hsp90B interactomes indicate that each paralogs is associated with unique biological processes, molecular functions and cellular components.

Heat shock protein 90kDa alpha (cytosolic), member A1 has been shown to interact with:

{{div col|colwidth=20em}}

• AHSA1,{{cite journal | vauthors = Panaretou B, Siligardi G, Meyer P, Maloney A, Sullivan JK, Singh S, Millson SH, Clarke PA, Naaby-Hansen S, Stein R, Cramer R, Mollapour M, Workman P, Piper PW, Pearl LH, Prodromou C | title = Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1 | journal = Molecular Cell | volume = 10 | issue = 6 | pages = 1307–18 | date = Dec 2002 | pmid = 12504007 | doi = 10.1016/S1097-2765(02)00785-2 | url = http://sro.sussex.ac.uk/id/eprint/44349/1/1-s2.0-S1097276502007852-main.pdf }}
• AKT1,{{cite journal | vauthors = Haendeler J, Hoffmann J, Rahman S, Zeiher AM, Dimmeler S | title = Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation | journal = FEBS Letters | volume = 536 | issue = 1–3 | pages = 180–6 | date = Feb 2003 | pmid = 12586360 | doi = 10.1016/S0014-5793(03)00058-9 | doi-access = free | bibcode = 2003FEBSL.536..180H }}{{cite journal | vauthors = Kawauchi K, Ihjima K, Yamada O | title = IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells | journal = Journal of Immunology | volume = 174 | issue = 9 | pages = 5261–9 | date = May 2005 | pmid = 15843522 | doi = 10.4049/jimmunol.174.9.5261 | doi-access = free }}{{cite journal | vauthors = Sato S, Fujita N, Tsuruo T | title = Modulation of Akt kinase activity by binding to Hsp90 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 20 | pages = 10832–7 | date = Sep 2000 | pmid = 10995457 | pmc = 27109 | doi = 10.1073/pnas.170276797 | bibcode = 2000PNAS...9710832S | doi-access = free }}
• AR,{{cite journal | vauthors = Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E | title = Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation | journal = Biochemistry | volume = 31 | issue = 8 | pages = 2393–9 | date = Mar 1992 | pmid = 1540595 | doi = 10.1021/bi00123a026 }}{{cite journal | vauthors = Nemoto T, Ohara-Nemoto Y, Ota M | title = Association of the 90-kDa heat shock protein does not affect the ligand-binding ability of androgen receptor | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 42 | issue = 8 | pages = 803–12 | date = Sep 1992 | pmid = 1525041 | doi = 10.1016/0960-0760(92)90088-Z | s2cid = 24978960 }}
• C-Raf,{{cite journal | vauthors = Stancato LF, Chow YH, Hutchison KA, Perdew GH, Jove R, Pratt WB | title = Raf exists in a native heterocomplex with hsp90 and p50 that can be reconstituted in a cell-free system | journal = The Journal of Biological Chemistry | volume = 268 | issue = 29 | pages = 21711–6 | date = Oct 1993 | doi = 10.1016/S0021-9258(20)80600-0 | pmid = 8408024 | doi-access = free }}{{cite journal | vauthors = Dogan T, Harms GS, Hekman M, Karreman C, Oberoi TK, Alnemri ES, Rapp UR, Rajalingam K | title = X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility | journal = Nature Cell Biology | volume = 10 | issue = 12 | pages = 1447–55 | date = Dec 2008 | pmid = 19011619 | doi = 10.1038/ncb1804 | s2cid = 6553549 }}
• CDC37,{{cite journal | vauthors = Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH | title = The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37) | journal = Cell | volume = 116 | issue = 1 | pages = 87–98 | date = Jan 2004 | pmid = 14718169 | doi = 10.1016/S0092-8674(03)01027-4 | doi-access = free }}{{cite journal | vauthors = Silverstein AM, Grammatikakis N, Cochran BH, Chinkers M, Pratt WB | title = p50(cdc37) binds directly to the catalytic domain of Raf as well as to a site on hsp90 that is topologically adjacent to the tetratricopeptide repeat binding site | journal = The Journal of Biological Chemistry | volume = 273 | issue = 32 | pages = 20090–5 | date = Aug 1998 | pmid = 9685350 | doi = 10.1074/jbc.273.32.20090 | doi-access = free }}
• DAP3,
• EPRS,{{cite journal | vauthors = Kang J, Kim T, Ko YG, Rho SB, Park SG, Kim MJ, Kwon HJ, Kim S | title = Heat shock protein 90 mediates protein-protein interactions between human aminoacyl-tRNA synthetases | journal = The Journal of Biological Chemistry | volume = 275 | issue = 41 | pages = 31682–8 | date = Oct 2000 | pmid = 10913161 | doi = 10.1074/jbc.M909965199 | doi-access = free }}
• ERN1,{{cite journal | vauthors = Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L | title = Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha | journal = Molecular and Cellular Biology | volume = 22 | issue = 24 | pages = 8506–13 | date = Dec 2002 | pmid = 12446770 | pmc = 139892 | doi = 10.1128/MCB.22.24.8506-8513.2002 }}
• ESR1{{cite journal | vauthors = Lee MO, Kim EO, Kwon HJ, Kim YM, Kang HJ, Kang H, Lee JE | title = Radicicol represses the transcriptional function of the estrogen receptor by suppressing the stabilization of the receptor by heat shock protein 90 | journal = Molecular and Cellular Endocrinology | volume = 188 | issue = 1–2 | pages = 47–54 | date = Feb 2002 | pmid = 11911945 | doi = 10.1016/S0303-7207(01)00753-5 | s2cid = 37933406 }}
• FKBP5,{{cite journal | vauthors = Nair SC, Rimerman RA, Toran EJ, Chen S, Prapapanich V, Butts RN, Smith DF | title = Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor | journal = Molecular and Cellular Biology | volume = 17 | issue = 2 | pages = 594–603 | date = Feb 1997 | pmid = 9001212 | pmc = 231784 | doi = 10.1128/MCB.17.2.594}}
• GNA12,{{cite journal | vauthors = Vaiskunaite R, Kozasa T, Voyno-Yasenetskaya TA | title = Interaction between the G alpha subunit of heterotrimeric G(12) protein and Hsp90 is required for G alpha(12) signaling | journal = The Journal of Biological Chemistry | volume = 276 | issue = 49 | pages = 46088–93 | date = Dec 2001 | pmid = 11598136 | doi = 10.1074/jbc.M108711200 | doi-access = free }}
• GUCY1B3,
• HER2/neu,{{cite journal | vauthors = Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L | title = Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 5 | pages = 3702–8 | date = Feb 2001 | pmid = 11071886 | doi = 10.1074/jbc.M006864200 | doi-access = free }}{{cite journal | vauthors = Jeong JH, An JY, Kwon YT, Li LY, Lee YJ | title = Quercetin-induced ubiquitination and down-regulation of Her-2/neu | journal = Journal of Cellular Biochemistry | volume = 105 | issue = 2 | pages = 585–95 | date = Oct 2008 | pmid = 18655187 | pmc = 2575035 | doi = 10.1002/jcb.21859 }}
• HSF1,{{cite journal | vauthors = Nair SC, Toran EJ, Rimerman RA, Hjermstad S, Smithgall TE, Smith DF | title = A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor | journal = Cell Stress & Chaperones | volume = 1 | issue = 4 | pages = 237–50 | date = Dec 1996 | doi = 10.1379/1466-1268(1996)001<0237:apomci>2.3.co;2 | doi-broken-date = 2024-11-02 | pmid = 9222609 | pmc = 376461 }}{{cite journal | vauthors = Hu Y, Mivechi NF | title = HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo | journal = The Journal of Biological Chemistry | volume = 278 | issue = 19 | pages = 17299–306 | date = May 2003 | pmid = 12621024 | doi = 10.1074/jbc.M300788200 | doi-access = free }}
• Hop,{{cite journal | vauthors = Scheufler C, Brinker A, Bourenkov G, Pegoraro S, Moroder L, Bartunik H, Hartl FU, Moarefi I | title = Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine | journal = Cell | volume = 101 | issue = 2 | pages = 199–210 | date = Apr 2000 | pmid = 10786835 | doi = 10.1016/S0092-8674(00)80830-2 | doi-access = free }}{{cite journal | vauthors = Johnson BD, Schumacher RJ, Ross ED, Toft DO | title = Hop modulates Hsp70/Hsp90 interactions in protein folding | journal = The Journal of Biological Chemistry | volume = 273 | issue = 6 | pages = 3679–86 | date = Feb 1998 | pmid = 9452498 | doi = 10.1074/jbc.273.6.3679 | doi-access = free }}
• NOS3,{{cite journal | vauthors = Venema RC, Venema VJ, Ju H, Harris MB, Snead C, Jilling T, Dimitropoulou C, Maragoudakis ME, Catravas JD | title = Novel complexes of guanylate cyclase with heat shock protein 90 and nitric oxide synthase | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 285 | issue = 2 | pages = H669–78 | date = Aug 2003 | pmid = 12676772 | doi = 10.1152/ajpheart.01025.2002 }}{{cite journal | vauthors = Harris MB, Ju H, Venema VJ, Blackstone M, Venema RC | title = Role of heat shock protein 90 in bradykinin-stimulated endothelial nitric oxide release | journal = General Pharmacology | volume = 35 | issue = 3 | pages = 165–70 | date = Sep 2000 | pmid = 11744239 | doi = 10.1016/S0306-3623(01)00104-5 }}{{cite journal | vauthors = Stepp DW, Ou J, Ackerman AW, Welak S, Klick D, Pritchard KA | title = Native LDL and minimally oxidized LDL differentially regulate superoxide anion in vascular endothelium in situ | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 283 | issue = 2 | pages = H750–9 | date = Aug 2002 | pmid = 12124224 | doi = 10.1152/ajpheart.00029.2002 | s2cid = 30652156 }}
• NR3C1,{{cite journal | vauthors = Hulkko SM, Wakui H, Zilliacus J | title = The pro-apoptotic protein death-associated protein 3 (DAP3) interacts with the glucocorticoid receptor and affects the receptor function | journal = The Biochemical Journal | volume = 349 | issue = 3 | pages = 885–93 | date = Aug 2000 | pmid = 10903152 | pmc = 1221218 | doi = 10.1042/bj3490885}}{{cite journal | vauthors = Jibard N, Meng X, Leclerc P, Rajkowski K, Fortin D, Schweizer-Groyer G, Catelli MG, Baulieu EE, Cadepond F | title = Delimitation of two regions in the 90-kDa heat shock protein (Hsp90) able to interact with the glucocorticosteroid receptor (GR) | journal = Experimental Cell Research | volume = 247 | issue = 2 | pages = 461–74 | date = Mar 1999 | pmid = 10066374 | doi = 10.1006/excr.1998.4375 }}{{cite journal | vauthors = Kanelakis KC, Shewach DS, Pratt WB | title = Nucleotide binding states of hsp70 and hsp90 during sequential steps in the process of glucocorticoid receptor.hsp90 heterocomplex assembly | journal = The Journal of Biological Chemistry | volume = 277 | issue = 37 | pages = 33698–703 | date = Sep 2002 | pmid = 12093808 | doi = 10.1074/jbc.M204164200 | doi-access = free }}{{cite journal | vauthors = Hecht K, Carlstedt-Duke J, Stierna P, Gustafsson J, Brönnegârd M, Wikström AC | title = Evidence that the beta-isoform of the human glucocorticoid receptor does not act as a physiologically significant repressor | journal = The Journal of Biological Chemistry | volume = 272 | issue = 42 | pages = 26659–64 | date = Oct 1997 | pmid = 9334248 | doi = 10.1074/jbc.272.42.26659 | doi-access = free }}{{cite journal | vauthors = de Castro M, Elliot S, Kino T, Bamberger C, Karl M, Webster E, Chrousos GP | title = The non-ligand binding beta-isoform of the human glucocorticoid receptor (hGR beta): tissue levels, mechanism of action, and potential physiologic role | journal = Molecular Medicine | volume = 2 | issue = 5 | pages = 597–607 | date = Sep 1996 | pmid = 8898375 | pmc = 2230188 | doi = 10.1007/BF03401643}}{{cite journal | vauthors = van den Berg JD, Smets LA, van Rooij H | title = Agonist-free transformation of the glucocorticoid receptor in human B-lymphoma cells | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 57 | issue = 3–4 | pages = 239–49 | date = Feb 1996 | pmid = 8645634 | doi = 10.1016/0960-0760(95)00271-5 | s2cid = 20582144 }}{{cite journal | vauthors = Stancato LF, Silverstein AM, Gitler C, Groner B, Pratt WB | title = Use of the thiol-specific derivatizing agent N-iodoacetyl-3-[125I]iodotyrosine to demonstrate conformational differences between the unbound and hsp90-bound glucocorticoid receptor hormone binding domain | journal = The Journal of Biological Chemistry | volume = 271 | issue = 15 | pages = 8831–6 | date = Apr 1996 | pmid = 8621522 | doi = 10.1074/jbc.271.15.8831 | doi-access = free }}
• P53,{{cite journal | vauthors = Wang C, Chen J | title = Phosphorylation and hsp90 binding mediate heat shock stabilization of p53 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 3 | pages = 2066–71 | date = Jan 2003 | pmid = 12427754 | doi = 10.1074/jbc.M206697200 | doi-access = free }}{{cite journal | vauthors = Akakura S, Yoshida M, Yoneda Y, Horinouchi S | title = A role for Hsc70 in regulating nucleocytoplasmic transport of a temperature-sensitive p53 (p53Val-135) | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 14649–57 | date = May 2001 | pmid = 11297531 | doi = 10.1074/jbc.M100200200 | doi-access = free }}{{cite journal | vauthors = Peng Y, Chen L, Li C, Lu W, Chen J | title = Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization | journal = The Journal of Biological Chemistry | volume = 276 | issue = 44 | pages = 40583–90 | date = Nov 2001 | pmid = 11507088 | doi = 10.1074/jbc.M102817200 | doi-access = free }}
• PIM1,{{cite journal | vauthors = Mizuno K, Shirogane T, Shinohara A, Iwamatsu A, Hibi M, Hirano T | title = Regulation of Pim-1 by Hsp90 | journal = Biochemical and Biophysical Research Communications | volume = 281 | issue = 3 | pages = 663–9 | date = Mar 2001 | pmid = 11237709 | doi = 10.1006/bbrc.2001.4405 }}
• PPARA,{{cite journal | vauthors = Sumanasekera WK, Tien ES, Turpey R, Vanden Heuvel JP, Perdew GH | title = Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 7 | pages = 4467–73 | date = Feb 2003 | pmid = 12482853 | doi = 10.1074/jbc.M211261200 | doi-access = free }}
• SMYD3,{{cite journal | vauthors = Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y | title = SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells | journal = Nature Cell Biology | volume = 6 | issue = 8 | pages = 731–40 | date = Aug 2004 | pmid = 15235609 | doi = 10.1038/ncb1151 | s2cid = 13456531 }}
• STK11,{{cite journal | vauthors = Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR | title = Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability | journal = The Biochemical Journal | volume = 370 | issue = Pt 3 | pages = 849–57 | date = Mar 2003 | pmid = 12489981 | pmc = 1223241 | doi = 10.1042/BJ20021813 }}
• TGFBR1,
• TGFBR2,{{cite journal | vauthors = Wrighton KH, Lin X, Feng XH | title = Critical regulation of TGFbeta signaling by Hsp90 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 27 | pages = 9244–9 | date = Jul 2008 | pmid = 18591668 | pmc = 2453700 | doi = 10.1073/pnas.0800163105 | bibcode = 2008PNAS..105.9244W | doi-access = free }} and
• TERT.

{{Div col end}}

Post-translational modifications have a large impact on Hsp90 regulation. Phosphorylation, acetylation, S-nitrosylation, oxidation and ubiquitination are ways in which Hsp90 is modified in order to modulate its many functions. A summary of these sites can be found at PhosphoSitePlus.{{cite journal | vauthors = Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E | title = PhosphoSitePlus, 2014: mutations, PTMs and recalibrations | journal = Nucleic Acids Research | volume = 43 | issue = Database issue | pages = D512–20 | date = Jan 2015 | pmid = 25514926 | doi = 10.1093/nar/gku1267 | pmc=4383998}} Many of these sites are conserved between Hsp90A and Hsp90B. However, there are a few distinctions between the two that allow for specific functions to be performed by Hsp90A.

Phosphorylation of Hsp90 has been shown to have affect its binding to clients, co-chaperones and nucleotide.{{cite journal | vauthors = Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP, Vojtesek B | title = C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances | journal = Oncogene | volume = 32 | issue = 25 | pages = 3101–10 | date = Jun 2013 | pmid = 22824801 | doi = 10.1038/onc.2012.314 | doi-access = free }}{{cite journal | vauthors = Mollapour M, Tsutsumi S, Truman AW, Xu W, Vaughan CK, Beebe K, Konstantinova A, Vourganti S, Panaretou B, Piper PW, Trepel JB, Prodromou C, Pearl LH, Neckers L | title = Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity | journal = Molecular Cell | volume = 41 | issue = 6 | pages = 672–81 | date = Mar 2011 | pmid = 21419342 | doi = 10.1016/j.molcel.2011.02.011 | pmc=3062913}}{{cite journal | vauthors = Mollapour M, Tsutsumi S, Neckers L | title = Hsp90 phosphorylation, Wee1 and the cell cycle | journal = Cell Cycle | volume = 9 | issue = 12 | pages = 2310–6 | date = Jun 2010 | pmid = 20519952 | doi=10.4161/cc.9.12.12054| pmc = 7316391 | doi-access = free }}{{cite journal | vauthors = Quanz M, Herbette A, Sayarath M, de Koning L, Dubois T, Sun JS, Dutreix M | title = Heat shock protein 90α (Hsp90α) is phosphorylated in response to DNA damage and accumulates in repair foci | journal = The Journal of Biological Chemistry | volume = 287 | issue = 12 | pages = 8803–15 | date = Mar 2012 | pmid = 22270370 | doi = 10.1074/jbc.M111.320887 | pmc=3308794| doi-access = free }}{{cite journal | vauthors = Zhao YG, Gilmore R, Leone G, Coffey MC, Weber B, Lee PW | title = Hsp90 phosphorylation is linked to its chaperoning function. Assembly of the reovirus cell attachment protein | journal = The Journal of Biological Chemistry | volume = 276 | issue = 35 | pages = 32822–7 | date = Aug 2001 | pmid = 11438552 | doi = 10.1074/jbc.M105562200 | doi-access = free }}{{cite journal | vauthors = Xu W, Mollapour M, Prodromou C, Wang S, Scroggins BT, Palchick Z, Beebe K, Siderius M, Lee MJ, Couvillon A, Trepel JB, Miyata Y, Matts R, Neckers L | title = Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine | journal = Molecular Cell | volume = 47 | issue = 3 | pages = 434–43 | date = Aug 2012 | pmid = 22727666 | doi = 10.1016/j.molcel.2012.05.015 | pmc=3418412}} Specific phosphorylation of Hsp90A residues have been shown to occur. These unique phosphorylation sites signal Hsp90A for functions such as secretion, allow it to locate to regions of DNA damage and interact with specific co-chaperones.{{cite journal | vauthors = Wang X, Song X, Zhuo W, Fu Y, Shi H, Liang Y, Tong M, Chang G, Luo Y | title = The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 50 | pages = 21288–93 | date = Dec 2009 | pmid = 19965370 | doi = 10.1073/pnas.0908151106 | pmc=2795546| bibcode = 2009PNAS..10621288W | doi-access = free }}{{cite journal | vauthors = Lei H, Venkatakrishnan A, Yu S, Kazlauskas A | title = Protein kinase A-dependent translocation of Hsp90 alpha impairs endothelial nitric-oxide synthase activity in high glucose and diabetes | journal = The Journal of Biological Chemistry | volume = 282 | issue = 13 | pages = 9364–71 | date = Mar 2007 | pmid = 17202141 | doi = 10.1074/jbc.M608985200 | doi-access = free }} Hyperacetylation also occurs with Hsp90A which leading to its secretion and increased cancer invasiveness.{{cite journal | vauthors = Yang Y, Rao R, Shen J, Tang Y, Fiskus W, Nechtman J, Atadja P, Bhalla K | title = Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion | journal = Cancer Research | volume = 68 | issue = 12 | pages = 4833–42 | date = Jun 2008 | pmid = 18559531 | doi = 10.1158/0008-5472.CAN-08-0644 | pmc=2665713}}

Expression of Hsp90A also correlates with disease prognosis. Increased levels of Hsp90A are found in leukemia, breast and pancreatic cancers as well as in patients with chronic obstructive pulmonary disease (COPD).{{cite journal | vauthors = Yufu Y, Nishimura J, Nawata H | title = High constitutive expression of heat shock protein 90 alpha in human acute leukemia cells | journal = Leukemia Research | volume = 16 | issue = 6–7 | pages = 597–605 | date = 1992 | pmid = 1635378 | doi=10.1016/0145-2126(92)90008-u}}{{cite journal | vauthors = Tian WL, He F, Fu X, Lin JT, Tang P, Huang YM, Guo R, Sun L | title = High expression of heat shock protein 90 alpha and its significance in human acute leukemia cells | journal = Gene | volume = 542 | issue = 2 | pages = 122–8 | date = Jun 2014 | pmid = 24680776 | doi = 10.1016/j.gene.2014.03.046 }}{{cite journal | vauthors = Jameel A, Skilton RA, Campbell TA, Chander SK, Coombes RC, Luqmani YA | title = Clinical and biological significance of HSP89 alpha in human breast cancer | journal = International Journal of Cancer | volume = 50 | issue = 3 | pages = 409–15 | date = Feb 1992 | pmid = 1735610 | doi=10.1002/ijc.2910500315| s2cid = 45804047 }}{{cite journal | vauthors = Gress TM, Müller-Pillasch F, Weber C, Lerch MM, Friess H, Büchler M, Beger HG, Adler G | title = Differential expression of heat shock proteins in pancreatic carcinoma | journal = Cancer Research | volume = 54 | issue = 2 | pages = 547–51 | date = Jan 1994 | pmid = 8275493 }}{{cite journal | vauthors = Hacker S, Lambers C, Hoetzenecker K, Pollreisz A, Aigner C, Lichtenauer M, Mangold A, Niederpold T, Zimmermann M, Taghavi S, Klepetko W, Ankersmit HJ | title = Elevated HSP27, HSP70 and HSP90 alpha in chronic obstructive pulmonary disease: markers for immune activation and tissue destruction | journal = Clinical Laboratory | volume = 55 | issue = 1–2 | pages = 31–40 | date = 2009 | pmid = 19350847 }} In human T-cells, HSP90AA1 expression is increased by the cytokines IL-2, IL-4 and IL-13.{{cite journal | vauthors = Metz K, Ezernieks J, Sebald W, Duschl A | title = Interleukin-4 upregulates the heat shock protein Hsp90alpha and enhances transcription of a reporter gene coupled to a single heat shock element | journal = FEBS Letters | volume = 385 | issue = 1–2 | pages = 25–8 | date = Apr 1996 | pmid = 8641459 | doi=10.1016/0014-5793(96)00341-9| doi-access = free | bibcode = 1996FEBSL.385...25M }} HSP90, alongside other conserved chaperones and co-chaperones that interact to safeguard proteostasis, is repressed in aging human brains. This repression was found to be further exacerbated in the brains of patients with age-onset neurodegenerative diseases such as Alzheimer's or Huntington's disease.{{cite journal | vauthors=Brehme M, Voisine C, Rolland T, Wachi S, Soper JH, Zhu Y, Orton K, Villella A, Garza D, Vidal M, Ge H, Morimoto RI | title=A conserved chaperome sub-network safeguards protein homeostasis in aging and neurodegenerative disease| journal=Cell Rep.| volume=9 | issue=3| pages=1135–1150 | date=2014 | pmid= 25437566 | doi=10.1016/j.celrep.2014.09.042 | pmc=4255334}}

Over the last two decades HSP90 has emerged as an intriguing target in the war on cancer. HSP90 interacts and supports numerous proteins that promote oncogenesis, thus distinguishing Hsp90 as a cancer enabler as it is regarded as essential for malignant transformation and progression. Moreover, through their extensive interactomes, both paralogs are associated with each hallmark of cancer.{{cite journal | vauthors = Workman P, Burrows F, Neckers L, Rosen N | title = Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress | journal = Annals of the New York Academy of Sciences | volume = 1113 | pages = 202–16 | date = Oct 2007 | issue = 1 | pmid = 17513464 | doi = 10.1196/annals.1391.012 | bibcode = 2007NYASA1113..202W | s2cid = 8590411 }}{{cite journal | vauthors = Trepel J, Mollapour M, Giaccone G, Neckers L | title = Targeting the dynamic HSP90 complex in cancer | journal = Nature Reviews. Cancer | volume = 10 | issue = 8 | pages = 537–49 | date = Aug 2010 | pmid = 20651736 | doi = 10.1038/nrc2887 | pmc = 6778733 | url = https://zenodo.org/record/1233496 }} The HSP90AA1 gene however is not altered in a majority of tumors according to The Cancer Genome Atlas (TCGA). Currently bladder cancer is found to have the largest number of alterations followed by pancreatic cancer.{{cite journal | vauthors = Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N | title = Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal | journal = Science Signaling | volume = 6 | issue = 269 | pages = pl1 | date = Apr 2013 | pmid = 23550210 | doi = 10.1126/scisignal.2004088 | pmc=4160307}}{{cite journal | vauthors = Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N | title = The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data | journal = Cancer Discovery | volume = 2 | issue = 5 | pages = 401–4 | date = May 2012 | pmid = 22588877 | doi = 10.1158/2159-8290.CD-12-0095 | pmc=3956037}} This may not come as a surprise since overall Hsp90 expression levels are held at such a high level compared to most all other proteins within the cell,{{cite journal | vauthors = Finka A, Goloubinoff P | title = Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis | journal = Cell Stress & Chaperones | volume = 18 | issue = 5 | pages = 591–605 | date = Sep 2013 | pmid = 23430704 | doi = 10.1007/s12192-013-0413-3 | pmc=3745260}} therefore further increasing Hsp90 levels may not provide any benefit to cancer growth. Additionally, whole genome sequencing across all tumor types and cancer cell lines reveals that there are presently 115 different mutations within the HSP90AA1 open reading frame. The effects of these mutations on HSP90A function, however, remain unknown. Remarkably, in a number of tumors the HSP90AA1 gene is homozygously deleted, suggesting that these tumors may have a reduced level of malignancy. This is supported by a comparative genome-wide analysis of 206 gastric cancer patients that reported loss of HSP90AA1 is indeed associated with favorable outcomes after surgery alone.{{cite journal | vauthors = Buffart TE, Carvalho B, van Grieken NC, van Wieringen WN, Tijssen M, Kranenbarg EM, Verheul HM, Grabsch HI, Ylstra B, van de Velde CJ, Meijer GA | title = Losses of chromosome 5q and 14q are associated with favorable clinical outcome of patients with gastric cancer | journal = The Oncologist | volume = 17 | issue = 5 | pages = 653–62 | date = 2012 | pmid = 22531355 | doi = 10.1634/theoncologist.2010-0379 | pmc=3360905}} This supports the possibility that the absence of Hsp90A in tumor biopsies may serve as a biomarker for positive clinical outcomes.{{cite journal | vauthors = Gallegos Ruiz MI, Floor K, Roepman P, Rodriguez JA, Meijer GA, Mooi WJ, Jassem E, Niklinski J, Muley T, van Zandwijk N, Smit EF, Beebe K, Neckers L, Ylstra B, Giaccone G | title = Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target | journal = PLOS ONE | volume = 3 | issue = 3 | pages = e0001722 | date = 5 March 2008 | pmid = 18320023 | doi = 10.1371/journal.pone.0001722 | pmc=2254495| bibcode = 2008PLoSO...3.1722G | doi-access = free }}{{cite journal | vauthors = Cheng Q, Chang JT, Geradts J, Neckers LM, Haystead T, Spector NL, Lyerly HK | title = Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer | journal = Breast Cancer Research | volume = 14 | issue = 2 | pages = R62 | date = 17 April 2012 | pmid = 22510516 | doi = 10.1186/bcr3168 | pmc=3446397 | doi-access = free }}

Biologically, Hsp90A differs from Hsp90B in that Hsp90A is presently understood to function as a secreted extracellular agent in wound healing and inflammation in addition to its intracellular roles. These two processes are often hijacked by cancer allowing for malignant cell motility, metastasis and extravasion.{{cite journal | vauthors = Eustace BK, Sakurai T, Stewart JK, Yimlamai D, Unger C, Zehetmeier C, Lain B, Torella C, Henning SW, Beste G, Scroggins BT, Neckers L, Ilag LL, Jay DG | title = Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness | journal = Nature Cell Biology | volume = 6 | issue = 6 | pages = 507–14 | date = Jun 2004 | pmid = 15146192 | doi = 10.1038/ncb1131 | s2cid = 40025264 }} Current research in prostate cancer indicates that extracellular Hsp90A transduces signals that promote the chronic inflammation of cancer-associated fibroblasts. This reprogramming of the extracellular milieu surrounding malignant adenocarcinoma cells is understood to stimulate prostate cancer progression. Extracellular HSP90A induces inflammation through the activation of the NF-κB (RELA) and STAT3 transcription programs that include the pro-inflammatory cytokines IL-6 and IL-8.{{cite journal | vauthors = Bohonowych JE, Hance MW, Nolan KD, Defee M, Parsons CH, Isaacs JS | title = Extracellular Hsp90 mediates an NF-κB dependent inflammatory stromal program: implications for the prostate tumor microenvironment | journal = The Prostate | volume = 74 | issue = 4 | pages = 395–407 | date = Apr 2014 | pmid = 24338924 | doi = 10.1002/pros.22761 | pmc=4306584}} Coincidentally NF-κB also induces expression Hsp90A., thus providing a model where newly expressed Hsp90A would also be secreted from the stimulated fibroblast thereby creating positive autocrine and paracrine feedback loops resulting in an inflammatory storm at the site of malignancy. This concept requires further attention as it may explain the correlation of increased levels of Hsp90A in the plasma of patients with advanced stages of malignancy.

Hsp90 is exploited by cancer cells to support activated oncoproteins, including many kinases and transcription factors. These clients are often mutated, amplified or translocated in malignancy, and Hsp90 works to buffer these cellular stresses induced by malignant transformation. Inhibition of Hsp90 leads to the degradation or instability of many of its client proteins.{{cite journal | vauthors = Blagg BS, Kerr TD | title = Hsp90 inhibitors: small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation | journal = Medicinal Research Reviews | volume = 26 | issue = 3 | pages = 310–38 | date = May 2006 | pmid = 16385472 | doi = 10.1002/med.20052 | s2cid = 13316474 | doi-access = free }} Thus, Hsp90 has become an attractive target for cancer therapy.

As with all ATPases, ATP binding and hydrolysis is essential for the chaperoning function of Hsp90 in vivo. Hsp90 inhibitors interfere with this cycle at its early stages by replacing ATP, leading to the regulated ubiquitination and proteasome-mediated degradation of most client proteins.{{cite journal | vauthors = Eleuteri AM, Cuccioloni M, Bellesi J, Lupidi G, Fioretti E, Angeletti M | title = Interaction of Hsp90 with 20S proteasome: thermodynamic and kinetic characterization | journal = Proteins | volume = 48 | issue = 2 | pages = 169–77 | date = Aug 2002 | pmid = 12112686 | doi = 10.1002/prot.10101 | s2cid = 37257142 }}{{cite journal | vauthors = Theodoraki MA, Caplan AJ | title = Quality control and fate determination of Hsp90 client proteins | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1823 | issue = 3 | pages = 683–8 | date = Mar 2012 | pmid = 21871502 | doi = 10.1016/j.bbamcr.2011.08.006 | pmc=3242914}} As such, the nucleotide binding pocket remains that most amenable to inhibitor generation.{{cite journal | vauthors = Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM | title = Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 18 | pages = 8324–8 | date = Aug 1994 | pmid = 8078881 | doi=10.1073/pnas.91.18.8324 | pmc=44598| bibcode = 1994PNAS...91.8324W | doi-access = free }}{{cite journal | vauthors = Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH | title = Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone | journal = Cell | volume = 90 | issue = 1 | pages = 65–75 | date = Jul 1997 | pmid = 9230303 | doi=10.1016/s0092-8674(00)80314-1| doi-access = free }}{{cite journal | vauthors = Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP | title = Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent | journal = Cell | volume = 89 | issue = 2 | pages = 239–50 | date = Apr 1997 | pmid = 9108479 | doi=10.1016/s0092-8674(00)80203-2| doi-access = free }}{{cite journal | vauthors = Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO | title = The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation | journal = The Journal of Biological Chemistry | volume = 272 | issue = 38 | pages = 23843–50 | date = Sep 1997 | pmid = 9295332 | doi=10.1074/jbc.272.38.23843| doi-access = free }}{{cite journal | vauthors = Sharma SV, Agatsuma T, Nakano H | title = Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol | journal = Oncogene | volume = 16 | issue = 20 | pages = 2639–45 | date = May 1998 | pmid = 9632140 | doi = 10.1038/sj.onc.1201790 | doi-access = free }}{{cite journal | vauthors = Schulte TW, Akinaga S, Soga S, Sullivan W, Stensgard B, Toft D, Neckers LM | title = Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin | journal = Cell Stress & Chaperones | volume = 3 | issue = 2 | pages = 100–8 | date = Jun 1998 | doi = 10.1379/1466-1268(1998)003<0100:arbttn>2.3.co;2 | doi-broken-date = 1 November 2024 | pmid = 9672245 | pmc=312953}}{{cite journal | vauthors = Banerji U, Walton M, Raynaud F, Grimshaw R, Kelland L, Valenti M, Judson I, Workman P | title = Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models | journal = Clinical Cancer Research | volume = 11 | issue = 19 Pt 1 | pages = 7023–32 | date = Oct 2005 | pmid = 16203796 | doi = 10.1158/1078-0432.CCR-05-0518 | doi-access = free }}{{cite journal | vauthors = Chiosis G, Tao H | title = Purine-scaffold Hsp90 inhibitors | journal = IDrugs: The Investigational Drugs Journal | volume = 9 | issue = 11 | pages = 778–82 | date = Nov 2006 | pmid = 17096299 }}{{cite journal | vauthors = Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M, Patterson L, de Haven Brandon A, Gowan S, Boxall F, Aherne W, Rowlands M, Hayes A, Martins V, Urban F, Boxall K, Prodromou C, Pearl L, James K, Matthews TP, Cheung KM, Kalusa A, Jones K, McDonald E, Barril X, Brough PA, Cansfield JE, Dymock B, Drysdale MJ, Finch H, Howes R, Hubbard RE, Surgenor A, Webb P, Wood M, Wright L, Workman P | title = NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis | journal = Cancer Research | volume = 68 | issue = 8 | pages = 2850–60 | date = Apr 2008 | pmid = 18413753 | doi = 10.1158/0008-5472.CAN-07-5256 | doi-access = free }}{{cite journal | vauthors = Kummar S, Gutierrez ME, Gardner ER, Chen X, Figg WD, Zajac-Kaye M, Chen M, Steinberg SM, Muir CA, Yancey MA, Horneffer YR, Juwara L, Melillo G, Ivy SP, Merino M, Neckers L, Steeg PS, Conley BA, Giaccone G, Doroshow JH, Murgo AJ | title = Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies | journal = European Journal of Cancer | volume = 46 | issue = 2 | pages = 340–7 | date = Jan 2010 | pmid = 19945858 | doi = 10.1016/j.ejca.2009.10.026 | pmc=2818572}}{{cite journal | vauthors = Lancet JE, Gojo I, Burton M, Quinn M, Tighe SM, Kersey K, Zhong Z, Albitar MX, Bhalla K, Hannah AL, Baer MR | title = Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia | journal = Leukemia | volume = 24 | issue = 4 | pages = 699–705 | date = Apr 2010 | pmid = 20111068 | doi = 10.1038/leu.2009.292 | doi-access = free }}{{cite journal | vauthors = Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, Arkenau HT, Moreno-Farre J, Banerji U, Roels B, Peachey H, Aherne W, de Bono JS, Raynaud F, Workman P, Judson I | title = A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors | journal = Clinical Cancer Research | volume = 17 | issue = 6 | pages = 1561–70 | date = Mar 2011 | pmid = 21278242 | doi = 10.1158/1078-0432.CCR-10-1927 | pmc=3060938}}{{cite book | vauthors = Jhaveri K, Modi S | title = Current Challenges in Personalized Cancer Medicine | chapter = HSP90 inhibitors for cancer therapy and overcoming drug resistance | series = Advances in Pharmacology | volume = 65 | pages = 471–517 | date = 2012 | pmid = 22959035 | doi = 10.1016/B978-0-12-397927-8.00015-4 | isbn = 978-0-12-397927-8 }}{{cite journal | vauthors = Jego G, Hazoumé A, Seigneuric R, Garrido C | title = Targeting heat shock proteins in cancer | journal = Cancer Letters | volume = 332 | issue = 2 | pages = 275–85 | date = May 2013 | pmid = 21078542 | doi = 10.1016/j.canlet.2010.10.014 }}{{cite journal | vauthors = Taldone T, Ochiana SO, Patel PD, Chiosis G | title = Selective targeting of the stress chaperome as a therapeutic strategy | journal = Trends in Pharmacological Sciences | volume = 35 | issue = 11 | pages = 592–603 | date = Nov 2014 | pmid = 25262919 | doi = 10.1016/j.tips.2014.09.001 | pmc=4254259}} To date, there are 23 active Hsp90 inhibitor oncology trials, and 13 HSP90 inhibitors are currently undergoing clinical evaluation in cancer patients, 10 of which have entered the clinic in the past few years.{{cite journal | vauthors = Neckers L, Trepel JB | title = Stressing the development of small molecules targeting HSP90 | journal = Clinical Cancer Research | volume = 20 | issue = 2 | pages = 275–7 | date = Jan 2014 | pmid = 24166908 | doi = 10.1158/1078-0432.CCR-13-2571 | doi-access = free }}

While the N-terminal nucleotide-binding pocket of Hsp90 is most widely studied and thus targeted, recent studies have suggested that a second ATP-binding site is located in the Hsp90 C-terminus.{{cite journal | vauthors = Csermely P, Schnaider T, Soti C, Prohászka Z, Nardai G | title = The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review | journal = Pharmacology & Therapeutics | volume = 79 | issue = 2 | pages = 129–68 | date = Aug 1998 | pmid = 9749880 | doi=10.1016/s0163-7258(98)00013-8}}{{cite journal | vauthors = Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM | title = The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone | journal = The Journal of Biological Chemistry | volume = 275 | issue = 47 | pages = 37181–6 | date = Nov 2000 | pmid = 10945979 | doi = 10.1074/jbc.M003701200 | doi-access = free }}{{cite journal | vauthors = Garnier C, Lafitte D, Tsvetkov PO, Barbier P, Leclerc-Devin J, Millot JM, Briand C, Makarov AA, Catelli MG, Peyrot V | title = Binding of ATP to heat shock protein 90: evidence for an ATP-binding site in the C-terminal domain | journal = The Journal of Biological Chemistry | volume = 277 | issue = 14 | pages = 12208–14 | date = Apr 2002 | pmid = 11805114 | doi = 10.1074/jbc.M111874200 | doi-access = free }}{{cite journal | vauthors = Soti C, Vermes A, Haystead TA, Csermely P | title = Comparative analysis of the ATP-binding sites of Hsp90 by nucleotide affinity cleavage: a distinct nucleotide specificity of the C-terminal ATP-binding site | journal = European Journal of Biochemistry | volume = 270 | issue = 11 | pages = 2421–8 | date = Jun 2003 | pmid = 12755697 | doi=10.1046/j.1432-1033.2003.03610.x| doi-access = free }}{{cite journal | vauthors = Matts RL, Dixit A, Peterson LB, Sun L, Voruganti S, Kalyanaraman P, Hartson SD, Verkhivker GM, Blagg BS | title = Elucidation of the Hsp90 C-terminal inhibitor binding site | journal = ACS Chemical Biology | volume = 6 | issue = 8 | pages = 800–7 | date = Aug 2011 | pmid = 21548602 | doi = 10.1021/cb200052x | pmc=3164513}} Targeting of this region has resulted in specific reduced Hsp90-hormone interactions and has been shown to influence Hsp90 nucleotide binding.{{cite journal | vauthors = Sreedhar AS, Soti C, Csermely P | title = Inhibition of Hsp90: a new strategy for inhibiting protein kinases | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1697 | issue = 1–2 | pages = 233–42 | date = Mar 2004 | pmid = 15023364 | doi = 10.1016/j.bbapap.2003.11.027 }}{{cite journal | vauthors = Rosenhagen MC, Sōti C, Schmidt U, Wochnik GM, Hartl FU, Holsboer F, Young JC, Rein T | title = The heat shock protein 90-targeting drug cisplatin selectively inhibits steroid receptor activation | journal = Molecular Endocrinology | volume = 17 | issue = 10 | pages = 1991–2001 | date = Oct 2003 | pmid = 12869591 | doi = 10.1210/me.2003-0141 | doi-access = free }} Although none of the C-terminal Hsp90 inhibitors have yet to enter the clinic, the use of both N- and C-terminal Hsp90 inhibitors in combination represents an exciting new strategy for chemotherapy.

Although many of the afore-mentioned inhibitors share the same Hsp90 binding site (either N- or C-terminal), it has been shown that some of these drugs preferentially access distinct Hsp90 populations, which are differentiated by the extent of their post-translational modification.{{cite journal | vauthors = Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G | title = Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90 | journal = Nature Chemical Biology | volume = 7 | issue = 11 | pages = 818–26 | date = Nov 2011 | pmid = 21946277 | doi = 10.1038/nchembio.670 | pmc=3265389}}{{cite journal | vauthors = Beebe K, Mollapour M, Scroggins B, Prodromou C, Xu W, Tokita M, Taldone T, Pullen L, Zierer BK, Lee MJ, Trepel J, Buchner J, Bolon D, Chiosis G, Neckers L | title = Posttranslational modification and conformational state of heat shock protein 90 differentially affect binding of chemically diverse small molecule inhibitors | journal = Oncotarget | volume = 4 | issue = 7 | pages = 1065–74 | date = Jul 2013 | pmid = 23867252 | doi=10.18632/oncotarget.1099 | pmc=3759666}} Though no published inhibitor has yet to distinguish between Hsp90A and Hsp90B, a recent study has shown that phosphorylation of a particular residue in the Hsp90 N-terminus can provide isoform specificity to inhibitor binding, thus providing an additional level of regulation for optimal Hsp90 targeting.

{{Academic-written review

| wikidate = 2015

| journal = Gene

| Q = Q28646043

}}

{{reflist|33em}}

{{refbegin |33em}}

• {{cite journal | vauthors = Csermely P, Schnaider T, Soti C, Prohászka Z, Nardai G | title = The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review | journal = Pharmacology & Therapeutics | volume = 79 | issue = 2 | pages = 129–68 | date = Aug 1998 | pmid = 9749880 | doi = 10.1016/S0163-7258(98)00013-8 }}
• {{cite journal | vauthors = Young JC, Moarefi I, Hartl FU | title = Hsp90: a specialized but essential protein-folding tool | journal = The Journal of Cell Biology | volume = 154 | issue = 2 | pages = 267–73 | date = Jul 2001 | pmid = 11470816 | pmc = 2150759 | doi = 10.1083/jcb.200104079 }}
• {{cite journal | vauthors = Hamblin AD, Hamblin TJ | title = Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia | journal = Expert Opinion on Therapeutic Targets | volume = 9 | issue = 6 | pages = 1165–78 | date = Dec 2005 | pmid = 16300468 | doi = 10.1517/14728222.9.6.1165 | s2cid = 20808988 }}
• {{cite journal | vauthors = Lattouf JB, Srinivasan R, Pinto PA, Linehan WM, Neckers L | title = Mechanisms of disease: the role of heat-shock protein 90 in genitourinary malignancy | journal = Nature Clinical Practice Urology | volume = 3 | issue = 11 | pages = 590–601 | date = Nov 2006 | pmid = 17088927 | doi = 10.1038/ncpuro0604 | s2cid = 23054181 | url = https://zenodo.org/record/1233373 }}

{{refend}}

• {{PDBe-KB2|P07900|Heat shock protein HSP 90-alpha}}

{{PDB Gallery|geneid=3320}}

{{Chaperones}}