BBA - Molecular Cell Research (v.1823, #3)
Editorial Board (i).
Preface to Hsp90 by Didier Picard (605-606).
Evolution and function of diverse Hsp90 homologs and cochaperone proteins by Jill L. Johnson (607-613).
Members of the Hsp90 molecular chaperone family are found in the cytosol, ER, mitochondria and chloroplasts of eukaryotic cells, as well as in bacteria. These diverse family members cooperate with other proteins, such as the molecular chaperone Hsp70, to mediate protein folding, activation and assembly into multiprotein complexes. All examined Hsp90 homologs exhibit similar ATPase rates and undergo similar conformational changes. One of the key differences is that cytosolic Hsp90 interacts with a large number of cochaperones that regulate the ATPase activity of Hsp90 or have other functions, such as targeting clients to Hsp90. Diverse Hsp90 homologs appear to chaperone different types of client proteins. This difference may reflect either the pool of clients requiring Hsp90 function or the requirement for cochaperones to target clients to Hsp90. This review discusses known functions, similarities and differences between Hsp90 family members and how cochaperones are known to affect these functions. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Genes encoding Hsp90 family members have undergone multiple gene duplication events. ► Cytosolic Hsp90, but not other homologs, functions with a species-specific set of multiple cochaperones. ► Conserved functions of all Hsp90 family members include cooperation with the molecular chaperone Hsp70.
Keywords: Hsp90; Cochaperones; Tetratricopeptide repeats; Evolution;
The ‘active life’ of Hsp90 complexes by Chrisostomos Prodromou (614-623).
Hsp90 forms a variety of complexes differing both in clientele and co-chaperones. Central to the role of co-chaperones in the formation of Hsp90 complexes is the delivery of client proteins and the regulation of the ATPase activity of Hsp90. Determining the mechanisms by which co-chaperones regulate Hsp90 is essential in understanding the assembly of these complexes and the activation and maturation of Hsp90's clientele. Mechanistically, co-chaperones alter the kinetics of the ATP-coupled conformational changes of Hsp90. The structural changes leading to the formation of a catalytically active unit involve all regions of the Hsp90 dimer. Their complexity has allowed different orthologues of Hsp90 to evolve kinetically in slightly different ways. The interaction of the cytosolic Hsp90 with a variety of co-chaperones lends itself to a complex set of different regulatory mechanisms that modulate Hsp90's conformation and ATPase activity. It also appears that the conformational switches of Hsp90 are not necessarily coupled under all circumstances. Here, I described different co-chaperone complexes and then discuss in detail the mechanisms and role that specific co-chaperones play in this. I will also discuss emerging evidence that post-translational modifications also affect the ATPase activity of Hsp90, and thus complex formation. Finally, I will present evidence showing how Hsp90's active site, although being highly conserved, can be altered to show resistance to drug binding, but still maintain ATP binding and ATPase activity. Such changes are therefore unlikely to significantly alter Hsp90's interactions with client proteins and co-chaperones. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90)► The regulatory role of co-chaperones in the formation of Hsp90 complexes is reviewed. ► I summarize the role of Hsp90 co-chaperones that regulate the ATPase cycle of Hsp90. ► The role of post-translational modification on the Hsp90 chaperone cycle. ► Hsp90s active site although highly conserved can mutate without loss of function.
Keywords: Hsp90; Heat shock protein 90; Chaperone; Cochaperone; Stress response; ATPase activity;
The Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones by Jing Li; Joanna Soroka; Johannes Buchner (624-635).
Hsp90 is a dimeric molecular chaperone required for the activation and stabilization of numerous client proteins many of which are involved in essential cellular processes like signal transduction pathways. This activation process is regulated by ATP-induced large conformational changes, co-chaperones and posttranslational modifications. For some co-chaperones, a detailed picture on their structures and functions exists, for others their contributions to the Hsp90 system is still unclear. Recent progress on the conformational dynamics of Hsp90 and how co-chaperones affect the Hsp90 chaperone cycle significantly increased our understanding of the gearings of this complex molecular machinery. This article is part of a Special Issue entitled: Heat Shock Protein 90 (Hsp90).► Hsp90 is a complex molecular chaperone machine. ► During the ATPase cycle Hsp90 undergoes large conformational changes. ► Hsp90 is subject to several posttranslational modifications that modify its function. ► Eukaryotic Hsp90 associates with a large cohort of co-chaperones. ► Co-chaperones drive Hsp90-client protein interactions.
Keywords: Co-chaperones; Hsp90 clients; Conformational regulation; ATPase; Posttranslational modifications;
Hsp90 structure and function studied by NMR spectroscopy by Tatiana Didenko; Afonso M.S. Duarte; G. Elif Karagöz; Stefan G.D. Rüdiger (636-647).
The molecular chaperone Hsp90 plays a crucial role in folding and maturation of regulatory proteins. Key aspects of Hsp90's molecular mechanism and its adenosine-5'-triphosphate (ATP)-controlled active cycle remain elusive. In particular the role of conformational changes during the ATPase cycle and the molecular basis of the interactions with substrate proteins are poorly understood. The dynamic nature of the Hsp90 machine designates nuclear magnetic resonance (NMR) spectroscopy as an attractive method to unravel both the chaperoning mechanism and interaction with partner proteins. NMR is particularly suitable to provide a dynamic picture of protein–protein interactions at atomic resolution. Hsp90 is rather a challenging protein for NMR studies, due to its high molecular weight and its structural flexibility. The recent technologic advances allowed overcoming many of the traditional obstacles. Here, we describe the different approaches that allowed the investigation of Hsp90 using state-of-the-art NMR methods and the results that were obtained. NMR spectroscopy contributed to understanding Hsp90's interaction with the co-chaperones p23, Aha1 and Cdc37. A particular exciting prospect of NMR, however, is the analysis of Hsp90 interaction with substrate proteins. Here, the ability of this method to contribute to the structural characterization of not fully folded proteins becomes crucial. Especially the interaction of Hsp90 with one of its natural clients, the tumour suppressor p53, has been intensively studied by NMR spectroscopy. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Hsp90 is a challenging molecule for NMR spectroscopy due to its big size and dynamic properties. ► Hsp90 domains are suitable for high‐resolution NMR studies. ► Full‐length Hsp90 is accessible for NMR studies using methyl‐specific labelling. ► NMR allows mapping of interaction sites of co‐chaperones and client proteins. ► NMR studies on the Hsp90–p53 interaction suggest various and to some extent controversial models.
Keywords: Protein folding; TROSY; Protein–protein interaction; Selective isotope labelling;
Post-translational modifications of Hsp90 and their contributions to chaperone regulation by Mehdi Mollapour; Len Neckers (648-655).
Molecular chaperones, as the name suggests, are involved in folding, maintenance, intracellular transport, and degradation of proteins as well as in facilitating cell signaling. Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone that carries out these processes in normal and cancer cells. Hsp90 function in vivo is coupled to its ability to hydrolyze ATP and this can be regulated by co-chaperones and post-translational modifications. In this review, we explore the varied roles of known post-translational modifications of cytosolic and nuclear Hsp90 (phosphorylation, acetylation, S-nitrosylation, oxidation and ubiquitination) in fine-tuning chaperone function in eukaryotes. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Heat shock protein 90 (Hsp90) is evolutionarily conserved. ► Hsp90 activates and maintains numerous signaling networks in normal and cancer cells. ► Hsp90 chaperone function is regulated by post-translational modifications of Hsp90 and various co-chaperones. ► Hsp90 post-translational modifications include phosphorylation, acetylation, S-nitrosylation, oxidation, and ubiquitination.
Keywords: Heat shock protein 90; Hsp82; Post-translational modification phosphorylation; Acetylation; Oxidation; Nitrosylation;
Approaches for defining the Hsp90-dependent proteome by Steven D. Hartson; Robert L. Matts (656-667).
Hsp90 is the target of ongoing drug discovery studies seeking new compounds to treat cancer, neurodegenerative diseases, and protein folding disorders. To better understand Hsp90's roles in cellular pathologies and in normal cells, numerous studies have utilized proteomics assays and related high-throughput tools to characterize its physical and functional protein partnerships. This review surveys these studies, and summarizes the strengths and limitations of the individual attacks. We also include downloadable spreadsheets compiling all of the Hsp90-interacting proteins identified in more than 23 studies. These tools include cross-references among gene aliases, human homologues of yeast Hsp90-interacting proteins, hyperlinks to database entries, summaries of canonical pathways that are enriched in the Hsp90 interactome, and additional bioinformatic annotations. In addition to summarizing Hsp90 proteomics studies performed to date and the insights they have provided, we identify gaps in our current understanding of Hsp90-mediated proteostasis. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Summary of findings from past proteomic studies examining the Hsp90-interactome. ► Critical assessment of methodologies used in past Hsp90 proteomic studies. ► Discussion of new insights gained from proteomic studies into Hsp90 function. ► Future perspectives on studies of Hsp90 proteomics: reaching the next level.
Keywords: Hsp90-interactome; Proteomics; LC–MS/MS; High-throughput screen; Hsp90 inhibitor;
Expanding the cellular molecular chaperone network through the ubiquitous cochaperones by Frank J. Echtenkamp; Brian C. Freeman (668-673).
Cellular environments are highly complex and contain a copious variety of proteins that must operate in unison to achieve homeostasis. To guide and preserve order, multifaceted molecular chaperone networks are present within each cell type. To handle the vast client diversity and regulatory demands, a wide assortment of chaperones are needed. In addition to the classic heat shock proteins, cochaperones with inherent chaperoning abilities (e.g., p23, Hsp40, Cdc37, etc.) are likely used to complete a system. In this review, we focus on the HSP90-associated cochaperones and provide evidence supporting a model in which select cochaperones are used to differentially modulate target proteins, contribute to combinatorial client regulation, and increase the overall reach of a cellular molecular chaperone network. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Cochaperones function in conjunction with and sovereign to focal chaperones (e.g., Hsp90). ► Cochaperones extend the cellular molecular chaperone system. ► The cochaperone-expanded chaperone network is necessary to achieve homeostasis.
Keywords: Hsp90; p23; Cdc37; Large immunophilin; Cochaperone; Molecular chaperone;
The role of Hsp90 in protein complex assembly by Taras Makhnevych; Walid A. Houry (674-682).
Hsp90 is a ubiquitous and essential molecular chaperone that plays central roles in many signaling and other cellular pathways. The in vivo and in vitro activity of Hsp90 depends on its association with a wide variety of cochaperones and cofactors, which form large multi-protein complexes involved in folding client proteins. Based on our proteomic work mapping the molecular chaperone interaction networks in yeast, especially that of Hsp90, as well as, on experiments and results presented in the published literature, one major role of Hsp90 appears to be the promotion and maintenance of proper assembly of protein complexes. To highlight this role of Hsp90, the effect of the chaperone on the assembly of the following seven complexes is discussed in this review: snoRNP, RNA polymerase II, phosphatidylinositol-3 kinase-related protein kinase (PIKK), telomere complex, kinetochore, RNA induced silencing complexes (RISC), and 26S proteasome. For some complexes, it is observed that Hsp90 mediates complex assembly by stabilizing an unstable protein subunit and facilitating its incorporation into the complex; for other complexes, Hsp90 promotes change in the composition of that complex. In all cases, Hsp90 does not appear to be part of the final assembled complex. This article is part of a Special Issue entitled:Heat Shock Protein 90 (HSP90).► Hsp90 is a ubiquitous chaperone that plays central roles in many cellular pathways. ► We propose that a major role of Hsp90 is to promote protein complex assembly. ► The effect of the chaperone on the assembly of seven complexes is discussed. ► Hsp90 can stabilize a protein subunit to facilitate complex formation. ► Hsp90 can promote change in the subunit composition of a complex.
Keywords: Hsp90; Complex assembly; snoRNP; RNA polymerase II; Phosphatidylinositol-3 kinase-related protein kinase; Telomere complex;
Quality control and fate determination of Hsp90 client proteins by Maria A. Theodoraki; Avrom J. Caplan (683-688).
Quality control processes regulate the proteome by determining whether a protein is to be folded or degraded. Hsp90 is a hub in the network of molecular chaperones that maintain this process because it promotes both folding and degradation, in addition to regulating expression of other quality control components. The significance of Hsp90's role in quality control is enhanced by the function of its clients, which include protein kinases and transcription factors, in cellular signaling. The inhibition of Hsp90 with small molecules results in the rapid degradation of such clients via the ubiquitin/proteasome pathway, and also in the induction of the Hsp70 molecular chaperone. These two events result in markedly different outcomes depending on cell type. For tumor cells there is a profound loss of signaling in growth promoting pathways. By contrast, increased amounts of Hsp70 in neuronal cells ameliorate the toxicity that is associated with the formation of aggregates observed in neurodegenerative conditions. In this review we discuss the mechanisms underlying these differential effects of Hsp90 inhibition on the quality control of distinct client proteins. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Small molecule Hsp90 inhibitors promote client protein degradation via the actions of molecular chaperones. ► Hsp90 can promote degradation as well as protect against degradation of misfolded proteins. ► Several ubiquitin ligases in the degradation of Hsp90 client proteins including CHIP, Ubr1 and Cul5. ► Inhibition of Hsp90 can protect against neurodegeneration.
Keywords: Molecular chaperone; Ubiquitin/proteasome pathway; Quality control; Hsp90;
The HSP90 complex of plants by Yasuhiro Kadota; Ken Shirasu (689-697).
Heat shock protein 90 (HSP90) is a highly conserved and essential molecular chaperone involved in maturation and activation of signaling proteins in eukaryotes. HSP90 operates as a dimer in a conformational cycle driven by ATP binding and hydrolysis. HSP90 often functions together with co-chaperones that regulate the conformational cycle and/or load a substrate “client” protein onto HSP90. In plants, immune sensing NLR (nucleotide-binding domain and leucine-rich repeat containing) proteins are among the few known client proteins of HSP90. In the process of chaperoning NLR proteins, co-chaperones, RAR1 and SGT1 function together with HSP90. Recent structural and functional analyses indicate that RAR1 dynamically controls conformational changes of the HSP90 dimer, allowing SGT1 to bridge the interaction between NLR proteins and HSP90. Here, we discuss the regulation of NLR proteins by HSP90 upon interaction with RAR1 and SGT1, emphasizing the recent progress in our understanding of the structure and function of the complex. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► HSP90 is a highly conserved molecular chaperone involved in maturation and activation of signaling proteins in eukaryotes. ► In plants and animals, immune sensing NLR proteins are client proteins of HSP90. ► In the process of chaperoning NLR proteins, co-chaperons, RAR1 and SGT1 function together with HSP90. ► The structure and function of HSP90–SGT1–RAR1 complex are reviewed.
Keywords: HSP90; Molecular chaperone; Disease resistance; NLR protein; Protein structure; Innate immunity;
Broad action of Hsp90 as a host chaperone required for viral replication by Ron Geller; Shuhei Taguwa; Judith Frydman (698-706).
Viruses are intracellular pathogens responsible for a vast number of human diseases. Due to their small genome size, viruses rely primarily on the biosynthetic apparatus of the host for their replication. Recent work has shown that the molecular chaperone Hsp90 is nearly universally required for viral protein homeostasis. As observed for many endogenous cellular proteins, numerous different viral proteins have been shown to require Hsp90 for their folding, assembly, and maturation. Importantly, the unique characteristics of viral replication cause viruses to be hypersensitive to Hsp90 inhibition, thus providing a novel therapeutic avenue for the development of broad-spectrum antiviral drugs. The major developments in this emerging field are hereby discussed. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Viruses are intracellular pathogens responsible for a vast number of human diseases. ► The molecular chaperone Hsp90 is nearly universally required for viral protein replication. ► The unique characteristics of viral replication cause viruses to be hypersensitive to pharmacological inhibitors of Hsp90. ► The ubiquitous requirement for Hsp90 provides a novel therapeutic avenue for development of broad-spectrum antiviral drugs.
Keywords: Hsp90; Antiviral; Chaperone; Drug resistance; Hsp90 inhibitor; Virus, protein folding;
Heat shock protein 90 from neglected protozoan parasites by Nainita Roy; Rishi Kumar Nageshan; Shatakshi Ranade; Utpal Tatu (707-711).
Significant advances have been made in our understanding of heat shock protein 90 (Hsp90) in terms of its structure, biochemical characteristics, post-translational modifications, interactomes, regulation and functions. In addition to yeast as a model several new systems have now been examined including flies, worms, plants as well as mammalian cells. This review discusses themes emerging out of studies reported on Hsp90 from infectious disease causing protozoa. A common theme of sensing and responding to host cell microenvironment emerges out of analysis of Hsp90 in Malaria, Trypanosmiasis as well as Leishmaniasis. In addition to their functional roles, the potential of Hsp90 from these infectious disease causing organisms to serve as drug targets and the current status of this drug development endeavor are discussed. Finally, a unique and the only known example of a split Hsp90 gene from another disease causing protozoan Giardia lamblia and its evolutionary significance are discussed. Clearly studies on Hsp90 from protozoan parasites promise to reveal important new paradigms in Hsp90 biology while exploring its potential as an anti-infective drug target. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► Hsp90 is critically important for the growth of protozoan parasites in their hosts. ► Hsp90 of protozoan parasites senses and responds to environmental cues available in their hosts. ► Inhibition of Hsp90 abrogates growth of protozoan parasites in their hosts. ► Hsp90 from Giardia lamblia is organized as a split gene that undergoes trans-splicing.
Keywords: Hsp90; Chaperone; Protozoan; Plasmodium; Giardia; Trans-splicing;
Hsp90 in non-mammalian metazoan model systems by Veronika Haslbeck; Christoph J.O. Kaiser; Klaus Richter (712-721).
The molecular chaperone Hsp90 has been discovered in the heat-shock response of the fruit fly more than 30 years ago. Today, it is becoming clear that Hsp90 is in the middle of a regulatory system, participating in the modulation of many essential client proteins and signaling pathways. Exerting these activities, Hsp90 works together with about a dozen of cochaperones.Due to their organismal simplicity and the possibility to influence their genetics on a large scale, many studies have addressed the function of Hsp90 in several multicellular model systems. Defined pathways involving Hsp90 client proteins have been identified in the metazoan model systems of Caenorhabditis elegans, Drosophila melanogaster and the zebrafish Danio rerio. Here, we summarize the functions of Hsp90 during muscle maintenance, development of phenotypic traits and the involvement of Hsp90 in stress responses, all of which were largely uncovered using the model organisms covered in this review. These findings highlight the many specific and general actions of the Hsp90 chaperone machinery. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► The first comprehensive summary of Hsp90 literature in non-mammalian metazoan organisms. ► A cross-comparison between different species. ► The beautiful analogy of pathways, which are supported by Hsp90 activity in the three model organisms. ► A summary of the ideas about the origin of phenotypic variability, which was observed as a result of compromised Hsp90 activity. ► An overview of the cochaperone network and its interaction with Hsp90 during the performance of cellular functions.
Keywords: Caenorhabditis elegans; Drosophila melanogaster; Danio rerio; Cochaperone; Client; Hsp90;
Chaperoning steroidal physiology: Lessons from mouse genetic models of Hsp90 and its cochaperones by Edwin R. Sanchez (722-729).
The molecular chaperone Hsp90 is abundant, ubiquitous, and catholic to biological processes in eukaryotes, controlling phosphorylation cascades, protein stability and turnover, client localization and trafficking, and ligand–receptor interactions. Not surprisingly, Hsp90 does not accomplish these activities alone. Instead, an ever-growing number of cochaperones have been identified, leading to an explosion of reports on their molecular and cellular effects on Hsp90 chaperoning of client substrates. Notable among these clients are many members of the steroid receptor family, such as glucocorticoid, androgen, estrogen and progesterone receptors. Cochaperones typically associated with the mature, hormone-competent states of these receptors include p23, the FK506-binding protein 52 (FKBP52), FKBP51, protein phosphatase 5 (PP5) and cyclophilin 40 (Cyp40). The ultimate relevance of these cochaperones to steroid receptor action depends on their physiological effects. In recent years, the first mouse genetic models of these cochaperones have been developed. This work will review the complex and intriguing phenotypes so far obtained in genetically-altered mice and compare them to the known molecular and cellular impacts of cochaperones on steroid receptors. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► The roles of Hsp90 and select cochaperones in steroidal physiology are reviewed. ► Mouse genetic models of Hsp90, p23, FKBP51, FKBP52 and PP5 are described in detail. ► Effects on glucocorticoid, androgen, and progesterone physiology have been found.
Keywords: Hsp90; FKBP52; FKBP51; Protein phosphatase 5; p23; Steroids;
Secreted heat shock protein-90 (Hsp90) in wound healing and cancer by Wei Li; Divya Sahu; Fred Tsen (730-741).
Extracellular Hsp90 proteins, including “membrane-bound”, “released” and “secreted”, were first reported more than two decades ago. Only studies of the past 7 years have begun to reveal a picture for when, how and why Hsp90 gets exported by both normal and tumor cells. Normal cells secrete Hsp90 in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90 for tissue invasion. In either case, sufficient supply of the extracellular Hsp90 can be guaranteed by its unusually abundant storage inside the cells. A well-characterized function of secreted Hsp90α is to promote cell motility, a crucial event for both wound healing and cancer. The reported targets for extracellular Hsp90α include MMP2, LRP-1, tyrosine kinase receptors and possibly more. The pro-motility activity of secreted Hsp90α resides within a fragment, called 'F-5', at the boundary between linker region and middle domain. Inhibition of its secretion, neutralization of its extracellular action or interruption of its signaling through LRP-1 block wound healing and tumor invasion in vitro and in vivo. In normal tissue, topical application of F-5 promotes acute and diabetic wound healing far more effectively than US FDA-approved conventional growth factor therapy in mice. In cancer, drugs that selectively target the F-5 region of secreted Hsp90 by cancer cells may be more effective and less toxic than those that target the ATPase of the intracellular Hsp90. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).►Normal cells secrete Hsp90 only under a stress, whereas tumor cells secrete Hsp90 always. ►Secreted Hsp90α is an unconventional pro-motility factor, independent of ATPase. ►Secreted Hsp90α, but not conventional growth factors, works against TGFβ inhibition. ► Topical application of Hsp90α protein promotes acute and chronic wound healing. ► Drugs that selectively target F-5 region of Hsp90 may be more effective and less toxic than those targeting the ATPase.
Keywords: Secreted Hsp90; Wound healing; Cancer;
Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers by Komal Jhaveri; Tony Taldone; Shanu Modi; Gabriela Chiosis (742-755).
Hsp90 is an ATP dependent molecular chaperone protein which integrates multiple oncogenic pathways. As such, Hsp90 inhibition is a promising anti-cancer strategy. Several inhibitors that act on Hsp90 by binding to its N-terminal ATP pocket have entered clinical evaluation. Robust pre-clinical data suggested anti-tumor activity in multiple cancer types. Clinically, encouraging results have been demonstrated in melanoma, acute myeloid leukemia, castrate refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma. In breast cancer, proof-of-concept was demonstrated by first generation Hsp90 inhibitors in combination with trastuzumab mainly in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer. There are a multitude of second generation Hsp90 inhibitors currently under investigation. To date, however, there is no FDA approved Hsp90 inhibitor nor standardized assay to ascertain Hsp90 inhibition. This review summarizes the current status of both first and second generation Hsp90 inhibitors based on their chemical classification and stage of clinical development. It also discusses the pharmacodynamic assays currently implemented in clinic as well as other novel strategies aimed at enhancing the effectiveness of Hsp90 inhibitors. Ultimately, these efforts will aid in maximizing the full potential of this class of agents. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► We summarize the current status of Hsp90 inhibitors based on their chemical classification. ► We present the current stage of clinical development for Hsp90 inhibitors in cancers. ► We discuss the assays and biomarkers currently implemented in clinic for Hsp90 inhibitors. ► We present strategies aimed at enhancing the clinical effectiveness of Hsp90 inhibitors in cancer.
Keywords: Heat shock protein 90; Chaperone; Cancer; Targeted therapy;
HSP90 as a platform for the assembly of more effective cancer chemotherapy by Luke Whitesell; Nancy U. Lin (756-766).
Since initial discovery of the first HSP90 inhibitor over a decade and a half ago, tremendous progress has been made in developing potent and selective compounds with which to target this chaperone in the treatment of cancers. These compounds have been invaluable in dissecting how HSP90 supports the dramatic alterations in cellular physiology that constitute the malignant phenotype and give rise to the clinical manifestations of diverse cancers. Unfortunately, single agent activity for HSP90 inhibitors has been disappointingly modest against recurrent, refractory cancers in most of the clinical trials that have been reported to date. This problem could be due to pharmacological limitations of the first-generation inhibitors that have been most extensively studied. But we suggest it may well be intrinsic to the target itself. This review will focus on how the utilization of HSP90 by cancer cells might be targeted to enhance the activity of other anticancer drugs while at the same time limiting the ability of advanced cancers to adapt and evolve drug resistance; the net result being more durable disease control. A better understanding of these fundamental issues will surely make the ongoing clinical development of HSP90 inhibitors as anticancer drugs less empiric, more efficient and hopefully more successful. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).►Inhibitors of HSP90 have been valuable probes in learning how this chaperone supports malignancy. ►Clinical activity for first generation inhibitors has been limited against advanced cancers. ►Next generation drugs with better pharmacology are more promising, but remain far from curative. ►Combining HSP90 inhibitors with other anticancer drugs could limit the evolvability of cancers. ►Hurdles arise in executing trials that combine proprietary agents, but the rewards could be great.
Keywords: Combination chemotherapy; Clinical trial; Drug resistance; Cancer evolution;
TRAP-1, the mitochondrial Hsp90 by Dario C. Altieri; Gary S. Stein; Jane B. Lian; Lucia R. Languino (767-773).
Protein folding quality control does not occur randomly in cells, but requires the action of specialized molecular chaperones compartmentalized in subcellular microenvironments and organelles. Fresh experimental evidence has now linked a mitochondrial-specific Heat Shock Protein-90 (Hsp90) homolog, Tumor Necrosis Factor Receptor-Associated Protein-1 (TRAP-1) to pleiotropic signaling circuitries of organelle integrity and cellular homeostasis. TRAP-1-directed compartmentalized protein folding is broadly exploited in cancer and neurodegenerative diseases, presenting new opportunities for therapeutic intervention in humans. This article is part of a Special Issue entitled: Heat Shock Protein 90 (Hsp90).► TRAP-1 is a mitochondrial-specific Hsp90 chaperone. ► Antagonizes mitochondrial apoptosis and oxidative stress. ► Regulates the mitochondrial permeability transition pore. ► Controls the protein folding environment in mitochondria. ► Couples to the cellular stress response and gene expression.
Keywords: Mitochondria; Apoptosis; Permeability transition pore; Chaperone; Tumor growth;
GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum by Michal Marzec; Davide Eletto; Yair Argon (774-787).
Glucose-regulated protein 94 is the HSP90-like protein in the lumen of the endoplasmic reticulum and therefore it chaperones secreted and membrane proteins. It has essential functions in development and physiology of multicellular organisms, at least in part because of this unique clientele. GRP94 shares many biochemical features with other HSP90 proteins, in particular its domain structure and ATPase activity, but also displays distinct activities, such as calcium binding, necessitated by the conditions in the endoplasmic reticulum. GRP94's mode of action varies from the general HSP90 theme in the conformational changes induced by nucleotide binding, and in its interactions with co-chaperones, which are very different from known cytosolic co-chaperones. GRP94 is more selective than many of the ER chaperones and the basis for this selectivity remains obscure. Recent development of molecular tools and functional assays has expanded the spectrum of clients that rely on GRP94 activity, but it is still not clear how the chaperone binds them, or what aspect of folding it impacts. These mechanistic questions and the regulation of GRP94 activity by other proteins and by post-translational modification differences pose new questions and present future research avenues. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).► GRP94 is an endoplasmic reticulum resident chaperone that belongs to HSP90 family. ► GRP94 chaperones secreted and membrane proteins. ► GRP94 is essential in development and physiology of multi-cellular organisms. ► GRP94 shares biochemical features with HSP90 but displays distinct activities.
Keywords: Glucose-regulated protein 94; Endoplasmic reticulum; Protein folding; Secretory proteins pathway; ER stress response;