RESUMO
Posttranslational modifications (PTMs) regulate myriad cellular processes by modulating protein function and protein-protein interaction. Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone whose activity is responsible for the stabilization and maturation of more than 300 client proteins. Hsp90 is a substrate for numerous PTMs, which have diverse effects on Hsp90 function. Interestingly, many Hsp90 clients are enzymes that catalyze PTM, demonstrating one of the several modes of regulation of Hsp90 activity. Approximately 25 co-chaperone regulatory proteins of Hsp90 impact structural rearrangements, ATP hydrolysis, and client interaction, representing a second layer of influence on Hsp90 activity. A growing body of literature has also established that PTM of these co-chaperones fine-tune their activity toward Hsp90; however, many of the identified PTMs remain uncharacterized. Given the critical role of Hsp90 in supporting signaling in cancer, clinical evaluation of Hsp90 inhibitors is an area of great interest. Interestingly, differential PTM and co-chaperone interaction have been shown to impact Hsp90 binding to its inhibitors. Therefore, understanding these layers of Hsp90 regulation will provide a more complete understanding of the chaperone code, facilitating the development of new biomarkers and combination therapies.
Assuntos
Proteínas de Choque Térmico HSP90 , Neoplasias , Humanos , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/metabolismo , Processamento de Proteína Pós-Traducional , Neoplasias/tratamento farmacológico , Trifosfato de Adenosina/metabolismoRESUMO
The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone heat shock protein 90 (Hsp90). Hsp90's function is coupled to ATP binding and hydrolysis and requires a series of conformational changes that are regulated by cochaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least-understood Hsp90 PTMs. Here, we show that asymmetric SUMOylation of a conserved lysine residue in the N domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the adenosine triphosphatase (ATPase)-activating cochaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N domain SUMOylation, and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.
Assuntos
Trifosfato de Adenosina/metabolismo , Chaperoninas/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/fisiologia , Humanos , Estrutura Terciária de Proteína , SumoilaçãoRESUMO
The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients-including Tsc2-thereby preventing their ubiquitination and proteasomal degradation.
Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Células HEK293 , Proteínas de Choque Térmico HSP90/genética , Humanos , Fosforilação , Fosfotransferases/metabolismo , Complexo de Endopeptidases do Proteassoma , Dobramento de Proteína , Proteólise , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , UbiquitinaçãoRESUMO
Protein folding quality control in cells requires the activity of a class of proteins known as molecular chaperones. Heat shock protein-90 (Hsp90), a multidomain ATP driven molecular machine, is a prime representative of this family of proteins. Interactions between Hsp90, its co-chaperones, and client proteins have been shown to be important in facilitating the correct folding and activation of clients. Hsp90 levels and functions are elevated in tumor cells. Here, we computationally predict the regions on the native structures of clients c-Abl, c-Src, Cdk4, B-Raf and Glucocorticoid Receptor, that have the highest probability of undergoing local unfolding, despite being ordered in their native structures. Such regions represent potential ideal interaction points with the Hsp90-system. We synthesize mimics spanning these regions and confirm their interaction with partners of the Hsp90 complex (Hsp90, Cdc37 and Aha1) by Nuclear Magnetic Resonance (NMR). Designed mimics selectively disrupt the association of their respective clients with the Hsp90 machinery, leaving unrelated clients unperturbed and causing apoptosis in cancer cells. Overall, selective targeting of Hsp90 protein-protein interactions is achieved without causing indiscriminate degradation of all clients, setting the stage for the development of therapeutics based on specific chaperone:client perturbation.
Assuntos
Carcinógenos/química , Proteínas de Ciclo Celular/química , Chaperoninas/química , Proteínas de Choque Térmico HSP90/química , Chaperonas Moleculares/química , Carcinógenos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Dobramento de ProteínaRESUMO
The serine/threonine phosphatase protein phosphatase 5 (PP5) regulates hormone- and stress-induced cellular signaling by association with the molecular chaperone heat shock protein 90 (Hsp90). PP5-mediated dephosphorylation of the cochaperone Cdc37 is essential for activation of Hsp90-dependent kinases. However, the details of this mechanism remain unknown. We determined the crystal structure of a Cdc37 phosphomimetic peptide bound to the catalytic domain of PP5. The structure reveals PP5 utilization of conserved elements of phosphoprotein phosphatase (PPP) structure to bind substrate and provides a template for many PPP-substrate interactions. Our data show that, despite a highly conserved structure, elements of substrate specificity are determined within the phosphatase catalytic domain itself. Structure-based mutations in vivo reveal that PP5-mediated dephosphorylation is required for kinase and steroid hormone receptor release from the chaperone complex. Finally, our data show that hyper- or hypoactivity of PP5 mutants increases Hsp90 binding to its inhibitor, suggesting a mechanism to enhance the efficacy of Hsp90 inhibitors by regulation of PP5 activity in tumors.
Assuntos
Proteínas Nucleares/química , Fosfoproteínas Fosfatases/química , Domínio Catalítico , Proteínas de Ciclo Celular/química , Chaperoninas/química , Cristalização , Proteínas de Choque Térmico HSP90/fisiologia , Proteínas Nucleares/fisiologia , Fosfoproteínas Fosfatases/fisiologia , Fosforilação , Especificidade por SubstratoRESUMO
Saccharomyces WEE1 (Swe1), the only "true" tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1(Wee1) phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90alpha) in the N domain of Hsp90. Phosphorylation is cell-cycle associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Nonphosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific posttranslational modification of a unique subcellular pool of the chaperone, and they provide a strategy to increase the cellular potency of Hsp90 inhibitors.
Assuntos
Proteínas de Ciclo Celular/fisiologia , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas Tirosina Quinases/fisiologia , Proteínas de Saccharomyces cerevisiae/fisiologia , Tirosina/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Dimerização , Proteínas de Choque Térmico HSP90/fisiologia , Humanos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Interferência de RNA , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/genética , UbiquitinaçãoRESUMO
The biology of Kaposi sarcoma is poorly understood because the dominant cell type in Kaposi sarcoma lesions is not known. We show by gene expression microarrays that neoplastic cells of Kaposi sarcoma are closely related to lymphatic endothelial cells (LECs) and that Kaposi sarcoma herpesvirus (KSHV) infects both LECs and blood vascular endothelial cells (BECs) in vitro. The gene expression microarray profiles of infected LECs and BECs show that KSHV induces transcriptional reprogramming of both cell types. The lymphangiogenic molecules VEGF-D and angiopoietin-2 were elevated in the plasma of individuals with acquired immune deficiency syndrome and Kaposi sarcoma. These data show that the gene expression profile of Kaposi sarcoma resembles that of LECs, that KSHV induces a transcriptional drift in both LECs and BECs and that lymphangiogenic molecules are involved in the pathogenesis of Kaposi sarcoma.
Assuntos
Endotélio/patologia , Perfilação da Expressão Gênica , Herpesvirus Humano 8/fisiologia , Vasos Linfáticos/patologia , Linhagem Celular , Endotélio/metabolismo , Endotélio/virologia , Humanos , Vasos Linfáticos/metabolismo , Vasos Linfáticos/virologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Secreted, or extracellular, heat shock protein 90 (eHsp90) is considered a recent discovery in eukaryotes. Over the last two decades, studies have provided significant supporting evidence that implicates eHsp90 both in normal cellular processes such as wound healing and in the development of human pathologies and diseases including fibrosis and cancer. In the early 2000s, Eustace et al. demonstrated that eHsp90 promotes the invasion of breast cancer cells by binding to and regulating the activity of an extracellular matrix (ECM) remodeling enzyme, the matrix metalloproteinase 2 or MMP2. Interestingly, inside mammalian cells, Hsp90 is an essential chaperone that interacts with hundreds of newly synthesized proteins, known as "clients," that require Hsp90's assistance to perform their function. Several methods are routinely used to characterize the role and impact of Hsp90 on a client protein's functionality in vitro and in vivo. However, the mechanistic role of eHsp90 is less well-defined since, so far, only a handful of extracellular client proteins have been identified. Here, we describe methods to characterize the impact of the secreted chaperone on MMP2 activity, the most characterized extracellular client of eHsp90. The procedures described here can be applied and adapted to characterize other extracellular clients, particularly members of the MMP family.
Assuntos
Metaloproteinase 2 da Matriz , Neoplasias , Animais , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Chaperonas Moleculares , Proteínas de Choque Térmico HSP90/metabolismo , Matriz Extracelular/metabolismo , Mamíferos/metabolismoRESUMO
The hormone-like protein irisin is involved in browning of adipose tissue and regulation of metabolism. Recently, Mu et al. identified the extracellular chaperone heat shock protein-90 (Hsp90) as the activating factor for "opening" αVß5 integrin receptor, allowing for high-affinity irisin binding and effective signal transduction.
Assuntos
Fibronectinas , Integrinas , Fibronectinas/metabolismo , Transdução de Sinais , Tecido Adiposo/metabolismo , Proteínas de Choque Térmico HSP90/metabolismoRESUMO
Cellular Src tyrosine kinase (c-Src) exists in the secretomes of several human cancers (extracellular, e-Src). Phosphoproteomics has demonstrated the existence of 114 potential extracellular e-Src substrates in addition to Tissue Inhibitor of Metalloproteinases 2. Here, we present a protocol to characterize secreted tyrosine-phosphorylated substrates as a result of c-Src expression and secretion. We describe steps for collecting cell secretomes and extracts, performing antibody treatment and Ni-NTA pull-down, and detecting protein-protein interaction and substrate Y-phosphorylation. This protocol is adaptable for studies examining the function of other extracellular kinases. For complete details on the use and execution of this protocol, please refer to Backe et al. (2023)1 and Sánchez-Pozo et al. (2018).2.
Assuntos
Proteínas Tirosina Quinases , Quinases da Família src , Humanos , Quinases da Família src/metabolismo , Fosforilação , Proteína Tirosina Quinase CSK/metabolismo , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Tirosina/metabolismoRESUMO
c-Src tyrosine kinase is a renowned key intracellular signaling molecule and a potential target for cancer therapy. Secreted c-Src is a recent observation, but how it contributes to extracellular phosphorylation remains elusive. Using a series of domain deletion mutants, we show that the N-proximal region of c-Src is essential for its secretion. The tissue inhibitor of metalloproteinases 2 (TIMP2) is an extracellular substrate of c-Src. Limited proteolysis-coupled mass spectrometry and mutagenesis studies verify that the Src homology 3 (SH3) domain of c-Src and the P31VHP34 motif of TIMP2 are critical for their interaction. Comparative phosphoproteomic analyses identify an enrichment of PxxP motifs in phosY-containing secretomes from c-Src-expressing cells with cancer-promoting roles. Inhibition of extracellular c-Src using custom SH3-targeting antibodies disrupt kinase-substrate complexes and inhibit cancer cell proliferation. These findings point toward an intricate role for c-Src in generating phosphosecretomes, which will likely influence cell-cell communication, particularly in c-Src-overexpressing cancers.
Assuntos
Proteínas Tirosina Quinases , Secretoma , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Fosfotransferases , Fosforilação , Domínios de Homologia de src , Comunicação Celular , Quinases da Família srcRESUMO
Cellular homeostasis relies on both the chaperoning of proteins and the intracellular degradation system that delivers cytoplasmic constituents to the lysosome, a process known as autophagy. The crosstalk between these processes and their underlying regulatory mechanisms is poorly understood. Here, we show that the molecular chaperone heat shock protein 90 (Hsp90) forms a complex with the autophagy-initiating kinase Atg1 (yeast)/Ulk1 (mammalian), which suppresses its kinase activity. Conversely, environmental cues lead to Atg1/Ulk1-mediated phosphorylation of a conserved serine in the amino domain of Hsp90, inhibiting its ATPase activity and altering the chaperone dynamics. These events impact a conformotypic peptide adjacent to the activation and catalytic loop of Atg1/Ulk1. Finally, Atg1/Ulk1-mediated phosphorylation of Hsp90 leads to dissociation of the Hsp90:Atg1/Ulk1 complex and activation of Atg1/Ulk1, which is essential for initiation of autophagy. Our work indicates a reciprocal regulatory mechanism between the chaperone Hsp90 and the autophagy kinase Atg1/Ulk1 and consequent maintenance of cellular proteostasis.
Assuntos
Autofagia , Proteínas de Choque Térmico HSP90 , Animais , Fosforilação , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia/fisiologia , Proteínas de Choque Térmico HSP90/metabolismo , Saccharomyces cerevisiae/metabolismo , Serina/metabolismo , Mamíferos/metabolismoRESUMO
Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer.
Assuntos
Neoplasias Renais , Fosfoproteínas Fosfatases , Humanos , Proteínas Nucleares/metabolismo , Apoptose , Neoplasias Renais/tratamento farmacológicoRESUMO
The Second International Symposium on Cellular and Organismal Stress Responses took place virtually on September 8-9, 2022. This meeting was supported by the Cell Stress Society International (CSSI) and organized by Patricija Van Oosten-Hawle and Andrew Truman (University of North Carolina at Charlotte, USA) and Mehdi Mollapour (SUNY Upstate Medical University, USA). The goal of this symposium was to continue the theme from the initial meeting in 2020 by providing a platform for established researchers, new investigators, postdoctoral fellows, and students to present and exchange ideas on various topics on cellular stress and chaperones. We will summarize the highlights of the meeting here and recognize those that received recognition from the CSSI.
Assuntos
Chaperonas Moleculares , Estresse Fisiológico , Humanos , Proteínas de Choque Térmico HSP70 , Chaperonas Moleculares/fisiologia , Estresse Fisiológico/fisiologiaRESUMO
Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) belongs to a small family of endogenous proteins that inhibits a group of enzymes, the matrix metalloproteinases (MMPs). TIMP-2 inhibits endothelial cell proliferation and migration in vitro and angiogenesis in vivo, through MMP-dependent and -independent mechanisms. However, little is known regarding the contribution of these mechanisms to the antitumor effects of TIMP-2. Using a retroviral delivery system, we stably overexpressed TIMP-2 and its mutant Ala+TIMP-2 (devoid of MMP inhibitory activity) in human adenocarcinoma A549 cells. Using real time PCR, and enzyme-linked immunosorbent assay (ELISA), we confirmed enhanced TIMP-2 expression and its MMP inhibitory activity by reverse zymography. In vitro, growth assays suggested that TIMP-2 and Ala+TIMP-2 did not alter basal cell proliferation rates, however, tumor cell migration and invasion were inhibited. In vivo, both TIMP-2 and Ala+TIMP-2 A549 xenografts exhibited reduced growth rate, CD31 immunostaining indicated decreased intratumoral microvascular density, and TUNEL demonstrated enhanced tumor cell apoptosis. Immunoblotting and immunohistochemical analyses of A549 xenograft tissues with either phospho-FAK (Tyr397) or phospho-AKT (Ser473) showed decreased activation in both TIMP-2 and Ala+TIMP-2 tumor cells. We conclude that TIMP-2-mediated inhibition of tumor growth occurs, at least in part, independently of MMP inhibition, and is a consequence of both direct effects of TIMP-2 on tumor cells and modulation of the tumor microenvironment.
Assuntos
Adenocarcinoma/irrigação sanguínea , Neoplasias Pulmonares/irrigação sanguínea , Inibidores de Metaloproteinases de Matriz , Neovascularização Patológica/enzimologia , Inibidor Tecidual de Metaloproteinase-2/fisiologia , Microambiente Tumoral/fisiologia , Adenocarcinoma/enzimologia , Animais , Apoptose/fisiologia , Movimento Celular , Proliferação de Células , Feminino , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Camundongos , Camundongos Nus , Microvasos , Invasividade Neoplásica , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Cells adhere to one another and/or to matrices that surround them. Regulation of cell-cell (intercellular) and cell-matrix adhesion is tightly controlled in normal cells, however, defects in cell adhesion are common in the majority of human cancers. Multilateral communication among tumor cells with the extracellular matrix (ECM) and neighbor cells is accomplished through adhesion molecules, ECM components, proteolytic enzymes and their endogenous inhibitors. There is sufficient evidence to suggest that reduced adherence is a tumor cell property engaged during tumor progression. Tumor cells acquire the ability to change shape, detach and easily move through spaces disorganizing the normal tissue architecture. This property is due to changes in expression levels of adhesion molecules and/or due to elevated levels of secreted proteolytic enzymes, including matrix metalloproteinases (MMPs). Among other roles, MMPs degrade the ECM and, therefore, prepare the path for tumor cells to migrate, invade and spread to distant secondary areas, where they form metastasis. Tissue inhibitors of metalloproteinases or TIMPs control MMP activities and, therefore, minimize matrix degradation. Both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell progression including tumor angiogenesis. In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression.
Assuntos
Metaloproteinases da Matriz/fisiologia , Neoplasias/enzimologia , Neoplasias/patologia , Inibidores Teciduais de Metaloproteinases/fisiologia , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Progressão da Doença , Regulação para Baixo/fisiologia , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiologia , Humanos , Metaloproteinases da Matriz/metabolismo , Modelos Biológicos , Neoplasias/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Regulação para Cima/fisiologiaRESUMO
Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases.
Assuntos
Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Esclerose Tuberosa , Proteínas Supressoras de Tumor , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Chaperonas Moleculares , Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or 'clients'. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1.