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      Membrane-Associated Heat Shock Proteins in Oncology: From Basic Research to New Theranostic Targets

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          Abstract

          Heat shock proteins (HSPs) constitute a large family of conserved proteins acting as molecular chaperones that play a key role in intracellular protein homeostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSP families such as small HSPs, HSP40, HSP60, HSP70 and HSP90 have been found to be localized on the plasma membrane of malignantly transformed cells. In the current article, the role of membrane-associated molecular chaperones in normal and tumor cells is comprehensively reviewed with implications of these proteins as plausible targets for cancer therapy and diagnostics.

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          Most cited references181

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          Heat shock proteins in cancer: chaperones of tumorigenesis.

          The heat shock proteins (HSPs) induced by cell stress are expressed at high levels in a wide range of tumors and are closely associated with a poor prognosis and resistance to therapy. The increased transcription of HSPs in tumor cells is due to loss of p53 function and to higher expression of the proto-oncogenes HER2 and c-Myc, and is crucial to tumorigenesis. The HSP family members play overlapping, essential roles in tumor growth both by promoting autonomous cell proliferation and by inhibiting death pathways. The HSPs have thus become targets for rational anti-cancer drug design: HSP90 inhibitors are currently showing much promise in clinical trials, whereas the increased expression of HSPs in tumors is forming the basis of chaperone-based immunotherapy.
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            Systematic functional prioritization of protein posttranslational modifications.

            Protein function is often regulated by posttranslational modifications (PTMs), and recent advances in mass spectrometry have resulted in an exponential increase in PTM identification. However, the functional significance of the vast majority of these modifications remains unknown. To address this problem, we compiled nearly 200,000 phosphorylation, acetylation, and ubiquitination sites from 11 eukaryotic species, including 2,500 newly identified ubiquitylation sites for Saccharomyces cerevisiae. We developed methods to prioritize the functional relevance of these PTMs by predicting those that likely participate in cross-regulatory events, regulate domain activity, or mediate protein-protein interactions. PTM conservation within domain families identifies regulatory "hot spots" that overlap with functionally important regions, a concept that we experimentally validated on the HSP70 domain family. Finally, our analysis of the evolution of PTM regulation highlights potential routes for neutral drift in regulatory interactions and suggests that only a fraction of modification sites are likely to have a significant biological role. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness.

              Tumour cell invasiveness is crucial for cancer metastasis and is not yet understood. Here we describe two functional screens for proteins required for the invasion of fibrosarcoma cells that identified the molecular chaperone heat shock protein 90 (hsp90). The hsp90 alpha isoform, but not hsp90 beta, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90 alpha decreases both MMP2 activity and invasiveness. This role for extracellular hsp90 alpha in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                20 May 2020
                May 2020
                : 9
                : 5
                : 1263
                Affiliations
                [1 ]Center for Translational Cancer Research Technische Universität München (TranslaTUM), Radiation Immuno-Oncology group, Klinikum rechts der Isar, Einstein Str. 25, 81675 Munich, Germany; gabriele.multhoff@ 123456tum.de
                [2 ]Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky ave., 4, 194064 St. Petersburg, Russia
                [3 ]Pavlov First Saint Petersburg State Medical University, L. Tolstogo str. 6/8, 197022 St. Petersburg, Russia
                [4 ]Almazov National Medical Research Centre, Polenov Russian Scientific Research Institute of Neurosurgery, Mayakovskogo str. 12, 191104 St. Petersburg, Russia; wakhns@ 123456gmail.com
                [5 ]National Center for Neurosurgery, Turan Ave., 34/1, Nur-Sultan 010000, Kazakhstan
                [6 ]Far Eastern Federal University, Russky Island, 690000 Vladivostok, Russia
                [7 ]Institute of Biochemistry and Medical Chemistry, Medical School, University of Pecs, Szigeti str. 12, 7624 Pecs, Hungary; zsolt.balogi@ 123456aok.pte.hu
                [8 ]Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China; gaohuile@ 123456scu.edu.cn
                [9 ]Institute of Biochemistry, Biological Research Centre, Temesvári krt. 62, 6726 Szeged, Hungary; vigh@ 123456lipidart.com
                Author notes
                [* ]Correspondence: maxim.shevtsov@ 123456tum.de ; Tel.: +49-174-442-1888
                Author information
                https://orcid.org/0000-0002-5355-7238
                Article
                cells-09-01263
                10.3390/cells9051263
                7290778
                32443761
                d145ee46-8e65-41f0-8667-2b2ccb75ce0c
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 March 2020
                : 18 May 2020
                Categories
                Review

                heat shock proteins,hsp90,grp96,hsp70,grp78,hsp60,hsp40,hsp27,calreticulin,targeted diagnostics and therapy

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