Journal ArticleDOI
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
TLDR
Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.Abstract:
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.read more
Citations
More filters
Journal ArticleDOI
The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer.
Donald L. Smith,Jaime Acquaviva,Manuel Sequeira,John-Paul Jimenez,Chaohua Zhang,Jim Sang,Richard C. Bates,David A. Proia +7 more
TL;DR: Combined ganetespib/erlotinib exposure stabilized EGFR protein levels in an inactive state and completely abrogated extracellular-signal-regulated kinase (ERK) and AKT signaling activity, indicating a potentially important complementary strategy to targeted TKI inhibition alone for inducing substantial antitumor responses and overcoming resistance.
Journal ArticleDOI
C-terminal modulators of heat shock protein of 90 kDa (HSP90): State of development and modes of action.
TL;DR: The current development state of characteristic C-terminal inhibitors is summarized, with an emphasis on their (proposed) molecular modes of action and binding sites.
Journal ArticleDOI
Exploring the Trypanosoma brucei Hsp83 Potential as a Target for Structure Guided Drug Design
Juan C. Pizarro,Tanya Hills,Guillermo Senisterra,Amy K. Wernimont,Claire J. MacKenzie,Neil R. Norcross,Michael A. J. Ferguson,Paul G. Wyatt,Ian H. Gilbert,Raymond Hui +9 more
TL;DR: The exploration of T. brucei Hsp83 – a homolog of human Hsp90 – as a drug target using multiple biophysical and biochemical techniques and the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity are reported.
Book ChapterDOI
Hsp90: A Global Regulator of the Genotype-to-Phenotype Map in Cancers.
TL;DR: An overview of Hsp90 function is provided, its relationship to genetic variation and the evolution of new traits are reviewed, and the importance of these findings for cancer biology and future efforts to drug this pathway are discussed.
Journal ArticleDOI
Expanding Proteostasis by Membrane Trafficking Networks
Darren M. Hutt,William E. Balch +1 more
TL;DR: It is suggested that the TPN builds compartments by generating a mosaic of integrated cargo-specific trafficking signatures (TRaCKS), which control the temporal and spatial features of protein-folding biology based on the Anfinsen principle that the local environment plays a critical role in managing protein structure.
References
More filters
Journal ArticleDOI
Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
Paul T C Wan,Mathew J. Garnett,S. Mark Roe,Sharlene Lee,Dan Niculescu-Duvaz,Valerie M. Good,Cancer Genome,C. Michael Jones,Christopher J. Marshall,Caroline J. Springer,David Barford,Richard Marais +11 more
TL;DR: The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
Journal ArticleDOI
HSP90 and the chaperoning of cancer.
TL;DR: Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.
Journal ArticleDOI
Hsp90 as a capacitor for morphological evolution
TL;DR: It is reported that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations.
Journal ArticleDOI
Adapting proteostasis for disease intervention.
TL;DR: The proteostasis network is described, a set of interacting activities that maintain the health of proteome and the organism that has the potential to ameliorate some of the most challenging diseases of this era.
Journal ArticleDOI
Function and regulation of cullin-RING ubiquitin ligases.
TL;DR: This review focuses on the composition, regulation and function of cullin–RING ligases, and describes how these enzymes can be characterized by a set of general principles.