ABSTRACT
Background and Biology of Hsp90 ........................................................................ 236 Posttranslational Modifications of Hsp90 .............................................................. 237
Phosphorylation................................................................................................. 237 Nitrosylation/Oxidation..................................................................................... 239 Acetylation ........................................................................................................ 239 Client-Dependent Regulation of Hsp90 PTMs: A Novel Approach to Therapy? .........................................................................240
Targeting Hsp90: Implications and Best Clinical Outcomes ................................. 241 Targeting Sensitive Clients That Are Also Tumor Drivers ................................242 Hsp90 and Proteotoxic Stress............................................................................245 Hsp90 Inhibitors and TKIs ................................................................................246
Concluding Remarks .............................................................................................. 247 References .............................................................................................................. 247
During the past decade, much has been learned about the nature and function of heat shock protein 90 (Hsp90), especially concerning its association with several molecules and pathways important in cancer. Hsp90 is an abundant (2%–5% of total cellular protein) molecular chaperone whose homeostatic functions include stabilization and modulation of a number of proteins (clients) that comprise various cell signaling nodes, and fostering cellular responses to environmental stress.1-3 The chaperone has been high jacked by and represents a nononcogene addiction of cancer cells, where its expression is further elevated above that of untransformed cells.4 Hsp90 is found in all kingdoms except Archaea.5 In humans, as in other eukaryotes, there are two Hsp90 isoforms: stress-inducible Hsp90α and constitutively expressed Hsp90β.6 These isoforms, although highly homologous, do not fully complement each other. Hsp90β knockout is embryologically lethal, while mice lacking Hsp90α are viable but sterile.7 Eukaryotes also express organelle specific Hsp90 paralogs: Glucose-regulated protein 94 (Grp94), also known as Hsp90B1, is found in the endoplasmic reticulum, where it participates in folding proteins destined for secretion.8,9 Hsp75, also known as TNF receptor-associated protein 1 (TRAP1), is a mitochondrial paralog that provides protection from proteotoxic stress and may impact mitochondrial metabolism.10,11 Hsp90 is a member of the ATPase/kinase GHKL (DNA gyrase, Hsp90, histidine kinase, MutL) superfamily-a small group of proteins that are characterized by a unique ATP binding cleft.2,12 The N-terminal domain of the chaperone contains an ATP-binding site, which is also the target for Hsp90 inhibitors now in clinical trial. The middle (M) domain has binding sites for clients and co-chaperones, and the C-terminal domain contains a dimerization motif and binding sites for other co-chaperones. Connecting the N-and M-domains are a number of charged amino acids. This unstructured region is referred to as the “charged linker” and plays an important role in Hsp90 chaperone function.13-15
