Heat-shock protein 90 (Hsp90) is a conserved ATP-dependent chaperone with diverse cellular functions. Hsp90 is ubiquitously expressed but is further induced upon cellular stress such as heat-shock or nutrient deprivation. Hsp90 is essential for the proper folding of a diverse set of proteins called clients. These client proteins consist of important signal transduction proteins including transcription factors, kinases, and steroid hormone receptors. By regulating the final folding steps of these client proteins Hsp90 plays an important role in many cellular signaling pathways. Hsp90 exists in two closely related isoforms; Hsp90A localizes to the cytosol while Hsp90B localizes to the endoplasmic reticulum. Hsp90A exists as a member of a protein complex and is associated with various co-chaperone proteins that mediate substrate recruitment. While the mechanism of protein folding is unclear an Hsp90A dimer is thought to bind to partially folded substrates and induce their folding through its ATPase activity. The binding of substrate and ATP triggers the dimerization of the two Hsp90 N-terminal nucleotide binding domains to induce substrate folding. Upon ATP hydrolysis the substrate is released allowing the protein complex to repeat the cycle. In addition to protein folding, the ATPase activity of Hsp90 acts during protein degradation by ensuring proper functioning of the proteasome. Hsp90 is often overexpressed in cancers and its role in diverse signaling pathways may offer a way to target multiple oncogenic signals with a single Hsp90 inhibitor.
Seeger-Nekpezah et al. identified a potential application for Hsp90 inhibitors to target multiple upregulated signaling proteins found in polycystic kidney disease (PKD) (1). They showed Hsp90 is also upregulated in PKD through immunohistochemistry with the Hsp90A antibody and demonstrated Hsp90 inhibition reduced the disease phenotype in a mouse model and improved kidney function. Similarly, Shelton et al. demonstrated the use of a novel Hsp90 inhibitor to halt the proliferation of human leukemic cells (2). They used the Hsp90A antibody to monitor protein levels following drug treatments. The Bird group at the University of Wisconsin used the Hsp90A antibody for immunohistochemistry and western blotting to examine Hsp90’s role in steroid synthesis in the adrenal cortex of sheep and in rhesus monkeys (3). They showed Hsp90 helps activate endothelial nitric oxide synthase which can then regulate steroid metabolism. De Nardo et al. identified interleukin-1 receptor associated kinase-1 (IRAK-1), an important component in innate immune signaling, as a substrate for Hsp90 (4). They showed an interaction between Hsp90 and IRAK-1 using the Hsp90A antibody in immunoprecipitation experiments. Additionally they showed Hsp90 inhibition leads to the degradation of IRAK-1. They then analyzed purified IRAK-1 containing complexes and used the Hsp90A antibody to show Hsp90 binds only to inactive IRAK-1, further demonstrating Hsp90’s role as a chaperone for IRAK-1.
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