IP6K2 is a client for HSP90 and a target for cancer therapeutics development

Abstract

The heat shock proteins (HSPs) comprise a family of highly conserved molecular chaperones that are central to protein structure homeostasis. HSPs prevent aggregation of cellular proteins, assist in protein folding, and act as “biochemical buffers” to guard proteins against diverse types of cellular stress including heat, changes in cellular pH, and hypoxia. The major functions of the HSPs in normal cells include coordination of higher-order interactions between “client” proteins and macromolecular machines, organelles, trafficking and metabolic vesicles, and structural proteins such as microtubules and actin filaments. The HSPs, and HSP90 in particular, facilitate signal transduction and gene transcription by stabilizing interactions between client proteins, proteins and nucleic acids, and proteins and their ligands (1, 2). A unique aspect of HSP90 biochemistry is that this protein stabilizes rather than modifies its client proteins; and this, too, seems to be how it is involved in malignant transformation (3). Mutations and/or amplifications in oncogenic receptor tyrosine kinases, such as EGFR and HER2, or oncogenic signal transducers, such as RAF and SRC, frequently lead to constitutively active proteins. In the normal course of events, intact negative feedback loops result in higher levels of protein degradation, thus maintaining relatively normal levels of growth promoting signal transduction. However, tumor cells harbor extensive genetic damage and exist in physiologically stressful conditions (hypoxia, pH, cytokine storm) and thus also tend to have elevated levels of activated HSP90. These higher levels of activated HSP90 can lead to stabilization of constitutively activated client proteins, in essence establishing a positive feedback loop that perpetuates growth signaling and survival in opposition to the normal regulatory pathways that induce growth arrest and programmed cell death (4, 5). In a recent issue of PNAS, Chakraborty et al. (6) extend the purview of HSP90-dependent tumor promoting activity by demonstrating that it acts as …