THE ROLE OF THEhsp90-BASED CHAPERONE SYSTEM IN SIGNAL TRANSDUCTION BY NUCLEAR RECEPTORS AND RECEPTORS SIGNALING VIA MAP KINASE

Abstract

The multicomponent heat-shock protein (hsp) 90-based chaperone system is an ubiquitous protein-folding system in the cytoplasm of eukaryotes. Several signal transduction systems utilize an interaction with hsp90 as an essential component of the signaling pathway. The steroid and dioxin receptors are bound to hsp90 through their hormone-binding domains, and several of them must be bound to hsp90 in order to have a ligand-binding site. The binding of ligands to these receptors promotes their dissociation from hsp90, an event that is the first step in their signaling pathways. Several protein kinases, including the Src and Raf components of the MAP kinase system, are also bound to hsp90. Genetic studies in yeast have demonstrated that hsp90 is required for normal signaling via steroid and dioxin receptors and for the activity of Src in vivo. The hsp90-based chaperone system has been reconstituted from purified components, permitting detailed analysis of the molecular basis of the chaperone's role in signal transduction.

Oncogenic potential of Hsp72

“…Currently, we know of two levels of involvement of Hsp72 in cellular functions: as a molecular chaperone, facilitating proper folding of newly synthesized polypeptides and the refolding or degradation of abnormal and damaged proteins (Georgopoulos and Welch, 1993), and as a moderator of stress kinases activities (Gabai et al, 1997;Mosser et al, 1997a) and of signaling pathways in general (Pratt, 1997), acting, for example, through activation of JNK phosphatase (Volloch et al, ms. in preparation). Which, if any, of its known properties confers on Hsp72 its transforming ability remains to be determined.…”

The Inhibitory Action of Sodium Arsenite on Lipopolysaccharide-Induced Nitric Oxide Production in RAW 267.4 Macrophage Cells: A Role of Raf-1 in Lipopolysaccharide Signaling

“…Of particular interest are a series of recent reports implicating HSP90 and its associated proteins in signal transduction of macrophage activation (24,25). Raf-1 protein exists in native complexes with HSP90 that can be formed in vitro by reticulocyte lysate, and its catalytic domain is sufficient for HSP90 binding (29,30). Based on the fact that geldanamycin, which binds to HSP90 and leads to a block in Raf-1/HSP90 heteromeric complex assembly (31, 32), significantly inhibits LPS-induced NO production in RAW cells, the Raf-1/ HSP90 heteromeric complexes are likely to participate in iNOS induction in LPS-stimulated RAW cells.…”

Cross-talk between glucocorticoid receptor and AP-1

“…These are yet ill-understood and I will not discuss them in further detail. It has been proposed that signaling components associate with Hsp90 or Hsp70 the availability of which could depend on hormone-dependent release (see also review by Pratt, 1997). Ligand-activated nuclear receptors, shown for ERa, can associate with and modulate cytoplasmic PI3-kinase (Simoncini et al, 2000).…”