13 Modulation of Steroid Receptor Signal Transduction by Heat Shock Proteins

Abstract

I. INTRODUCTION
The 90-kD heat shock protein (hsp90) associates with numerous cytosolic and nuclear proteins involved in cell signaling, including certain steroid hormone receptors (Joab et al. 1984; Catelli et al. 1985; Sanchez et al. 1985; Wilhelmsson et al. 1990), tyrosine kinases (Oppermann et al. 1981; Lindquist and Craig 1988), serine-threonine kinases (Rose et al. 1987; Matts and Hurst 1989; Miyata and Yahara 1992; Stancato et al. 1993), and actin (Koyasu et al. 1986) and tubulin (Sanchez et al. 1988); in addition, hsp90 interacts with hsp56 and hsp70 (Sanchez et al. 1990a; Perdew and Whitelaw 1991). The association of hsp90 with steroid hormone receptors has been most thoroughly studied and is the central focus of this chapter. We suggest that hsp90 may bind and alter the activity of a large class of cellular signaling proteins, thereby playing a common role in their function and regulation.

Members of the “nuclear receptor” superfamily respond to their cognate ligands, such as steroids, by binding to specific DNA sequences and altering the transcriptional activity of adjacent promoters (Yamamoto 1985; Evans 1988). Aspects of the signal transduction pathway that triggers these alterations are schematized in Figure 1. In their unliganded, inactive state, certain of these receptors are components of hetero-oligomers, which we term aporeceptor complexes. An aporeceptor complex consists minimally of a receptor monomer, an hsp90 dimer, and an hsp56 monomer (Table 1) (Rexin et al. 1991; Rehberger et al. 1992). One function of the complex is to recognize and bind the cognate ligand. Concomitant with...