HSP90 chaperone cycle for steroid hormone receptors (SHR)

Stable Identifier
R-HSA-3371497
Type
Pathway
Species
Homo sapiens
Compartment
Synonyms
HSP90 chaperone cycle for SHRs
Locations in the PathwayBrowser
Summation

Steroid hormone receptors (SHR) are transcription factors that become activated upon sensing steroid hormones such as glucocorticoids, mineralocorticoids, progesterone, androgens, or estrogen (Escriva et al 2000; Griekspoor A et al. 2007; Eick GN & Thornton JW. 2011). Depending on SHR type and the presence of ligand, they show different subcellular localizations. Whereas both unliganded and liganded estrogen receptors (ERalpha and ERbeta) are predominantly nuclear, unliganded glucocorticoid (GR) and androgen receptors (AR) are mostly located in the cytoplasm and completely translocate to the nucleus only after binding hormone (Htun H et al. 1999; Stenoien D et al. 2000; Tyagi RK et al. 2000; Cadepond F et al. 1992; Jewell CM et al. 1995; Kumar S et al. 2006). The unliganded mineralocorticoid receptor (MR) is partially cytoplasmic but can be found in nucleus in the ligand-bound or ligand-free form (Nishi M & Kawata M 2007). The progesterone receptor (PR) exists in two forms (PRA and PRB) with different ratios of nuclear versus cytoplasmic localization of the unliganded receptor. In most cell contexts, the PRA isoform is a repressor of the shorter PRB isoform, and without hormone induction it is mostly located in the nucleus, whereas PRB distributes both in the nucleus and in the cytoplasm (Lim CS et al. 1999; Griekspoor A et al. 2007). In the absence of ligand, members of the steroid receptor family remain sequestered in the cytoplasm and/or nucleus in the complex with proteins of HSP70/HSP90 chaperone machinery (Pratt WB & Dittmar KD1998). The highly dynamic ATP-dependent interactions of SHRs with HSP90 complexes regulate SHR cellular location, protein stability, competency to bind steroid hormones and transcriptional activity (Echeverria PC & Picard D 2010). Understanding the mechanism of ATPase activity of HSP90 is mostly based on structural and functional studies of the Saccharomyces cerevisiae Hsp90 complexes (Meyer P et al. 2003, 2004; Ali MM et al. 2006; Prodromou C et al. 2000; Prodromou C 2012). The ATPase cycle of human HSP90 is less well understood, however several studies suggest that the underlying enzymatic mechanisms and a set of conformational changes that accompany the ATPase cycle are highly similar in both species (Richter K et al. 2008; Vaughan CK et al. 2009). Nascent SHR proteins are chaperoned by HSP70 and HSP40 to HSP90 cycle via STIP1 (HOP) (and its TPR domains) (Hernández MP et al. 2002a,b; EcheverriaPC & Picard D 2010; Li J et al. 2011). The ATP-bound form of HSP90 leads to the displacement of STIP1 by immunophilins FKBP5 or FKBP4 resulting in conformational changes that allow efficient hormone binding (Li J et al. 2011). PTGES3 (p23) binds to HSP90 complex finally stabilizing it in the conformation with a high hormone binding affinity. After hydrolysis of ATP the hormone bound SHR is released from HSP90 complex. The cytosolic hormone-bound SHR can be transported to the nucleus by several import pathways such as the dynein-based nuclear transport along microtubules involving the transport of the entire HSP90 complex or nuclear localization signals (NLS)-mediated nuclear targeting by importins (Tyagi RK et al. 2000; Cadepond F et al. 1992; Jewell CM et al. 1995; Kumar S et al. 2006). It is worth noting that GR-importin interactions can be ligand-dependent or independent (Freedman & Yamamoto 2004; Picard & Yamamoto 1987). In the nucleus ligand-activated SHR dimerizes, binds specific sequences in the DNA, called Hormone Responsive Elements (HRE), and recruits a number of coregulators that facilitate gene transcription. Nuclear localization is essential for SHRs to transactivate their target genes, but the same receptors also possess non-genomic functions in the cytoplasm.

The Reactome module describes the ATPase-driven conformational cycle of HSP90 that regulates ligand-dependent activation of SHRs.

Literature References
PubMed ID Title Journal Year
23806880 Structure, function and regulation of the hsp90 machinery

Li, J, Buchner, J

Biomed J 2013
22955504 Hsp90: structure and function

Jackson, SE

Top Curr Chem 2013
20006655 Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility

Echeverria, PC, Picard, D

Biochim. Biophys. Acta 2010
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