Chaperoning steroidal physiology: Lessons from mouse genetic models of Hsp90 and its cochaperones

Abstract

The molecular chaperone Hsp90 is abundant, ubiquitous, and catholic to biological processes in eukaryotes, controlling phosphorylation cascades, protein stability and turnover, client localization and trafficking, and ligand-receptor interactions. Not surprisingly, Hsp90 does not accomplish these activities alone. Instead, an ever-growing number of cochaperones have been identified, leading to an explosion of reports on their molecular and cellular effects on Hsp90 chaperoning of client substrates. Notable among these clients are many members of the steroid receptor family, such as glucocorticoid, androgen, estrogen and progesterone receptors. Cochaperones typically associated with the mature, hormone-competent states of these receptors include p23, the FK506-binding protein 52 (FKBP52), FKBP51, protein phosphatase 5 (PP5) and cyclophilin 40 (Cyp40). The ultimate relevance of these cochaperones to steroid receptor action depend on their physiological effects. In recent years, the first mouse genetic models of these cochaperones have been developed. This work will review the complex and intriguing phenotypes so far obtained in genetically-altered mice and compare them to the known molecular and cellular impacts of cochaperones on steroid receptors.

Interplay between diet-induced obesity and chronic stress in mice: potential role of FKBP51

“…Our data indicate that under basal conditions, increased expression of Fkbp5 mRNA is associated with increased weight gain and increased total caloric intake. This agrees with the 51KO mouse model, which is leaner compared with WT littermates , Sanchez 2012). When we compared the correlation coefficients between basal and stressed conditions, there was in fact no difference for Fkbp5 and caloric intake between conditions.…”

“…Interestingly, mice deficient in FKBP51 display a moderately lean phenotype under basal conditions , Sanchez 2012. In this regard, Fkbp5 is an interesting candidate gene to study in the context of stress and metabolic regulation.…”

Structural and functional basis of protein phosphatase 5 substrate specificity

“…3D), as seen in vitro. These mutations also impair PP5's ability to dephosphorylate phospho-GR-Ser211, another known target of PP5 discussed in detail later (2). These data are in agreement with our previous work, in which overexpression of PP5 in HCT116 colon cancer cells enhanced Cdc37 dephosphorylation (8).…”

“…Having established that particular residues in the catalytic cleft are necessary for Cdc37 recognition, the question arises whether these residues are able to confer specificity of phosphatase activity (i.e., does their mutation have differential effects on different substrates?). PP5 also dephosphorylates GR, another Hsp90 client, at Ser203, Ser211, and Ser226 and subsequently, controls its activity and nucleocytoplasmic translocation (2). To examine specificity, we, therefore, investigated the consequences of mutations in the PP5 catalytic cleft on its ability to dephosphorylate GR-Ser211.…”

“…Hsp90 | PP5 | Cdc37 | chaperone | phosphatase P rotein phosphatase 5 (PP5) has pleiotropic roles in cellular signaling, including DNA damage repair, proliferation of breast cancer cells, circadian cycling, response to cytotoxic stresses, Rac-dependent potassium ion channel activity, and activation of steroid hormone receptors [e.g., glucocorticoid receptor (GR) and estrogen receptor] (1,2). It is a member of the phosphoprotein phosphatase (PPP) family of serine/threonine phosphatases, which has members that share a highly conserved catalytic core and catalytic mechanism dependent on two metal ions, commonly Mn 2+ .…”