SGTA: A New Player in the Molecular Co-Chaperone Game

Abstract

Small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) is a steroid receptor molecular co-chaperone that may substantially influence hormone action and, consequently, hormone-mediated carcinogenesis. To date, published studies describe SGTA as a protein that is potentially critical in a range of biological processes, including viral infection, cell division, mitosis, and cell cycle checkpoint activation. SGTA interacts with the molecular chaperones, heat shock protein 70 (HSP70) and HSP90, and with steroid receptor complexes, including those containing the androgen receptor. Steroid receptors are critical for maintaining cell growth and differentiation in hormonally regulated tissues, such as male and female reproductive tissues, and also play a role in disease states involving these tissues. There is growing evidence that, through its interactions with chaperones and steroid receptors, SGTA may be a key player in the pathogenesis of hormonally influenced disease states, including prostate cancer and polycystic ovary syndrome. Research into the function of SGTA has been conducted in several model organisms and cell types, with these studies showing that SGTA functionality is cell-specific and tissue-specific. However, very few studies have been replicated in multiple cell types or experimental systems. Although a broad range of functions have been attributed to SGTA, there is a serious lack of mechanistic information to describe how SGTA acts. In this review, published evidence linking SGTA with hormonally regulated disease states is summarized and discussed, highlighting the need for future research to more clearly define the biological function(s) of this potentially important co-chaperone.

Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation

“…Upon androgen binding, SGTA is exchanged by another TPR containing protein such as the 52 kDa FK506 binding protein (FKBP52), an essential step for AR nuclear shuttling (17, 27, 28). It has been previously shown that the N-terminal region of SGTA (residues 21–40) is important for interaction with the AR hinge region (residues 630–645) (17, 29).…”

“…Since the BF3 pocket is considered a co-chaperone binding site and is at the boundary with the hinge region, we suspected that a similar motif could exist in the SGTA protein, a co-chaperone that interacts with the AR hinge and plays a role in receptor cytoplasmic regulation (28, 29). Indeed, analysis of the SGTA protein sequence has identified a P A RT P P motif (residues 78–83) that had the potential to be recognized by the BF3 site.…”

The Cochaperone SGTA (Small Glutamine-rich Tetratricopeptide Repeat-containing Protein Alpha) Demonstrates Regulatory Specificity for the Androgen, Glucocorticoid, and Progesterone Receptors

“…6). Philp et al (42) proposed that SGTA may have a more predominant role in early receptor folding events mediated by Hsp70. Buchanan et al (16) demonstrated that SGTA overexpression inhibits hormone-induced translocation of the androgen receptor to the nucleus and propose a model in which SGTA acts to retain the receptor in the cytoplasm.…”

Alternative Approaches to Hsp90 Modulation for the Treatment of Cancer

“…Small glutamine-rich tetratricopeptide repeat-containing protein-α (SGTA) is linked to several cellular processes including cell division, mitosis, cell cycle checkpoint activation, and viral infection. SGTA interacts directly with Hsp70 and may interact with Hsp90 via its TPR domain to facilitate maturation of the growth hormone and androgen receptors [42]. It has also been proposed that SGTA participates in the sequestration of client proteins in an inactive state.…”