Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 48

Fig. 2.3 Model of glucocorticoid receptor activation. In the absence of hormone (H), the GR
exists in the cytoplasm associated with the Hsp90-based heterocomplex formed by a dimer of
Hsp90, and one molecule of Hsp70, p23 and FKBP51. Upon steroid binding, FKBP51 is replaced
by FKBP52, an immunophilin able to recruit the dynein/dynactin motor complex. The whole GR
heterocomplex is retrotransported on microtubules tracks and translocates through the nuclear
pore complex (NPC) to the nucleoplasm still associated to the heterocomplex. Transformation
(i.e., Hsp90-complex dissociation) occurs in the nuclear compartment followed by receptor dimer-
ization. The receptor is targeted to the promoter binding-sites to trigger the proper biological
response and the heterocomplex is recycled
does not reach the nucleus because it is targeted to proteosomal degradation along
its pathway (Galigniana et al. 2004a ).
On the other hand, FKBP51, the highly homologous partner that shows low af-
finity for dynein motors (Wochnik et al. 2005 ; Galigniana et al. 2010b ), acts as a
competitive inhibitor of FKBP52. Therefore, it is not surprising that upon ligand
binding FKBP51 is released from steroid receptor complexes and replaced by
FKBP52 (Davies et al. 2002 ), which in turn recruits the dynein/dynactin motor
complex (Fig. 2.3 ). In line with this fact, it has been proposed that the FKBP52/
FKBP51 expression ratio may be one of the key regulatory factors for the nuclear
retention of steroid receptors (Galigniana et al. 2010b ; Tatro et al. 2009 ; Gallo et al.
2007 ).
It is possible that other TPR-domain immunophilins that are also able to interact
with dynein, such as CyP40 and PP5, may replace FKBP52 in the transport machin-
ery, although this has not been demonstrated. Nonetheless, recent evidence showed