Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 51

The physiological relevance of Xap2 interactions with AhR complexes has
not been examined in a whole animal model, but Xap2 could potentially influ-
ence any of several physiological and pathological pathways mediated by AhR.
Mice that are homozygous for a disrupted AhR gene have many physiological
and developmental defects; among these are immune system impairment, hepatic
fibrosis, cardiac hypertrophy, impaired insulin regulation, and defects in ovarian
and vascular development (Fernandez-Salguero et al. 1995 ; Lahvis et al. 2005 ;
Thackaberry et al. 2003 ; Benedict et al. 2000 ). In addition, many of the toxic
and teratogenic effects produced by AhR ligands require an intact AhR signaling
pathway (Mimura and Fujii-Kuriyama 2003 ; Fernandez-Salguero et al. 1996 ).
For example, dioxin induced defects in prostate development are absent in AhR
knockout mice (Lin et al. 2002 ). In a conditional Xap2 hepatic knockout mouse
model, AhR and Cyp1b1 levels were significantly reduced, however Cyp1a1 and
Cyp1a2 were induced to levels seen in wild type mice in response to dioxin chal-
lenge (Nukaya et al. 2010 ). Development of a mouse strain lacking Xap2 would
aid in determining the role Xap2 plays in these processes and might validate
Xap2 as a potential target for therapeutic intervention. In addition to the above
functional interactions, Xap2 has several other interacting partners including, but
not limited to, PDE4A5 and 2A3, HSC70, TIF-2, TRʲ1, RET, and TOMM20;
thereby modulating a host of physiological functions (Reviewed in Trivellin and
Korbonits 2011 ).
FKBP36
FKBP36 (gene name FKBP6 in humans) is another TPR-containing FKBP that
is structurally similar to Xap2, yet functionally distinct. FKBP36 has a single
N-terminal FK domain and a C-terminal TPR domain. In vitro studies show that
FKBP36 binds Hsp90 and can assemble with steroid receptor complexes (un-
published observation), but there is currently no evidence that FKBP36 alters
receptor activity. FKBP36 mRNA is broadly expressed in vertebrate tissues with
an exceptionally high level observed in the testis; male FKBP6 knockout mice
lack sperm and FKBP36 was shown to be a critical component in meiotic synap-
tonemal complexes (Crackower et al. 2003 ). FKBP36 interacts with and inhibits
GAPDH activity and expression (Jarczowski et al. 2009 ). FKBP36 forms a com-
plex with Hsp90 and GAPDH and this complex may regulate GAPDH activity
in a manner akin to FKBP/Hsp90/ steroid receptor complexes (Jarczowski et al.
2009 ). FKBP36 can exert an effect on GAPDH in an Hsp90 independent manner
by either directly inhibiting NAD + binding to GAPDH or by decreasing GAPDH
expression (Jarczowski et al. 2009 ). Patients with Williams syndrome, which is
characterized by congenital cardiovascular defects, dysmorphic facial features,
mental retardation, growth defects, azoospermia, and hypercalcemia, are typical-
ly haploinsufficient for FKBP6 (Meng et al. 1998 ); however, the contribution of