19p13.11

FKBP38,FKBPr38

Cell size regulation

FKBP8 plays an important role in tuberous sclerosis (TSC) mediated autosomal disorders. Human TSC1 and TSC2 genes regulate the cell size reduction while the dominant TSC2 mutant increases the cell size. Microarray studies revealed that ectopic overexpression of TSC1 or TSC2 (the wild type) induced high levels of FKBP8 while overexpression of TSC1 mutant 127 or TSC2ΔRL were unable to trigger increase in FKBP8 levels. Selective inhibition of FKBP8 by specific antisense oligonucleotide treatment showed the loss of TSC gene ability to control cell size (Figure 4A) (Rosner et al., 2003).

mTOR signaling

The mammalian target of rapamycin (mTOR) signaling is implicated in multiple processes such as cancer, mitochondrial biogenesis, hypoxia signaling, and cell cycle progression. FKBP8 functions as an endogenous inhibitor of mTOR by inhibiting mTORC1 activity both in vitro and in vivo (Bai et al., 2007; Wang et al., 2008; Uhlenbrock et al., 2009) (Figure 4B).
FKBP8 has been shown to inhibit mTOR activity in the presence of insulin only under an amino acid-deprived state. However, in the presence of excess amino acids, FKBP8 fails to inhibit mTOR. An excess of amino acids serves to stimulate the FAT domain of mTOR via a Rag-dependent mechanism and thereby antagonizes FKBP8-mediated mTOR inhibition (Dunlop et al., 2009). Furthermore, protein complexes like the GTP-bound Rheb/RhebL1 complex and signaling molecules such as excess amino acids and phosphatidic acid can modulate this FKBP8-mTOR interaction (Figure 4C) (Yoon et al., 2011).

Apoptosis

FKBP8 plays pivotal roles in modulating apoptosis by protecting Bcl-2 from caspase dependant degradation. FKBP8 by interacting with the flexible loop domain of Bcl-2 stabilizes Bcl-2 levels and prevents apoptosis (Kang et al., 2008). Thus FKBP8 enhances cell survival, promotes tumorigenesis and contributes to chemoresistance (Kang et al., 2005b; Kang et al., 2008; Choi et al., 2010; Choi and Yoon, 2011). On the other hand, Presenilins (PS1/PS2) and Hsp90 antagonize the chaperone effects of FKBP8. Presenilins blocks FKBP8-Bcl-2 interactions in a γ-secretase independent manner and thereby increase the susceptibility to apoptosis by promoting Bcl-2 degradation (Wang et al., 2005). Hsp90 negatively regulates FKBP8/Ca⁺²-calmodulin complex by preventing its interaction with Bcl-2 and controls programmed cell death of neuroblastoma cells (Erdmann et al., 2007) (Figure 5A).

Proteasomal degradation

FKBP8 influences proteasomal degradation by directly interacting with almost all the subunits of 26S proteasome via its TPR domain (Nakagawa et al., 2007) (Figure 5C). FKBP8 could probably serve to modulate proteasomal degradation of its substrate proteins like phosphatase of regenerating liver 3 (PRL-3) and prolylhydroxylase-2. FKBP8 interacts with PRL-3 and modulates the stability of PRL-3 by promoting the degradation of PRL-3 via proteasomal pathway and thus suppresses PRL-3 mediated p53 activity and cell proliferation (Choi et al., 2011).
FKBP8 with its glutamate region domain (ERD) specifically binds to prolyl-4-hydroxylase domain containing protein PHD-2. The membrane anchor targets FKBP8-PHD-2 complex to mitochondrial and ER membranes and promotes its proteasomal degradation and maintains in vivo levels of PHD-2 (Barth et al., 2009). FKBP8 mediated modulation of PHD-2-HIF-1a interaction plays key roles in regulating hypoxia responses. Depletion of FKBP8 prolongs PHD-2 stability; elevates its hydroxylation activity, leading to degradation and reduction of HIF-1a transcriptional activity (Figure 5B) (Barth et al., 2007).
Given that hypoxia plays a key role in the development of gliomas like glioblastoma multiforme (GBM), its modulation may present an alternative approach in the therapeutic intervention of gliomas. For example, growth factors like BMP-2 has been recently been used for GBM treatment. BMP-2, by lowering HIF-1a levels (via FKBP8 inhibition) and activating mTOR signaling, alters the activity of succinic dehydrogenase. This, in turn, prevents the proliferation of glioma cells and commits the cells to differentiation (Figure 5B) (Pistollato et al., 2009).

Negative regulator of Shh signaling and development of neural tubes

Sonic Hedgehog (Shh) signaling regulates neural patterning of central nervous system by altering the genes that mediate dorso-lateral and ventral fates (Briscoe and Ericson, 2001). FKBP8 gene knock out studies have revealed that it functions as a negative regulator of Shh signaling. Hedgehog signal transduction occurs mainly by modulating the activities of GLI2 transcriptional factors. FKBP8 primarily acts in a cell autonomous fashion and modulates hedgehog pathway independent of upstream activator smoothened but dependent on kinesin-2 motor subunit kif3a (which mediates in intra flagellar transport (IFT) and cilia assembly) (Figure 6). FKBP8 depletion modifies the neural progenitors-BMP signaling causing non-autonomous effects on neural patterning (Bulgakov et al., 2004; Cho et al., 2008).

Development and neuroprotective roles

FKBP8 plays a critical role in the development of various organs. FKBP8^(-/-) mice shows several developmental defects that includes improper eye development, spina bifida, skeletal defects, defective dorsal root ganglion and disorganized neural epithelium. The extension of nerve fibers in spinal cord is also abnormal in FKBP8 null embryos. Shirane et al. have shown that abnormal nerve extension in FKBP8^(-/-) mice is mediated by the hyperphosphorylation of Protrudin. Thus, it is likely that FKBP8 plays an important role in regulating protrudin-dependent neurite extension (Shirane et al., 2008; Saita et al., 2009).

Neurodegenerative disorders

Recent studies have highlighted the role of FKBP8 in modulating neurodegenerative amyloidoses disorders like Parkinsons disease. Stable overexpression of FKBP8 has been shown to enhance the aggregation of α-synuclein and cell death in neuronal cell culture model suggesting its probable role in Parkinson disease (Deleersnijder et al., 2011; Chattopadhaya et al., 2011). Selective inhibition of FKBP8 by specific inhibitor N-(N, N-dimethylcarboxamidomethyl) cycloheximide (DM-CHX) has shown promise in achieving neuronal protection in a rat model of transient focal cerebral ischemia. DM-CHX not only protected neurons from ischemic challenge but also induced neural stem cell proliferation and neuronal differentiation suggesting potential role of FKBP8 in neuronal cells (Edlich et al., 2006).

Chaperonic role in biogenesis of membrane proteins

FKBP8 plays key roles in modulating the biogenesis of membrane proteins such as HERG, CFTR. FKBP8 functions as a co-chaperone assisting maturation and trafficking of human ether-a-go-go-related gene (HERG), a voltage dependent potassium channel. Mutations in HERG, for example F805C, causes long QT syndrome which is characterized by a prolonged QT interval and increased susceptibility to cardiac arrhythmia. FKBP8 knock down shows reduction in HERG trafficking, while its overexpression rescues the mutant F805C HERG trafficking (Walker et al., 2007).
Similarly, mutations such as ΔF508 in cystic fibrosis transmembrane conductance regulator (CFTR, a chloride ion channel) alters the biogenesis, trafficking or stability of CFTR and disrupts the functioning of chloride ion channel. FKBP8 plays a rate limiting role as a co-chaperone on maturation and biogenesis of CFTR. FKBP8 by maintaining steady state levels of HSP90 regulates the biogenesis, maturation, trafficking and post-translational folding of both wild type and ΔF508 CFTR proteins (Wang et al., 2006b; Banasavadi-Siddegowda et al., 2011).

Invasion and adhesion - cancer cell progression

Gene expression analysis on B16-F10 cells treated with rapamycin or FKBP8 overexpression highlighted the role of FKBP8 gene during tumor cell invasion. FKBP8 overexpression prevents tumor cell invasion by up-regulation of anti-invasive Syndecan (Sdc1) levels and suppression of pro-invasive MMP9 (Fong et al., 2003).

Viral replication

Both in vitro and in vivo studies have shown that FKBP8 binds to HCV NS5. FKBP8 through its TPR domain binds tightly to BH-domain (Bcl-2- homology domain) of HCV NS5. Immunoprecipitation studies showed that FKBP8 forms a heteromeric complex with NS5 and Hsp90. Furthermore, fluorescence and electron microscopy have revealed that FKBP8 partially colocalizes with NS5 into web like cytoplasmic structures, which are probable sites of viral replication and might play an important role in HCV replication (Okamoto et al., 2006; Wang et al., 2006a; Okamoto et al., 2008).