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. Author manuscript; available in PMC: 2019 Jul 5.
Published in final edited form as: Curr Mol Pharmacol. 2015;9(1):48–65. doi: 10.2174/1874467208666150519113541

FK506-Binding Proteins and Their Diverse Functions

Mingming Tong 1, Yu Jiang 1,*
PMCID: PMC6611466  NIHMSID: NIHMS1034970  PMID: 25986568

Abstract

FK506 binding proteins (FKBPs) are a family of highly conserved proteins in eukaryotes. The prototype of this protein family, FKBP12, is the binding partner for immunosuppressive drugs FK506 and rapamycin. FKBP12 functions as a cis/trans peptidyl prolyl isomerase (PPIase) that catalyzes interconversion between prolyl cis/trans conformations. Members of the FKBP family contain one or several PPIase domains, which do not always exhibit PPIase activity yet are all essential for their function. FKBPs are involved in diverse cellular functions including protein folding, cellular signaling, apoptosis and transcription. They elicit their function through direct binding and altering conformation of their target proteins, hence acting as molecular switches. In this review, we provide a general summary for the structures and diverse functions of FKBPs found in mammalian cells.

Keywords: FK506, immunophilin, peptidyl prolyl cis/trans isomerase, FK506 binding proteins, calcineurin, mTOR

1. INTRODUCTION

FK506 binding proteins (FKBPs) are a large family of proteins that possess peptidyl prolyl cis/trans isomerase (PPIase) domains. The founding member of this family is FKBP12, which is a 108 amino acid peptide containing the minimal sequence for a PPIase [1, 2]. It binds to FK506 and rapamycin and mediates the immunosuppressive action of the drugs [3, 4]. Other members were subsequently identified in yeast, plants and mammals, based on their sequence similarity to FKBP12. A glance at human genome reveals at least 15 polypeptides that contain PPI domains similar to FKBP12 (Fig. 1). The closest homolog of FKBP12 is FKBP12.6, which displays 83% sequence identity to FKBP12 [5]. Many large FKBPs contain several PPIase domains. For instance, FKBP52 possesses two PPIase domains and FKBP65 has four [6, 7]. All FKBPs, except FKBP12 and FKBP12.6, possess additional functional domains (Fig. 1). The most common one is tetratricopeptide (TPR) domain, a sequence motif that is often involved in mediating protein-protein interactions. Some FKBPs also contain Ca2+ binding regions, such as Ca2+/Calmodulin (CaM) binding domain and EF-hand motif. Several FKBPs function in the endoplasmic reticulum (ER) and contain ER targeting and retention motifs. FKBP38 and FKBP19 are two unique members which contain a transmembrane domain that targets them to membrane structures [8, 9]. Despite the presence of PPIase domain, not all members exhibit the ability to catalyze interconversion of prolyl cis/trans conformations or to bind with FK506. However, the PPI domain appears to be essential for their function. It has been suggested that the domain binds to X-proline sites (where X can be any amino acid) in target proteins and alters their conformation through a PPIase-like activity, hence acting as a molecular switch [10].

Fig. (1). A schematic presentation of the domain structures of the human FKBP family.

Fig. (1).

The information is from UniProt database.

2. STRUCTURES AND FUNCTIONS OF FK506 BINDING PROTEINS

2.1. FKBP12

FKBP12 is a 12 kDa cytosolic protein that is abundantly expressed in all tissues. It possesses the enzymatic activity for catalyzing peptidyl prolyl cis/trans isomerization and functions as molecular chaperone in facilitating protein folding [1, 2].

2.1.1. FKBP12 as an Immunophilin

FKBP12 was originally identified as the target of FK506 and rapamycin [1]. Both drugs bind noncovalently to FKBP12 and inhibit its PPIase activity [3]. However, the inhibition of FKBP12 per se does not contribute to their immunosuppressive activity. Instead, the binding with FKBP12 allows the drugs to subsequently interact with the mechanistic targets of their action in immunosuppression. The FK506-FKBP12 complex specifically interacts with calcineurin (CaN), a Ca2+-dependent serine-threonine phosphatase [1114], whereas the rapamycin-FKBP12 complex targets mammalian target of rapamycin (mTOR) [1517].

In T lymphocytes, CaN is a key component in the T-cell receptor mediated signaling that is required for T activation [11, 18]. It is activated by CaM in response to the increasing calcium concentration following activation of the T-cell receptor by antigen stimulation [11]. Activated CaN dephosphorylates nuclear factor of activated T cells (NFAT) resided in the cytoplasm, allowing it to translocate into the nucleus, where it cooperates with other nuclear transcription factors to initiate the transcription program for T cell activation [18]. The FK506-FKBP12 complex binds to CaN and blocks the access of NFAT to its catalytic site, preventing NFAT dephosphorylation and consequently, T cell activation [18] (Fig. 2).

Fig. (2). The action mechanism of FK506 and rapamycin in T lymphocyte activation.

Fig. (2).

FK506 binds to cytosolic FKBP12 to form the FKBP12-FK506 complex. The complex inhibits CaN-dependent dephosphorylation of NFATs in the cytoplasm and prevents their nuclear translocation and transcription of T-cell activation genes. Rapamycin also form a complex with FKBP12. However, this rapamycin-FKBP12 targets mTOR and inhibits its function in cell growth, blocking cell cycle progression.

The Rapamycin-FKBP12 complex inhibits cytokine stimulated T lymphocyte proliferation [3, 1922]. Cytokines, such as interleukin-2 (IL-2), produced by activated T cells, bind to the cell surface receptors to activate the PI3K/AKT pathway and the downstream effector, mTOR [2224]. Activated mTOR phosphorylates ribosomal protein 6 kinase (S6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1), two factors involved in translation initiation, resulting in an increase in protein synthesis, which in turn promotes cell growth and proliferation [22, 24]. The rapamycin-FKBP12 complex specifically binds to mTOR and interferes with its kinase function, thus blocking the cytokine-stimulated protein synthesis (Fig. 2).

In clinic FK506 is currently a first-line immunosuppressive drug in prevention of allograft rejection and treatment of severe autoimmunity [25]. Because it specifically targets CaN, FK506 is often referred as a calcineurin inhibitor. The major side effect associated with FK506 is nephrotoxicity, caused by blocking the function of CaN [26]. Rapamycin, which acts by distinct mechanism, is devoid of nephrotoxicity and hence offers an alternative in immunotherapy [22]. While the clinic application of Fk506 is limited to immunosuppression, rapamycin and its analogs are currently used in treating various cancers, owing to its effect in blocking cell proliferation [2729].

2.1.2. FKBP12 and Ca2+ Release Channels

Following the identification of FKBP12 as the receptor for immunosuppressive drugs, extensive studies have been focused on uncovering the normal physiologic function of this small cytosolic protein. One surprising finding from those studies was that the protein not only resides in cytosol but also associates with many membrane receptors. In muscle cells FKBP12 has been found to interact with the major Ca2+ release channels of the sarcoplasmic reticulum (SR) ryanodine receptors (RyRs) [3033]. These channel receptors mediate the release of Ca2+ from the sarcoplasmic reticulum into the cytoplasm during muscle contraction [30, 34]. The receptor exists as a tetramer, which binds to four molecules of FKBP12, one for each subunit [34] (Fig. 3). The binding is sensitive to FK506 or rapamycin, which displaces FKBP12 from the receptor [34]. In the absence of FKBP12, RyR receptors are correctly assembled and presented on the sarcoplasmic reticulum, suggesting that FKBP12 does not act as a molecular chaperone for the assembly and presentation of the receptors [31]. However, removal of FKBP12 from the receptors by FK506 or rapamycin results in a ‘leaky’ channel with an increase in open probability and conductance, which leads to depletion of Ca2+ store and consequently reduction in muscle contractility [35]. These observations have led to the suggestion that FKBP12 stabilizes channel conformation and increases the threshold for channel opening [36]. However, how FKBP12 binding affects the stability of the receptors is unclear. An early study suggested that the PPIase activity of FKBP12 was not required [37]. This PPIase independent action of FKBP12 is reminiscent of its action in FK506 mediated inhibition of CaN [11]. A closer examination of the association between FKBP12 and RyRs revealed the presence of CaN in the complex, which was disrupted by FK506 and rapamycin [38]. This observation raises a possibility that FKBP12 may control the phosphorylation state of the receptors through the CaN associated with the receptors.

Fig. (3). FKBP12 and FKBP12.6 stabilize and modulate intercellular Ca2+ release channels.

Fig. (3).

FKBP12 and FKBP12.6 physically associate with Ca2+ release channels on the sarcoplasmic reticulum and endoplasmic reticulum. One molecule of FKBP12 or FKBP12.6 binds to one receptor within a tetramer. FKBP12 selectively binds to RyR1 and IP3R, whereas within FKBP12.6 preferentially associates with RyR2. CaN is anchored to IP3R through FKBP12 and modulates the phosphorylation of IP3R.

FKBP12.6, the closest isoform of FKBP12, also plays a role in regulating RyR Ca2+ release channels in a manner similar to that of FKBP12 [5]. However, these two FKBPs appear to have different specificity to different types of RyRs. FKBP12 is more selective for RyR1 in skeletal muscle, whereas FKBP12.6 preferentially targets RyR2 in cardiac muscle [5, 39, 40] (Fig. 3).

2.1.3. FKBP12 and IP3R

FKBP12 also associates with another type of Ca2+ channel receptors named as inositol 1, 4,5-trisphosphate receptors (IP3R), which are structurally and functionally related to RyRs [41] (Fig. 3). The receptor mediates the release of Ca2+ from the endoplasmic reticulum (ER) into cytosol and mitochondria in response to inositol trisphosphate (IP3) [42]. The effect of FKBP12 on IP3Rs appears to be the same as that on RyRs, which stabilizes the receptors [41]. When FKBP12 is stripped from the receptors by FK506 or rapamycin, a leaky channel is created [41]. As in the case for RyRs, CaN is found in complex with FKBP12 and IP3Rs [43]. Because IP3R is phosphorylated at multiple sites [44, 45], the significance of its association with a phosphatase is apparent. Indeed, CaN has been shown to modulate the phosphorylation status of the receptors. Importantly, changes in the phosphorylation status of the receptors appear to alter their calcium flux properties [43]. However, it remains unclear whether FKBP12 controls IP3R simply by targeting CaN to the receptors or its binding to the receptors may also contribute to the regulation.

In addition to binding with Ca2+ channel receptors, FKBP12 also interacts with type I receptor for transforming growth factor-β (TGF-β) [46]. In this case, FKBP12 serves as a natural ligand and binds to a glycine- and serine-rich motif of TGF-β receptor 1 (TGF-βR1). The binding does not directly inhibit the receptor but blocks its phosphorylation by TGF-βR2, hence trapping the receptor in an inactive state [46]. This mechanism is believed to provide a safeguard against leaky signaling activity of the receptors. As in the case for calcium channel receptors, the association of FKBP12 with TGF-βR1 is sensitive to FK506 and rapamycin. It has been shown that rapamycin is able to reverse the inhibitory action of FKBP12 on the receptors, presumably by removing FKBP12 from TGF-βR1 [47].

2.2. FKBP38

FKBP38 was originally isolated based on its sequence similarity to FKBP12 [48, 49]. It was later identified as a gene that was downregulated in Schwannomas as the tumor cells progressed into advanced stages [49]. The initially isolated cDNA contained an open reading frame encoding a protein of 355 amino acids (38 kDa) but the initial ATG was later found to be 58 codons upstream [48, 50]. The full size of FKBP38 is 413 amino acids with a predicted size of 45 kDa [50]. But on SDS page it shows an apparent molecular weight of 57 kDa [50, 51]. In addition to the PPIase domain that marks all members of FKBP family, FKBP38 contains several other sequence domains, including three TPR do mains located at the C-terminal half of the protein, followed by a putative Ca2+/CaM binding domain, and a transmembrane domain at the very C-terminus [48, 49] (Fig. 1). This transmembrane domain is responsible for anchoring FKBP38 to ER and mitochondrial membranes11.

FKBP38 is unique among the members of the FKBP family in that its PPIase activity is Ca2+/CaM dependent [52]. Interestingly, while a putative Ca2+/CaM binding motif is located at the C-terminus near the transmembrane domain, Ca2+/CaM binds has been found to bind to the N-terminal region of FKBP38 [53]. This binding releases the inhibitory effect of the N-terminal region on the PPIase domain of FKBP38, which potentiates the PPIase activity of FKBP38 and enhances its interaction with target proteins [53, 52].

The importance of FKBP38 in cell growth was first indicated by the inverse correlation between the levels of FKBP38 and the rate of cell growth. For cells derived from malignant Schwannomas, a faster growth rate was found to accompany a lower level of FKBP38 [49], indicating that FKBP38 may negatively mediate cell growth in Schwannomas. A similar phenomenon was also observed in melanoma cells [54]. These observations have led to the suggestion that FKBP38 may function as a tumor suppressor [54]. In addition, a high expression level of FKBP38 also correlates with a reduced cell size in cells overexpressing TSC1 tumor suppressor gene [55]. All these attributes indicate that FKBP38 is an important regulator for cell growth and proliferation. In the past several years, the action mechanism of FKBP38 in controlling cell growth has begun to emerge [49, 54, 55]. It is now well-established that FKBP38 regulates cell growth and proliferation through multiple mechanisms, including regulation of mTOR, apoptosis and hypoxia response [8, 52, 5658].

2.2.1. FKBP38 and mTOR

The mammalian target of rapamycin, mTOR, is a serinethreonine protein kinase that controls a wide spectrum of cellular events by integrating various environmental cues, such as growth factors, changes in energy levels and fluctuations in nutrient conditions [59, 60]. The kinase exists in two distinct complexes named as mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is the major downstream component of the PI3K and AKT pathway that controls cell growth and proliferation [61]. Rapamycin, in complex with FKBP12, specifically blocks mTORC1 activity and inhibits cell growth [62]. mTORC1 activity is negatively regulated by the TSC1 and TSC2 tumor suppressor complex, which functions as a GTPase activating protein for a Ras-like small GTPase, Rheb [63]. The TSC1/2 complex stimulates the intrinsic GTPase activity of Rheb, thus negatively regulating Rheb. In TSC deficient cells the inactivation of the TSC1/2 complex results in the accumulation of GTP-bound Rheb, which in turn stimulates mTORC1 [64].

FKBP38 has been shown to act as the endogenous inhibitor of mTOR [58]. In cells the level of FKBP38 expression has been reported to correlate inversely with the activity of mTORC1 [6567]. When FKBP38 is overexpressed, it inhibits growth factor or amino acids-stimulated mTORC1 activity. On the other hand, FKBP38 knockdown causes an increase in mTORC1 activity and renders mTORC1 activity partially insensitive to growth factor deprivation and amino acid starvation. The inhibitory effect of FKBP38 on mTORC1 is also recapitulated in vitro using purified recombinant FKBP38, which strongly inhibits mTORC1 kinase activity toward 4EBP1. The inhibition does not require rapamycin, although the drug appears to further augment the inhibitory effect [58]. These observations support the notion that FKBP38 is an endogenous inhibitor of mTORC1.

FKBP38 binds directly to mTOR. Deletion analysis shows that the PPIase domain of FKBP38 mediates the binding. The minimal region in mTOR responsible for binding with FKBP38 comprises amino acids 1967–2191, which overlaps the FKBP12-rapamycin binding region (amino acids 2015–2114), indicating that FKBP38 affects mTORC1 in a way similar to that of the FKBP12-rapamycin complex. In accordance with this notion, FKBP38, like the FKBP12-rapamycin complex, targets only mTORC1 but not mTORC2 [58].

The inhibitory effect of FKBP38 on mTOR can be antagonized by Rheb, which interacts directly with FKBP38 and prevents it from binding with mTOR [58, 68]. The interaction of Rheb with FKBP38 depends on its nucleotide binding status. In vitro GTP-bound Rheb exhibits much higher binding affinity toward FKBP38 than GDP-bound Rheb. Rheb interacts with FKBP38 through its switch I region, the region commonly referred to as the effector domain that is required for a small GTPases to interact with its effectors. Mutations within the region affect the ability of Rheb to interact with FKBP38, rendering the small GTPase incapable of stimulating mTORC1 activity [68]. This effector domain-mediated and GTP-dependent binding is a common mechanism for members of the Ras family of small GTPases to interact with their targets [69], hence indicating that FKBP38 is a bona fide effector of Rheb. This FKBP38-dependent regulation supports a notion that Rheb stimulates mTORC1 by disrupting FKBP38 from mTOR [58].

How does Rheb block the interaction of FKBP38 with mTOR? It has been found that Rheb binds to the PPIase domain in FKBP38 which is the same region for mTOR binding. However, the interactions of Rheb and mTOR with FKBP38 do not appear to be mutually exclusive. A dominant inactive mutant of Rheb is able to bind with FKBP38 without dissociating mTOR, indicating that Rheb regulates FKBP38 allosterically in a GTP-dependent manner and consequently alters its interaction with mTOR [68].

The interaction of Rheb with FKBP38 in cells is regulated by both growth factors and nutrient conditions [58]. Under growth factor derivation condition or when amino acid supply is limited, FKBP38 binds to mTOR and down-regulates its activity. The presence of growth factors and amino acids promotes accumulation of GTP-bound Rheb, which interacts with FKBP38 and releases mTOR from its inhibition [58] (Fig. 4). Growth factors, such as insulin, promote Rheb activation by activating the PI3K/AKT pathway, which reduces the GAP activity of the TSC1/2 complex, allowing GTP-bound Rheb to accumulate. However, how amino acid conditions affect Rheb GTP binding state is poorly understood. It has been suggested that amino acids control Rheb localization, hence its access to its effectors [60].

Fig. (4). The signaling mechanisms of FKBP38 in regulation of mTOR and apoptosis.

Fig. (4).

FKBP38, acting in a way similar to that of the rapamycin-FKBP12 complex, binds and inhibits mTORC1 function. This inhibitory action of FKBP38 is antagonized by the Ras-like small GTPase Rheb in response to growth factor and amino acid stimulation. Rheb binds directly FKBP38 and releases mTORC1 for activation. In apoptosis regulation, FKBP38 is responsible for recruiting Bcl-2 and Bcl-XL to mitochondria. Rheb is believed to disassociate the two antiapoptotic proteins from FKBP38 on mitochondria and facilitates their interaction with pro-apoptotic proteins, Bak and Bax.

In addition to Rheb, the interaction of FKBP38 with mTORC1 is also controlled by phosphatidic acid (PA), a secondary messenger that is produced by phospholipase D through hydrolysis of phosphatidylcholine [70]. PA binds directly to mTORC1 and stimulates its activity [7173]. A recent study has shown that PA binds to the same region in mTOR as does FKBP38. The binding reduces the affinity of mTOR for FKBP38, thus contributing to the PA-stimulated mTOR activation [72].

2.2.2. FKBP38 and Apoptosis

Bcl-2 and Bcl-XL are two major anti-apoptotic proteins that localize to various subcellular locations, including the cytoplasm, nucleus, ER and mitochondria. To perform their apoptotic function, these two proteins have to be recruited to mitochondria, where they bind to pro-apoptotic proteins, Bak and Bax, and prevent their oligomerization on mitochondrial outer membrane [74]. The mitochondrial recruitment of these two anti-apoptotic proteins is mediated by FKBP38, which resides on mitochondria via its C-terminal transmembrane domain [8]. Overexpressing FKBP38 results in accumulation of Bcl-2 and Bcl-XL on mitochondria, and consequently, renders cells resistance to various apoptotic inducers. On the other hand, downregulation of FKBP38 by shRNA reduces the amount of the Bcl-2 and Bcl-XL on mitochondria and sensitizes the cells to apoptosis [8, 75]. In addition, the level of Bcl-2 is also reduced when FKBP38 expression level is low, indicating that the presence of FKBP38 also stabilizes Bcl-2 [75]. It is believed that binding with FKBP38 protects Bcl-2 from the caspase-dependent cleavage [76]. Interestingly, during mitophagy, a process for selectively removal damaged or excessive mitochondria through autophagosomes [77], FKBP38 and Bcl-2 are able to escape the destruction by translocating to ER membrane [78]. This process is believed to prevent apoptosis from initiation during mitophagy [78]. However, how cells are able to selectively remove the proteins remains unclear.

FKBP38 binds to an N-terminal unstructured loop in Bcl-2 located between the Bcl-2 homology (BH) domains 3 and 4. The PPIase domain is required, although the three TPR domains may also contribute to the binding [8, 79]. However, a recent finding from a NMR analysis suggests that another region (amino acids 119–131) is involved in binding with FKBP38 [80]. It is possible that multiple regions in Bcl-2 are involved in its interaction with FKBP38. Alternatively, the interaction is a dynamic process that changes in responsible to other cues, such as Ca2+ concentration.

Two factors are involved in regulating the interaction of FKBP38 with the two anti-apoptotic proteins, Rheb and Ca2+ concentration. The mechanism by which Rheb controls the interaction of FKBP38 with the anti-apoptotic proteins mirrors the one for mTOR regulation. It has been shown that Rheb in its GTP-bound form is able to interact with FKBP38 and prevents it from association with Bcl-2 in vitro [81]. In cultured cells deprived of growth factor or amino acids the interaction between Bcl-2 and FKBP38 is strongly enhanced. Re-addition of the missed ingredients to culture medium or simply overexpressing Rheb reduces the interaction [81]. This Rheb-dependent regulation provides a link that allows both growth factor and nutrient signals to control apoptosis (Fig. 4). The growth factor and nutrient sensitive interaction of FKBP38 with the two anti-apoptotic proteins may constitute a protective mechanism that prevents a premature apoptosis initiation during growth factor deprivation or nutrient limitation, allowing time for other stress response mecha nisms, such as autophagy, to launch. This notion is consistent with the observation that both FKBP38 and Bcl-2 are selectively removed from mitochondria during mitophagy [78].

Ca2+ is another factor that plays a critical role in mediating the binding of FKBP38 with Bcl-2. An elevated Ca2+ concentration has been shown to enhance the interaction of FKBP38 with Bcl-2 [52]. FKBP38 exhibits a capacity for binding with Ca2+/CaM, which form a complex with FKBP38 and change its the affinity for Bcl-2 [52]. However, the regions in FKBP38 responsible for the binding remain controversial. A putative Ca2+/CaM binding site is located at the C-terminal region of FKBP38 (Fig. 1). However, a recent study shows that Ca2+/CaM bind to the N-terminal extension (1–32) in FKBP38. It has been suggested that binding with Ca2+/CaM removes the N-terminal extension away from the PPIase domain, allowing it to interact with Bcl-2 [53]. Despite these observations, the physiologic significance of Ca2+/CaM mediated interaction of FKBP38 with Bcl-2 in apoptotic regulation is unclear.

Phosphorylation represents another mechanism in mediating the interaction of FKBP38 with Bcl-2. An early study showed that JNK was able to phosphorylate Bcl-2 at the unstructured loop that is involved in binding with FKBP38 [79, 82]. Phosphorylation at this site decreases its interaction with FKBP38. This JNK mediated phosphorylation may play a role in autophagy, as it affects the formation of the Bcl-2/Beclin 1 complex [79].

2.2.3. FKBP38 Mediates a Crosstalk between mTOR and Bcl-2

A recent study has uncovered a novel crosstalk between mTOR and Bcl-2 which may have an implication in cancer development. It was found that changes in the expression levels of Bcl-2 and Bcl-XL had a dramatic effect on mTORC1 signaling activity. mTORC1 activity increased when Bcl-XL was overexpressed but decreased when Bcl-2 or Bcl-XL was downregulated. The effects of the two antiapoptotic proteins on mTORC1 are independent of the antiapoptotic function of the proteins. Because FKBP38 is able to bind both mTOR and Bcl-2/XL, it is conceivable that it may mediate the crosstalk. Indeed, mutants of the Bcl proteins defective for binding with FKBP38 are incapable of affecting mTORC1 activity [83]. During normal cell proliferation, such a crosstalk may not play a significant role in cell growth and survival, as the levels of Bcl-2 and Bcl-XL remain relative unchanged. However, during cancer development, the levels of the two proteins are often highly elevated, as a way for the cancer cells to escape apoptosis [74]. The overexpressed Bcl-2 and Bcl-XL may thus promote mTORC1 activity in addition to their function for enhancing cell survival.

2.2.4. FKBP38 in Hypoxia Response

FKBP38 has been found to associate with PHD2, a prolyl-4-hydroxylase domain-containing enzyme (PHDs) that catalyzes hydroxylation of two conserved prolyl residues in hypoxia-inducible transcription factor 1 alpha (HIF1α) [56]. HIF1 α is a key factor in regulation of hypoxia response and plays a central role in angiogenesis and tumor development. The PHD-dependent hydroxylation of HIF1α targets it for proteasomal degradation [84]. FKBP38 specifically interacts with PHD2 but not with other isoforms of PHD. The interaction is mediated by the N-terminal region of FKBP38 outside of the PPIase domain. In glioblastoma multiforme cells an increase in PHD2 level was found to correlate with a down-regulation of FKBP38, indicating that FKBP38 plays a negative role in regulating the stability of PHD2 [85]. Consistent with the notion, FKBP38 has been suggested to act as an adaptor protein to target PHD2 for proteasomal degradation [57].

Perturbation of FKBP38 function in apoptosis appears to underlie some pathogenesis of human diseases. The hepatitis C virus non-structural protein NS5A, which contains three BH domains and localizes to mitochondria, is structurally related to Bcl-2. This viral protein inhibits apoptosis through interaction with FKBP38, which is believed to contribute to the survival of the virus infected cells [86]. Presenilins 1 and 2, two proteins whose functions have been implicated in familial Alzheimer’s disease (FAD), promote the degradation of FKBP38 and Bcl-2 and inhibit FKBP38 mediated mitochondrial recruitment of Bcl-2 [87].

2.3. FKBP52

FKBP52 was isolated as a co-chaperone of heat-shock protein 90 (Hsp90) of steroid receptor complex [88, 89]. The protein resides in both the cytoplasm and nucleus. In the cytoplasm FKBP52 exists in complex with steroid receptors as well as with Hsp70 and Hsp90 [90]. FKBP52 elicits its role in steroid receptor regulation by stabilizing the steroid receptors as well as by promoting their shuttling into the nucleus from the cytoplasm [91, 92] (Fig. 5). The pattern of FKBP52 distribution in the cytoplasm is reminiscent that of cytoskeleton, which is due to its binding with microtubule motor protein dynein [93]. In the presence of Hsp90 FKBP52 forms a complex with receptor proteins and bring the receptors to microtubule motor protein dynein. Dynein together with associated microtubule then facilitate the nuclear translocation of the receptor proteins [92, 94] (Fig. 5).

Fig. (5). A general mechanism for the role of FKBP51 and FKBP52 in regulation of steroid receptors.

Fig. (5).

In the absence of ligand binding steroid receptors (SR) associate with Hsp90 through their interaction with FKBP51 and are sequestered in the cytoplasm. Upon ligand binding, the receptors exchange the binding with FKBP51 for FKBP52. FKBP52 then targets the receptor-Hsp90 complexes to dynein motor protein, leading to redistribution of the receptors into the nucleus through the nuclear pore complex (NPC), where they regulate transcription. FK506 disrupts the receptor complex by binding to the PPIase domain of FKBP52.

FKBP52 is comprised of two PPIase domains, three TRP domains, and two C-terminal putative binding Ca2+/CaM binding sites [6] (Fig. 1). The first PPIase domain (FK1) toward N-terminus exhibits enzymatic activity on its target proteins, which is inhibited by FK506 and rapamycin [95]. This PPIase domain is responsible for the interaction with steroid receptors and important for receptor activity [96, 97]. The PPIase domain also mediates the interaction between dynein and the steroid receptor complex [98]. The second PPIase domain (FK2) is remotely related to FKBP12 (share ~17% identical sequence). It is devoid of enzymatic activity and incapable of binding with FK506 and rapamycin [99]. An ATP and GTP binding site is found within this domain [100]. In the presence of Ca2+/CaM, binding of ATP at the site promotes FKBP52 phosphorylation [101]. Phosphorylation in the hinge region between FK1 and FK2 by casein kinase-2 inhibits the binding of FKBP52 with Hsp90 [102]. The three TPR domains are also involved in the association of FKBP52 with the steroid receptors and Hsp90 [103]. The two C-terminal Ca2+/CaM binding sites appear to be involved in the interaction of FKBP52 with Hsp90, as deletion of this region reduces the affinity of the interaction between the two proteins [104, 105].

2.3.1. FKBP52 in Steroid Receptor Regulation

FKBP52 plays a critical role in reproduction in rodents. It acts as a positive regulator for glucocorticoid, progesterone, and androgen receptors, but not for estrogen and mineralocorticoid receptors [96, 106, 107]. Male mice without FKBP52 are infertile. The animals display severe defects in reproductive tissues consistent with androgen insensitivity, including ambiguous external genitalia and dysgenic prostate. In addition, androgen receptor levels are reduced in testis and epididymis of the knockout animals [107]. The androgen insufficiency and insensitivity are believed to underlie the many birth defects in the reproductive system of the FKBP52 deficient animals [107109]. FKBP52 has been found to be a component of androgen receptor complex, in which FKBP52 promotes the receptor mediated transcriptional activity. In addition, binding with FKBP52 appears to stabilize androgen receptor, as the receptor level is reduced when FKBP52 is downregulated by siRNA [107, 110, 111]. The positive effect of FKBP52 in androgen receptor-mediated transactivation requires FK1 domain and is sensitive to FK506 [107].

In female mice FKBP52 knockout also causes infertility, due to defects in uterine receptivity during implantation. The defects are caused by loss of activity of progesterone receptors in the uterus [106, 112]. The absence of FKBP52 results in reduced progesterone receptor transcriptional activity and down-regulation of the receptor regulated gene expression [106]. In addition, FKBP52 knockout female mice are susceptible to oxidative stress and prone to the growth of endometriotic lesions with increased inflammation and angiogenesis [113]. A downregulation of peroxiredoxin (PRDX6), an antioxidant, in FKBP52 deficient animals is believed to contribute the defects [114].

A role of FKBP52 in regulation of glucocorticoid receptor was first tested using yeast cells. It was found that FKBP52 stabilized glucocorticoid receptors and increased hormone-binding affinity of the receptors. The effect of FKBP52 on the receptors requires its PPI activity and binding with Hsp90 [96]. In FKBP52-knockout mice, no obvious defects in glucocorticoid receptor regulated processes have been detected, indicating that FKBP52 is not an essential regulator of glucocorticoid receptor activity [115]. However, an analysis of glucocorticoid receptor activity at reporter genes shows significant reduction in receptor activity in mouse embryonic fibroblasts (MEF) of FKBP52 knock-out mice [115].

2.4. FKBP51

FKBP51 shares 60% sequence homology with FKBP52 and contains similar structural features, including two PPIase domains, three TPR domains, and a Ca2+/CaM binding motif [116] (Fig. 1). Like FKBP52, the first PPIase domain of FKBP51 displays enzymatic activity and is sensitive to FK506 and rapamycin [117]. The second PPIase domain lacks PPIase activity [116] and does not bind FK506 [118]. The C-terminal TRP domains serve as the region for the association with Hsp90 [118].

2.4.1. FKBP51 in Regulation of Steroid Receptors

FKBP51 was originally identified as a subunit of the progesterone receptor complex [119] and later found to associate with androgen, glucocorticoid, estrogen, and mineralocorticoid receptors [120]. Despite the sequence and structural similarity to FKBP52, FKBP51 does not act as a functionally redundant copy of FKBP52. In contrast, FKBP51 is a negative regulator for activity of steroid receptors, except androgen receptors. It competes with FKBP52 for binding with steroid receptors, consequently, antagonizes the positive effect of FKBP52 on these receptors [96, 121]. It has been shown that binding with FKBP51 sequesters glucocorticoid receptors in the cytoplasm and reduces its affinity for hormone-binding [122] (Fig. 5). However, the effect of FKBP51 on androgen receptors appears to be opposite of its effect on other receptors. Instead of reducing ligand binding activity, FKBP51 promotes the binding of the receptors with androgen and increases receptor transcriptional activity [123]. Interestingly, the expression of FKBP51 is regulated by androgen receptors in response to androgen. The mutual regulation of FKBP51 and the androgen receptor activity hence constitutes a positive feedback loop, which is believed to contribute to prostate cancer development [124, 125]. Therefore, targeting FKBP51 expression or activity may be an effective way to treat prostate cancers.

2.4.2. FKBP51 in NK-κB Regulation

In addition its role in regulation of steroid receptors, FKBP51 also involves in NK-κB activation as a positive regulator. In human melanoma cells knockdown of FKBP51 reduces the transactivation of NF-κB in the nucleus. Two different mechanisms count for the action of FKBP51 in NF-κB regulation, one through inhibitor of nuclear factor kappa-B (IκB) kinase subunit alpha (IKKα) and the other through CaN. IκB is a negative regulator of NF-κB. It binds to NF-κB and keeps it sequestered in an inactive state in the cytoplasm. Phosphorylation of IκB by IKKα removes IκB from NF-κB, allowing it to translocate into the nucleus [126]. FKBP51 has been found to associate with IKKα and stimulates IKK directed-phosphorylation of IκB [127] (Fig. 6), hence promoting NF-κB activation. The second mechanism involves CaN, which inhibits NF-κB activation by dephosphorylation of IκB. FKBP51 has been found to inhibits CaN activity independent of FK506 [117] (Fig. 6).

Fig. (6). The action mechanisms of FKBP51 in regulating the AKT and NF-κB pathways.

Fig. (6).

FKBP51 functions as a scaffolding protein that bridges the association of PHLPP with AKT. The association promotes PHLPP-mediated dephosphorylation of AKT at position 473, resulting in downregulation of AKT activity. In the NF-κB pathway FKBP51 regulates NF-κB activity by modulating the phosphorylation state of inhibitor of IκB. FKBP51 binds to IKKα and stimulates IKKα-directed phosphorylation of IκB. FKBP51 also interacts with CaN and inhibits CaN-dependent dephosphorylation of IκB. Therefore, FKBP51 promotes aberrant NF-κB activation and the expression of antiapoptotic proteins.(3) FKBP51 facilitates the activation of NF-κB pathway through the interaction with IKK0α and enhancing the IKK kinase activity. Rapamycin prevents the action of FKBP51 in the NK-κB pathway by inhibits the PPIase activity of FKBP51.

2.4.3. FKBP51 in the PI3K/AKT Pathway

FKBP51 also plays a role in the PI3K/AKT pathway. In this case, FKBP51 functions as a scaffolding protein for pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates AKT and downregulates its activity [128]. FKBP51 facilitates the association of PHLPP with AKT and enhances PHLPP-directed dephosphorylation of AKT at position 473 [129] (Fig. 6). The N-terminal PPIase domain of FKBP51 binds to AKT and the C-terminal TPR domain binds to the phosphatase, hence bridging the phosphatase to its substrates. Expression of FKBP51 has been found to be downregulated in many types of cancers, such as pancreatic and breast cancers. This reduced FKBP51 level causes dissociation of PHLPP from AKT and, consequently, an increase in AKT phosphorylation, which may contribute to cancer development [129].

2.4.4. Mitochondrial Localized FKB51 in Stress Response and Adipogenesis

In 3T3-L1 fibroblasts overexpression of FKBP51 has been found to protect the cells from oxidative stress [130]. This protective effect is mediated by mitochondrial localized FKBP51, where it forms complexes with glucocorticoid receptor, Hsp90, and Hsp70 [130]. The TRP domain of FKBP51 but not the PPIase domain is required for the mitochondrial localization. In response to oxidative stress, FKBP51 translocates to the nucleus from mitochondria, indicating that FKBP51 may play a role in oxidative stress response [130].

During 3T3-L1 preadipocyte differentiation, the level of FKBP51 progressively increases. At the onset of adipogenesis, the mitochondrial localized FKBP51 redistributes to the nucleus, where it interacts with chromatin and the nuclear matrix in complex with Hsp70 [131]. This redistribution is regulated by the cAMP/Protein kinase A (PKA) pathway, likely through direct phosphorylation by PKA [131].

2.5. FKBP36

FKBP36 was identified as one of the genes deleted in patients of Williams syndrome, a dominant autosomal disorder that is characterized by aortic and arterial stenoses. FKBP36 contains an N-terminal PPIase domain and a C-terminal TPR domain (Fig. 1). It lacks PPIase activity but is able to bind with several proteins through its PPIase and TPR domains [132]. The function of FKBP36 does not appear to be associated with Williams syndrome. Instead, FKBP36 has been found to be a component of synaptonemal complex, a key factor that mediates chromosome synapsis during meiosis [133]. The absence of FKBP36 causes aspermia in male mice without any negative effects in female mice, suggesting that the protein is involved in spermatogenesis [134]. In addition, FKBP36 has been found to form separate complexes with clathrin heavy chain (CHC) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The FKBP36-CHC complex also contains Hsp72 and may play a role in controlling the clathrin-coated vesicles [135]. The association of FKBP36 with GAPDH results in inhibition of GAPDH catalytic activity and reduction in the expression level of GAPDH [136]. These findings suggest that the action mechanism of FKBP36 is similar to that of FKBP51 and FKBP52, which involves formation of multiple complexes. It appears that FKBP36 acts as a scaffolding protein through its multiple binding domains to facilitate protein interactions.

2.6. FKBP37

FKBP37 is an aryl hydrocarbon receptor-interacting protein that contains a typical PPIase domain at its N-terminus and a TPR domain at its C-terminus (Fig. 1). FKBP37 does not bind to FK506 and exhibits no PPIase activity. FKBP37 has been found to interact with Hsp90 through its PPIase and TRP domains [137].

2.7. Endoplasmic reticulum FKBPs

There are six FKBP proteins known to be localized to the ER, including FKBP13, FKBP19, FKBP22, FKBP23, FKBP60, and FKBP65. These proteins contain an N-terminal ER-targeting sequence and a C-terminal ER retention motif, except FKBP19, which contains a lysine-rich C-terminal tail. These ER FKBPs are involved in regulation protein folding in the ER and secretory pathway.

FKBP13 is closely related to FKBP12. In comparison with FKBP12, the extra length of the protein is comprised of an N-terminal ER-targeting signal peptide and C-terminal ER retention sequence [138]. FKBP13 displays a PPIase activity that is sensitive to FK506 and rapamycin. However, it is unable to form a complex with CaN in the presence of FK506 [138, 139]. FKBP13 participates in protein folding and trafficking in the ER. It is constitutively expressed under normal condition, but can be induced in response to accumulation of unfolded proteins during ER stress [140]. FKBP13 has been found to interact with brefeldin A-inhibited guanine nucleotide-exchange protein 1(BIG1) for ADP-ribosylation factors that are involved in regulation of membrane trafficking [141]. FK506 but not rapamycin enhances the interaction, indicating that this association may be analogous to those of FKBP12 and CaN [142]. Surprisingly, FKBP13 is also found to interact with erythrocyte membrane cytoskeletal protein 4.1G outside of ER, indicating a novel function of FKBP13 in the membrane cytoskeleton [143].

FKBP19 is mainly expressed secretory tissues and is believed to function in protein folding and secretion. In addition to the PPIase domain, it possesses a cleavable leucinerich N-terminal sequence, a putative transmembrane domain, and a lysine-rich C-terminal tail often found in ER membrane proteins [9]. The PPIase domain binds FK506 weakly in vitro. FKBP19 is highly expressed in the tumor tissue of hepatocellular carcinoma, suggesting that it may play a role in hepatic tumor development [144].

The other members of the ER FKBPs all contain two EF-hand motifs that bind to Ca2+. In FKBP22, the EF-hand motifs mediate the dimerization of the protein [145, 146]. In FKBP23, the motifs are involved in regulating its interaction with the immunoglobulin(Ig) heavy-chain-binding protein (BiP), a molecular chaperone of Hsp70 family [147]. This interaction is mediated through the PPIase domain of FKBP23 but is regulated by Ca2+ concentration through the EF-hand motifs [147]. It is likely that the EF-hand motif imparts a Ca2+ dependent regulation on the function of these proteins.

Two members of the ER FKBP group, FKBP60 and FKBP65, are unique in that both contain four tandem PPIase domains [7, 148]. FKBP60 displays PPIase activity which is inhibited by FK506. It binds Ca2+ in vitro, presumably through its C-terminal EF-hand motifs, and is phosphorylated in vivo [148]. FKBP65 modulates the folding of collagen and interacts with tropoelastin, both of which are proline-rich proteins in the extracellular matrix of tissues [149]. FKBP65 is degraded following ER stresses along with the Ca2+ release from ER. The EF-hand Ca2+ binding motifs of FKBP65 influence the stability of FKBP65 [150].

2.8. FKBP25

FKBP25 is a nuclear DNA-binding protein in FKBPs family that is predominantly localizes to the nucleus. It is involved in regulating transcription and chromatin structure. The FKBP25 comprises a hydrophilic helix-loop-helix (HLH) motif at its N-terminus, PPIase domain at its C-terminus, and a nuclear targeting sequence [151]. The HLH motif is responsible for binding to DNA [152]. Its PPIase domain shares 43% homology with FKBP12 and displays PPIase activity, which is sensitive to rapamycin and FK506 [151]. FKBP25 physically interacts with the histone deacetylases HDAC1 and HDAC2 as well as the HDAC-binding transcriptional regulator YY1 [153]. The expression of FKBP25 can be repressed in a P53-dependent manner [154]. FKBP25 is also involved in regulating ubiquitination and degradation of oncogene MDM2 and P53 expression [155].

2.9. FKBP133

FKBP133, also named as WAFL, comprises a Wiskott-Aldrich syndrome protein homology region1(WH1) and a PPIase domain [156]. FKBP133 is mainly expressed in the developing nervous system. It localizes to the growth cones of dorsal root ganglion neurons and influences the growth cone size and the number of filopodia. Overexpressing FKBP133 protects neurons from Semaphorin-3A induced collapse response [156]. At cellular level the protein is involved in modulation of early endosomes at the actin and microtubule dynamics [157].

3. NEURONAL FUNCTIONS OF FKBPs AND THEIR IMPLICATIONS IN THE PATHOPHYSIOLOGY OF NEUROLOGICAL DISEASES

The peripheral and central nervous systems are highly enriched in FKBPs [158159]. Abundant expression of several FKBPs have been detected in neurons, including FKBP12, FKBP38, FKBP51, FKBP52 and FKBP65, which are collectively termed as neuroimmunophilins [160]. The initial interest in these neuroimmunophilins arose from the observations that FK506 possessed neurotrophic and neuroprotective effects in cultured neurons and in animal models. Early studies focused mainly on FKBP12 and calcineurin, the mechanistic target of FK506 in immunosuppression, which is also highly expressed in neuron and glial cells [161]. However, it was subsequently found that the mechanisms underlying the neurotrophic and neuroprotective effects of FK506 are far more complicated than initially expected, of which neither FKBP12 nor CaN appears to play a direct role.

3.1. FKBPs in Neuroprotection and Regeneration

The observation that FKBP12 was strongly expressed in the nervous system fueled studies into the neurological effects of immunophilin ligand FK506 [159]. Several studies demonstrated that FK506 possessed neurotrophic and neuroprotective properties. In cultured PC12 cells and rat sensory ganglia FK506 enhanced neurite outgrowth [162]. In a rat model of peripheral nerve injury, administration of FK506 increased functional recovery and nerve regeneration [163]. A neuronal protective effect of FK506 was also observed in an in vivo model of focal cerebral ischemia, in which case administration of FK506 was found to exhibit a profound protective effect against neuronal damage. The protective effect was not seen with another CaN inhibitor, CsA, indicating that it was not caused by inhibition of CaN [164]. Subsequently, several non-immunosuppressive FK506 analogs were developed and tested for their neurological effects in a variety of animal models. It was found that the nonimmunosuppressive analogs retained their activity in neuroprotection and recovery, ruling out CaN as the mediator of the neurotrophic effect for the immunophilin ligands [165167]. Surprisingly, the neurotrophic properties of FK506 were also preserved in FKBP12 deficient primary neurons, indicating that FKBP12 might not be involved [168]. Consistent with the notion, it was later found that immunophilin ligands devoid of FKBP12 binding activity retained their ability to promote neurite outgrowth and regeneration [169].

Because FK506 binds to other neuroimmunophilins in addition to FKBP12, several studies examined the role of some large neuroimmunophilins in FK506 mediated neurotrophic effect. In a rat model of transient focal cerebral ischemia, inhibition of FKBP38 by a cycloheximide derivative, N-(N’,N’-dimethylcarboxamidomethyl) cycloheximide, was able to reduce neuronal damage and enhance neuroregeneration. Since FKBP38 is also a target of FK506, this finding indicates that this immunophilin may mediate the neurotrophic effect of FK506 [170]. In human neuroblastoma SH-SY5Y cells, the neurotrophic action of FK506 was blocked by FKBP52 specific antibody, which had led to the suggestion that FKBP52, rather than FKBP12, might mediate the action of FK506 [171]. However, a recent study using inhibitors selective against FKBP51 but not FKBP52 showed that inhibition of FKBP51 enhanced neurite outgrowth in neuronal cultures, indicating that FKBP51 was responsible for the neuronal effect of FK506 [172]. The action of FKBP51 in neurite growth has been suggested to be mediated through the steroid hormone receptor signaling. Selective inhibition of FKBP51 enhances glucocorticoid receptor activation by increasing the receptor sensitivity to the hormone [173]. In animal models, in addition to the neurotrophic effect, inhibition of FKBP51 was found to improve stress-coping behavior [172]. This finding is consistent with the role of FKBP51 in stress-associated psychiatric diseases. Polymorphisms in this gene have been found to be associated with risks for developing depressive behavior in human [174]. Targeting FKBP51 may thus represent a potential therapeutic strategy for treating depression and other stress-related disorders.

3.2. FKBPs in Neurodegenerative Diseases

The functions of neuroimmunophilins are implicated in some neurodegenerative diseases, such as Parkinson ‘s dis ease (PD) and Alzheimer ‘s disease (AD). FKBP12 has been shown to associate with α-synuclein, a small soluble protein predominantly localized in presynaptic termini. In PD, α-synuclein aggregates and forms cytoplasmic proteinaceous inclusion bodies (Lewy bodies) that interfere with the function of dopaminergic neurons [175]. In vitro FKBP12 was found to bind and facilitate α-synuclein aggregation [176]. In cultured neurons knockdown of FKBP12 was able to reduce oxidative stress induced formation of α-synuclein aggregates and protect neurons from stress-induced cell death [177]. These observations indicate that FKBP12 may play a role PD pathophysiology through regulation of α-synuclein aggregation. Two other FKBPs, FKBP51 and FKBP52, are implicated in the pathophysiology of AD for their role in regulation of tau, a microtubule associated protein that stabilizes microtubule [178]. Hyperphosphorylated tau forms intraneuronal aggregates called neurofibrillary tangles which contribute to the degradation of the neurons in the regions of brain involved in learning and memory in AD patients [179]. FKBP52 binds to hyperphosphorylated Tau and blocks its ability to induce microtubule assembly [180]. When interacts with the pathological mutant of Tau (P301L), FKBP52 also promotes tau oligomerization [181]. In contrast, FKBP51, in complex with HSP90, binds to tau and promotes its dephosphorylation and reassociation with microtubule [182]. While these in vitro studies suggest a potential role for the neuroimmunophilins in PD and AD, the lacking of data from appropriate animal models of PD and AD hinders the evaluation of their pathological relevance in the neurodegenerative diseases.

4. FKBPs IN CANCER DEVELOPMENT

Given the diverse functions of FKBPs in intracellular signaling, it is not surprising that many of the proteins are found to be involved in cancer development. Among them, FKBP51 has emerged as a key regulator in several cancers, including prostate cancer, leukemia, melanoma and pancreatic cancer [129, 183185]. In prostate cancer FKBp51 plays a positive role in cancer progression. This cancer promoting function of FKBP51 is associated with its regulation of androgen dependent transcription [123, 186]. FKBP51 has been found to associate androgen receptor (AR) and overexpression of FKBP51 stimulates AR transcriptional activity and cell proliferation [187]. In androgen independent prostate cancer cells, high level of FKBP51 is believed to sustain AR signaling in the absence of androgen [188]. In melanomas FKBP51 expression correlates with the invasiveness and aggressiveness of the cancer [189]. It has been shown that FKBP51 exhibits anti-apoptosis activity and protects the cancer cells from irradiation induced cell death [127, 189]. This pro-survival function of FKBP51 is mediated through NF-κB [190]. In response to irradiation FKBP51 stimulates NF-κB activation, which suppresses apoptosis by stimulating X-linked inhibitor of apoptosis (XIAP) and downregulating Bax [189]. FKBP51 may also promote melanoma cell migration and invasion by increasing TGF-β signaling and activation of epithelial-to-mesenchymal transition (EMT) genes [191, 192]. In contrast to the positive role in prostate cancer and melanoma, FKBP51 appears to play a negative role in pancreatic cancer [193, 194]. Analysis of tumor samples of pancreatic cancer revealed a downregulation in the expression level of FKBP51 [129]. In a pancreatic cancer xenograft mice model, knockdown of FKBP5 was found to promote tumor growth and enhance resistance to gemcitabine, a chemotherapeutic agent. The negative effect of FKBP51 on pancreatic cancer is mediated through phosphatase PHLPP. It has been shown that FKBP51 associates with the phosphatase and stimulates its activity, which in turn dephopshorylates AKT and its pro-survival function [129]. This cancer cell specific effect of FKBP51 is consistent with its multifaceted activities in many signaling events. Depending on the signaling events that are dominant in different types of cancer cells, FKBP51 may exhibit different effects on cancer growth. In addition to FKBP51, several other FKBPs have also been implicated in cancer development, including FKBP38. In Schwannomas cell lines the expression level of FKBP38 has been found to correlate inversely with the rate of cell growth [49]. In a melanomas xenografts model, over-expression of FKBP38 was found to reduce tumor growth [54]. Study of the gene expression in a prostate cancer xenograft model also revealed an inverse correlation between the expression level of FKBP38 and the progression of tumors during androgen depletion treatment [195]. The tumor suppressive activity of FKBP38 is consistent with its negative role in regulation of mTOR. In many types of cancer cells an enhanced mTOR signaling activity is essential for tumor growth and progression. As an inhibitor of mTOR, an increase in FKBP38 expression is expected to reduce mTOR activity and hence inhibits tumor growth [196].

5. CONCLUSION

Since the isolation of FKBP12 as an immunophilin that displays PPIase activity 25 years ago, many proteins sharing sequence similarity to FKBP12 have been identified from yeast to human, hence constituting the family of FKBPs. The members of this conserved protein family are involved in diverse biological functions. In all the cases examined, the PPIase domain of the FKBPs appears to be essential for their function. In addition to protein folding and chaperone functions, the PPIase domain in many FKBPs is involved in mediating protein-protein interaction. It has been suggested that the PPIase activity of the domain acts as a molecular switch that allosterically regulates the conformation of the target proteins by catalyzing the interconversion of prolyl cis/trans isomerization [10]. Together with the TPR domains, which are commonly found in FKBPs, one FKBP is able to interact with multiple proteins, allowing it to function as a scaffolding protein to nucleate the formation of large protein complexes [197]. In addition, The Ca2+/CaM and EF-hand motifs impart Ca2+ dependent regulation into the action of FKBPs. In such a way, FKBPs act as a group of molecular switches that control many cellular functions.

The prospect for targeting FKBPs in disease prevention and treatment, particularly in neurodegenerative disorders, has been a central theme in field of FKBP related studies, since the discovery of FKBP12 as the mediator for the therapeutic effects of FK506 and rapamycin. However, the ensuing effort has so far met limited success. A few nonimmunosuppressive FK506 analogs that made to clinical trials have failed due to lack of therapeutic efficacy [198, 199]. However, accumulating data from the last decade have allowed a better understanding the roles of each FKBP in many diverse cellular processes and signaling events. The gained insights are to guide future development of therapeutic agents that specifically target individual member of FKBPs.

ACKNOWLEDGEMENTS

The authors would like to thank laboratory members for stimulating discussion and comments during the preparation of the manuscript. This work is supported by NIH grant (CA169186) to YJ.

Biography

graphic file with name nihms-1034970-b0001.gif

Yu Jiang

Footnotes

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

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