Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST -CNRS

Gene Section Review

FKBP5 (FK506 binding 5) Katarzyna Anna Ellsworth, Liewei Wang Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA (KAE, LW)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/FKBP5ID40578ch6p21.html DOI: 10.4267/2042/53641 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Description FKBP51 is a member of immunophilin family, Review on FKBP5, with data on DNA/RNA, on the characterized by their ability to bind protein encoded and where the is implicated. immunosuppresive drugs. Additionally, are peptidylprolyl Identity (PPIase) that catalyze the cis-trans conversion of Other names: AIG6, FKBP51, FKBP54, P54, peptidylprolyl bonds, a reaction important for PPIase, Ptg-10 protein folding (Fischer et al., 1984). Sinars et al. HGNC (Hugo): FKBP5 (Sinars et al., 2003) initially showed the structure of FKBP51 and the orientation of its domains. The N- Location: 6p21.31 terminal domain, FK1, is an active rotamase domain (peptidyl-prolyl ; PPIase) which DNA/RNA is required to bind immunosuppressive drugs, such Description as FK506 (). In addition, it is responsible for binding to the FKBP5 gene is located on short arm of kinase Akt (Pei et al., 2009). The FK2 domain, 6 (6p21.31). needed for interaction with some binding partners FKBP5 gene ranges from 35541362 to 35696360 (Figure 2), does not show measurable PPIase on reverse strand with a total length of 154999 bp activity. The TRP domain consists of three highly including 10 coding exons. degenerate 34 amino acid repeats TPR repeats, and Transcription is responsible for multiple protein-protein This gene has been found to have multiple interactions (figure 2), for example with sites. (Cheung-Flynn et al., 2003), Transcription of FKBP5 gene produces 4 different (PR) (Barent et al., 1998), PH domain and leucine transcript variants due to alternative splicing rich repeat protein phosphatase (PHLPP) (Pei et al., (RefSeq, Mar 2009). 2009). NM_004117 is the transcript most widely referred Expression to, and its mRNA is 3803 bp long. FKBP5 is ubiquitously expressed with different Protein levels of distribution in various tissues. Tissue examples include amygdala, kidney, heart, Note hippocampus, liver skeletal muscle, peripheral Protein name: FK506 binding protein 51, FKBP51, blood, placenta, thymus, testis, uterus, and others, Peptidyl-prolyl cis-trans isomerase (PPIase). It is with lower levels of expression in pancreas, spleen, encoded by the FKBP5 gene (Nair et al., 1997). and stomach (Baughman et al., 1997).

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Figure 1. (A) Schematic diagram of FKBP5 location on . FKBP5 localizes to chromosome 6p21.31, which is represented graphically. FKBP5 gene spans over 154 kbp from 35541362 to 35696360 on reverse strand. The region surrounding FKBP5 gene is enlarged. (B) Schematic representation of FKBP5 mRNA structure, with indicated ATG translation start site in exon 2.

Up to date it has been established that FKBP5 2010), NF κB pathway (Bouwmeester et al., 2004), expression is regulated by glucocorticoids, as well as Akt pathway (Pei et al., 2009). Moreover, progestins, and androgens (Hubler et al., 2003; FKBP5 plays a role in regulating drug responses Hubler and Scammell, 2004; Makkonen et al., (Jiang et al., 2008; Li et al., 2008; Hou and Wang, 2009; Paakinaho et al., 2010). 2012; Binder et al., 2004). Localisation FKBP5 localizes to cytoplasm and nucleus. Mutations Function Note FKBP5 plays multiple important roles in cellular Next Generation resequencing of FKBP5 gene was process. Since it has peptidyl- performed using 96 Caucasian American samples (PPIase) activity, it regulates protein folding (Galat, and identified 657 single nucleotide polymorphisms 1993; Fruman et al., 1994). In addition, FKBP5 can (SNPs) (Ellsworth et al., 2013b). In addition, Next associate with chaperones, thus playing a role in Generation resequencing was also performed using cell trafficking (Schiene-Fischer and Yu, 2001). 60 samples from pancreatic cancer patients and Also, it influences steroid receptor signaling identified 404 SNPs (Ellsworth et al., 2013a). All of (Denny et al., 2000; Barent et al., 1998; Ni et al., these polymorphisms are germinal SNPs.

Figure 2. Functional domains of FKBP51. FKBP1 consists of 457 amino acids with three functional domains, as shown. FKBP51 binding proteins are indicated and listed by domain they interact with.

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Figure 3. Importance of FKBP5 in regulating activity of Akt pathway. FKBP5 acts as a scaffolding protein, enhancing the interaction of PHLPP and Akt, therefore promoting de-phosphorylation of Akt's Serine residue 473. That in turn eventually leads to inactivation of Akt pathway. FKBP5 expression and interaction with PHLPP is especially important upon chemotherapy treatment, because it inactivation of Akt leads to chemotoxic stress and directs cells towards apoptosis, rather than survival pathway.

Somatic Pancreatic cancer It has been reported that four confirmed somatic Note mutations in various cancer tissues has been The Akt pathway is one of the most important identified (V37V: silent (ovary) M97I: missense signaling pathways, playing a role in regulation of (breast) (Cancer Genome Atlas Research Network, many cellular processes, including cell 2011), Y113Y: silent (pancreas) (Biankin et al., proliferation, growth, and other processes that 2012), S309L: missense (endometrium, lung, large crucial for cell survival (Manning and Cantley, intestine) (Liu et al., 2012). 2007). Akt is a serine/threonine kinase that in order to Implicated in become fully activated needs its residues: Ser473 Cancer and response to and Thr308 to be phosphorylated. This is facilitated by phosphoinositide 3-kinase chemotherapy (PIP3), as well as PDK1, and mTOR complex 2 Note (Alessi et al., 1996; Engelman et al., 2006; FKBP51 is an important protein involved in the Sarbassov et al., 2005). regulation of many key signaling cascades in the Conversely, phosphatases, such as PP2 cell, such as Akt (Pei et al., 2009), NF κB holoenzymes and PHLPP de-phosphorylate Akt, (Bouwmeester et al., 2004), and androgen receptor halting its activity (Brognard et al., 2007; pathways (Ni et al., 2010). Carracedo and Pandolfi, 2008; Gao et al., 2005; All of these signalling pathways are implicated in Padmanabhan et al., 2009). tumorigenesis and response to drug treatment. The balance in phosphorylation levels of Akt It has been suggested that the contribution of determines its pathway activity, therefore affecting FKBP5 in tumorgenesis and antineoplastic therapy all the downstream cellular events. is tissue-specific. If Akt pathway becomes highly up-regulated, it Depending on the cellular context, FKBP5 can potentially could lead to tumor development, either promote or inhibit tumor progression and progression and eventually to chemotherapy chemoresistance. resistance (Pei et al., 2010).

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Figure 4. FKBP5 enzymatic activity regulates NF-κB pathway activation. Peptidylprolyl isomerase enzymatic activity of FKBP5 is required for IKKa activation and further phosphorylation of NF κB, which promotes cell survival and chemoresistance. Rapamycin can specifically inhibit FKBP5 enzymatic activity, which leads to decrease in NF κB pathway activation and increase in apoptosis upon chemotherapy treatment.

Genome-wide association studies of cytidine activity, to anthracycline treatment of blasts from analogues identified FKBP5 low expression levels chronic childhood acute lymphoblastic leukemia to be associated with resistance to many (ALL) patients would sensitize these cells to chemotherapeutic drugs (Li et al., 2008; Pei et al., anthracyclines (Avellino et al., 2005). These 2009). Functional studies of FKBP5 demonstrated experiments suggested that the combination that FKBP51 acts as a scaffolding protein treatment of rapamycin and doxorubicin inhibits the increasing interaction between Akt's phosphatase - activation of the NF-κB pathway, which leads to an PHLPP and Akt, thus decreasing the increase in apoptosis, and, in turn, an increase in phosphorylation of Akt-Ser473 (Pei et al., 2009). It sensitivity to chemotherapy (Avellino et al., 2005). was shown, that in pancreatic and breast cancer Since NF-κB pathway activation leads to anti- cells FKBP5 expression levels are decreased, while apoptotic signals, therefore, in this case, FKBP5 the phosphorylation of Akt-Ser473 is increased, plays a role in chemoresistance to drugs such as which could lead to chemoresistance. Also, it anthracyclines. In addition, in glioma cells, FKBP5 suggested that FKBP5 might function as a tumor expression contributes to glioma cells growth and suppressor gene through the down-regulation of sensitivity to rapamycin through regulation of the Akt activation (Pei et al., 2009, Hou and Wang, NF-κB pathway (Jiang et al., 2008). FKBP5 was 2012). also described to influence radioresistance in Acute lymphoblastic leukemia, melanoma cells (Romano et al., 2010). Specifically, it was found that in melanoma samples FKBP51 glioma, melanoma controlled radioresistance through the activation of Note NF-κB pathway, and by silencing expression of FKBP5 plays a pivotal role in regulating NF-κB FKBP5 in tumors in vitro and in vivo, it contributed pathway (Bouwmeester et al., 2004). Specifically, to an increase in apoptosis after irradiation. FKBP51 interacts with several members of the NF- κB pathway including inhibitors of NF-κB kinase: Prostate cancer IKK α, IKK ε, TAK1 and MEKK1. It was shown, Note that FKBP51 enzymatic activity is required for IKK FKBP5 influences androgen receptor signaling in activation, which suggested that FKBP5 plays an prostate cancer. Androgen receptor (AR) is a important role in this pathway. Avellino et al. transcription factor, regulating expression of demonstrated, that the addition of rapamycin, a multiple , including FKBP5 (Makkonen et al., known inhibitor of FKBP51 enzymatic (PPIase) 2009).

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Figure 5. Prostate cancer cell growth promotion under low-androgen conditions. Formation of ATP-bound Hsp90-FKBP5- p23 superchaperone complex allows for increased androgen and androgen receptor binding which promotes cell growth.

Additionally, FKBP5 is a part of a positive Depression, post-traumatic stress feedback loop that not only is having its expression regulated by AR and androgen binding, but it also disorder facilitates androgen-dependent transcription. Note Ni et al. (Ni et al., 2010) reported that FKBP5 It has been established that one of the major forms a superchaperone complex with ATP-bound functions of FKBP51 is to co-chaperone with HSP Hsp90 and p23 that increases binding of androgen family members steroid receptors: glucocorticoid to its receptor. This allows for androgen-dependent (GR) (Denny et al., 2000), progesterone (PR) gene transcription activation and promotes cell (Barent et al., 1998), and androgen (AR) (Ni et al., growth, which is especially important during 2010). In addition, FKBP5 intronic regions contain prostate cancer progression to the androgen- hormone response elements (HRE) that upon GR, independent state during disease progression and PR, or AR activation bind their respective tumor growth (Ni et al., 2010). hormones.

Figure 6. Negative feedback loop on GR sensitivity. When HSP90-GR is bound to the FKBP51, it has a lower affinity for GR ligand (glucocorticoids). However, once glucocorticoids bind to the complex, FKBP51 dissociates from the complex and FKBP52 binds instead. That allows for the GR translocation into the nucleus and exertion of its action as a transcription factor. GR also acts on FKBP5 via its glucocorticoid response elements (GREs), increasing its transcription, which leads to an increase in amount of FKBP51 protein in the cell. That, in turn, decreases the GR affinity for its ligand, completing this negative feedback loop on GR sensitivity.

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That, in turn, induces the FKBP5 gene transcription chimeras and mutants for Hsp90 binding and association (Hubler et al., 2003; Hubler and Scammell, 2004; with progesterone receptor complexes. Mol Endocrinol. 1998 Mar;12(3):342-54 Makkonen et al., 2009; Paakinaho et al., 2010) leading to increases in the amount of FKBP51 Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG. Squirrel monkey immunophilin FKBP51 is a protein in the cell. FKBP5 modulates steroid potent inhibitor of binding. hormones binding affinity; therefore it affects their Endocrinology. 2000 Nov;141(11):4107-13 signaling pathways. Schiene-Fischer C, Yu C. Receptor accessory folding For example FKBP51 plays an important role in helper : the functional role of peptidyl prolyl regulating the activity of the glucocorticoid receptor cis/trans isomerases. FEBS Lett. 2001 Apr 20;495(1-2):1-6 (Davies et al., 2005). Cheung-Flynn J, Roberts PJ, Riggs DL, Smith DF. 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