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FKBP5 (FK506 binding protein 5)

Written2013-10Katarzyna Anna Ellsworth, Liewei Wang
Division of Clinical Pharmacology, Department of Molecular Pharmacology, Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA

(Note : for Links provided by Atlas : click)


Alias_namesFK506-binding protein 5
Alias_symbol (synonym)FKBP51
Other aliasAIG6
LocusID (NCBI) 2289
Atlas_Id 40578
Location 6p21.31  [Link to chromosome band 6p21]
Location_base_pair Starts at 35573585 and ends at 35728583 bp from pter ( according to hg19-Feb_2009)  [Mapping FKBP5.png]
Fusion genes
(updated 2016)
FKBP5 (6p21.31) / ASPH (8q12.3)FKBP5 (6p21.31) / FKBP5 (6p21.31)FKBP5 (6p21.31) / FNDC3B (3q26.31)
FKBP5 (6p21.31) / ZNF347 (19q13.42)LOC285847 (6p21.31) / FKBP5 (6p21.31)POU2AF1 (11q23.1) / FKBP5 (6p21.31)
TMPRSS2 (21q22.3) / FKBP5 (6p21.31)TRAPPC12 (2p25.3) / FKBP5 (6p21.31)


  Figure 1. (A) Schematic diagram of FKBP5 location on chromosome 6. 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.
Description FKBP5 gene is located on short arm of chromosome 6 (6p21.31). FKBP5 gene ranges from 35541362 to 35696360 on reverse strand with a total length of 154999 bp including 10 coding exons.
Transcription This gene has been found to have multiple polyadenylation sites. Transcription of FKBP5 gene produces 4 different transcript variants due to alternative splicing (RefSeq, Mar 2009). NM_004117 is the transcript most widely referred to, and its mRNA is 3803 bp long.


Note Protein name: FK506 binding protein 51, FKBP51, Peptidyl-prolyl cis-trans isomerase (PPIase). It is encoded by the FKBP5 gene (Nair et al., 1997).
  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.
Description FKBP51 is a member of immunophilin family, proteins characterized by their ability to bind immunosuppresive drugs. Additionally, immunophilins are peptidylprolyl isomerases (PPIase) that catalyze the cis-trans conversion of peptidylprolyl bonds, a reaction important for protein folding (Fischer et al., 1984). Sinars et al. (Sinars et al., 2003) initially showed the structure of FKBP51 and the orientation of its domains. The N-terminal domain, FK1, is an active rotamase domain (peptidyl-prolyl isomerase; PPIase) which is required to bind immunosuppressive drugs, such as FK506 (tacrolimus). In addition, it is responsible for binding to the kinase Akt (Pei et al., 2009). The FK2 domain, needed for interaction with some binding partners (Figure 2), does not show measurable PPIase activity. The TRP domain consists of three highly degenerate 34 amino acid repeats TPR repeats, and is responsible for multiple protein-protein interactions (figure 2), for example with Hsp90 (Cheung-Flynn et al., 2003), progesterone receptor (PR) (Barent et al., 1998), PH domain and leucine rich repeat protein phosphatase (PHLPP) (Pei et al., 2009).
Expression FKBP5 is ubiquitously expressed with different levels of distribution in various tissues. Tissue examples include amygdala, kidney, heart, hippocampus, liver skeletal muscle, peripheral blood, placenta, thymus, testis, uterus, and others, with lower levels of expression in pancreas, spleen, and stomach (Baughman et al., 1997). Up to date it has been established that FKBP5 expression is regulated by glucocorticoids, progestins, and androgens (Hubler et al., 2003; Hubler and Scammell, 2004; Makkonen et al., 2009; Paakinaho et al., 2010).
Localisation FKBP5 localizes to cytoplasm and nucleus.
Function FKBP5 plays multiple important roles in cellular process. Since it has peptidyl-prolyl isomerase (PPIase) activity, it regulates protein folding (Galat, 1993; Fruman et al., 1994). In addition, FKBP5 can associate with chaperones, thus playing a role in cell trafficking (Schiene-Fischer and Yu, 2001). Also, it influences steroid receptor signaling (Denny et al., 2000; Barent et al., 1998; Ni et al., 2010), NFκB pathway (Bouwmeester et al., 2004), as well as Akt pathway (Pei et al., 2009). Moreover, FKBP5 plays a role in regulating drug responses (Jiang et al., 2008; Li et al., 2008; Hou and Wang, 2012; Binder et al., 2004).


Note Next Generation resequencing of FKBP5 gene was performed using 96 Caucasian American samples and identified 657 single nucleotide polymorphisms (SNPs) (Ellsworth et al., 2013b). In addition, Next Generation resequencing was also performed using 60 samples from pancreatic cancer patients and identified 404 SNPs (Ellsworth et al., 2013a). All of these polymorphisms are germinal SNPs.
Somatic It has been reported that four confirmed somatic mutations in various cancer tissues has been identified (V37V: silent (ovary) M97I: missense (breast) (Cancer Genome Atlas Research Network, 2011), Y113Y: silent (pancreas) (Biankin et al., 2012), S309L: missense (endometrium, lung, large intestine) (Liu et al., 2012).

Implicated in

Entity Cancer and response to chemotherapy
Note FKBP51 is an important protein involved in the regulation of many key signaling cascades in the cell, such as Akt (Pei et al., 2009), NFκB (Bouwmeester et al., 2004), and androgen receptor pathways (Ni et al., 2010). All of these signalling pathways are implicated in tumorigenesis and response to drug treatment. It has been suggested that the contribution of FKBP5 in tumorgenesis and antineoplastic therapy is tissue-specific. Depending on the cellular context, FKBP5 can either promote or inhibit tumor progression and chemoresistance.
Entity Pancreatic cancer
Note The Akt pathway is one of the most important signaling pathways, playing a role in regulation of many cellular processes, including cell proliferation, growth, and other processes that crucial for cell survival (Manning and Cantley, 2007). Akt is a serine/threonine kinase that in order to become fully activated needs its residues: Ser473 and Thr308 to be phosphorylated. This is facilitated by phosphoinositide 3-kinase (PIP3), as well as PDK1, and mTOR complex 2 (Alessi et al., 1996; Engelman et al., 2006; Sarbassov et al., 2005). Conversely, phosphatases, such as PP2 holoenzymes and PHLPP de-phosphorylate Akt, halting its activity (Brognard et al., 2007; Carracedo and Pandolfi, 2008; Gao et al., 2005; Padmanabhan et al., 2009). The balance in phosphorylation levels of Akt determines its pathway activity, therefore affecting all the downstream cellular events. If Akt pathway becomes highly up-regulated, it potentially could lead to tumor development, progression and eventually to chemotherapy resistance (Pei et al., 2010). Genome-wide association studies of cytidine analogues identified FKBP5 low expression levels to be associated with resistance to many chemotherapeutic drugs (Li et al., 2008; Pei et al., 2009). Functional studies of FKBP5 demonstrated that FKBP51 acts as a scaffolding protein increasing interaction between Akt's phosphatase - PHLPP and Akt, thus decreasing the phosphorylation of Akt-Ser473 (Pei et al., 2009). It was shown, that in pancreatic and breast cancer cells FKBP5 expression levels are decreased, while the phosphorylation of Akt-Ser473 is increased, which could lead to chemoresistance. Also, it suggested that FKBP5 might function as a tumor suppressor gene through the down-regulation of Akt activation (Pei et al., 2009, Hou and Wang, 2012).
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.
Entity Acute lymphoblastic leukemia, glioma, melanoma
Note FKBP5 plays a pivotal role in regulating NF-κB pathway (Bouwmeester et al., 2004). Specifically, FKBP51 interacts with several members of the NF-κB pathway including inhibitors of NF-κB kinase: IKKα, IKKε, TAK1 and MEKK1. It was shown, that FKBP51 enzymatic activity is required for IKK activation, which suggested that FKBP5 plays an important role in this pathway. Avellino et al. demonstrated, that the addition of rapamycin, a known inhibitor of FKBP51 enzymatic (PPIase) activity, to anthracycline treatment of blasts from chronic childhood acute lymphoblastic leukemia (ALL) patients would sensitize these cells to anthracyclines (Avellino et al., 2005). These experiments suggested that the combination treatment of rapamycin and doxorubicin inhibits the activation of the NF-κB pathway, which leads to an increase in apoptosis, and, in turn, an increase in sensitivity to chemotherapy (Avellino et al., 2005). Since NF-κB pathway activation leads to anti-apoptotic signals, therefore, in this case, FKBP5 plays a role in chemoresistance to drugs such as anthracyclines. In addition, in glioma cells, FKBP5 expression contributes to glioma cells growth and sensitivity to rapamycin through regulation of the NF-κB pathway (Jiang et al., 2008). FKBP5 was also described to influence radioresistance in melanoma cells (Romano et al., 2010). Specifically, it was found that in melanoma samples FKBP51 controlled radioresistance through the activation of NF-κB pathway, and by silencing expression of FKBP5 in tumors in vitro and in vivo, it contributed to an increase in apoptosis after irradiation.
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 NFκB, which promotes cell survival and chemoresistance. Rapamycin can specifically inhibit FKBP5 enzymatic activity, which leads to decrease in NFκB pathway activation and increase in apoptosis upon chemotherapy treatment.
Entity Prostate cancer
Note FKBP5 influences androgen receptor signaling in prostate cancer. Androgen receptor (AR) is a transcription factor, regulating expression of multiple genes, including FKBP5 (Makkonen et al., 2009). Additionally, FKBP5 is a part of a positive feedback loop that not only is having its expression regulated by AR and androgen binding, but it also facilitates androgen-dependent transcription. Ni et al. (Ni et al., 2010) reported that FKBP5 forms a superchaperone complex with ATP-bound Hsp90 and p23 that increases binding of androgen to its receptor. This allows for androgen-dependent gene transcription activation and promotes cell growth, which is especially important during prostate cancer progression to the androgen-independent state during disease progression and tumor growth (Ni et al., 2010).
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.
Entity Depression, post-traumatic stress disorder
Note It has been established that one of the major functions of FKBP51 is to co-chaperone with HSP family members steroid receptors: glucocorticoid (GR) (Denny et al., 2000), progesterone (PR) (Barent et al., 1998), and androgen (AR) (Ni et al., 2010). In addition, FKBP5 intronic regions contain hormone response elements (HRE) that upon GR, PR, or AR activation bind their respective hormones. That, in turn, induces the FKBP5 gene transcription (Hubler et al., 2003; Hubler and Scammell, 2004; Makkonen et al., 2009; Paakinaho et al., 2010) leading to increases in the amount of FKBP51 protein in the cell. FKBP5 modulates steroid hormones binding affinity; therefore it affects their signaling pathways. For example FKBP51 plays an important role in regulating the activity of the glucocorticoid receptor (Davies et al., 2005). When FKBP51 is bound to the GR-complex, the receptor has lower affinity for glucocorticoids, which causes an increase of glucocorticoids in the intercellular environment. On the other hand, once glucocorticoid is bound, FKBP51 dissociate from the complex and is exchanged with FKBP52. That allows for the translocation of GR into the nucleus and interaction with DNA. Once, in the nucleus GR acts as a transcription factor and by binding to glucocorticoid receptor response elements (GRE) of FKBP5 increases its transcription. That leads to increased concentrations of FKBP51 that contribute to higher GR resistance, completing a negative feedback loop on GR sensitivity (Binder, 2009). Since GR plays a role in regulating a stress response, if FKBP5 expression is altered, it could potentially contribute to development of mood disorders, such as depression or post-traumatic stress disorder (Binder, 2009; Binder et al., 2008; Binder et al., 2004).
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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This paper should be referenced as such :
Ellsworth, KA ; Wang, L
FKBP5 (FK506 binding protein 5)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(5):314-320.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Prostate: Carcinoma with t(8;21)(q24;q22) NDRG1/ERG

External links

HGNC (Hugo)FKBP5   3721
Entrez_Gene (NCBI)FKBP5  2289  FK506 binding protein 5
AliasesAIG6; FKBP51; FKBP54; P54; 
PPIase; Ptg-10
GeneCards (Weizmann)FKBP5
Ensembl hg19 (Hinxton)ENSG00000096060 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000096060 [Gene_View]  chr6:35573585-35728583 [Contig_View]  FKBP5 [Vega]
ICGC DataPortalENSG00000096060
TCGA cBioPortalFKBP5
Genatlas (Paris)FKBP5
SOURCE (Princeton)FKBP5
Genetics Home Reference (NIH)FKBP5
Genomic and cartography
GoldenPath hg38 (UCSC)FKBP5  -     chr6:35573585-35728583 -  6p21.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FKBP5  -     6p21.31   [Description]    (hg19-Feb_2009)
EnsemblFKBP5 - 6p21.31 [CytoView hg19]  FKBP5 - 6p21.31 [CytoView hg38]
Mapping of homologs : NCBIFKBP5 [Mapview hg19]  FKBP5 [Mapview hg38]
OMIM602623   608516   
Gene and transcription
Genbank (Entrez)AB209893 AF194172 AK222807 AK302704 AK303356
RefSeq transcript (Entrez)NM_001145775 NM_001145776 NM_001145777 NM_004117
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)FKBP5
Cluster EST : UnigeneHs.407190 [ NCBI ]
CGAP (NCI)Hs.407190
Alternative Splicing GalleryENSG00000096060
Gene ExpressionFKBP5 [ NCBI-GEO ]   FKBP5 [ EBI - ARRAY_EXPRESS ]   FKBP5 [ SEEK ]   FKBP5 [ MEM ]
Gene Expression Viewer (FireBrowse)FKBP5 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2289
GTEX Portal (Tissue expression)FKBP5
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13451   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13451  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13451
Splice isoforms : SwissVarQ13451
Catalytic activity : Enzyme5.2.1.8 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   
Domaine pattern : Prosite (Expaxy)FKBP_PPIASE (PS50059)    TPR (PS50005)    TPR_REGION (PS50293)   
Domains : Interpro (EBI)Elongated_TPR_rpt_dom    FKBP5    PPIase_FKBP    PPIase_FKBP_dom    TPR-contain_dom    TPR-like_helical_dom    TPR_1    TPR_repeat   
Domain families : Pfam (Sanger)FKBP_C (PF00254)    TPR_1 (PF00515)    TPR_8 (PF13181)   
Domain families : Pfam (NCBI)pfam00254    pfam00515    pfam13181   
Domain families : Smart (EMBL)TPR (SM00028)  
Conserved Domain (NCBI)FKBP5
DMDM Disease mutations2289
Blocks (Seattle)FKBP5
PDB (SRS)1KT0    3O5D    3O5E    3O5F    3O5G    3O5I    3O5J    3O5K    3O5L    3O5M    3O5O    3O5P    3O5Q    3O5R    4DRH    4DRI    4DRK    4DRM    4DRN    4DRO    4DRP    4DRQ    4JFI    4JFJ    4JFK    4JFL    4JFM    4R0X    4TW6    4TW7    4TX0    4W9O    4W9P    4W9Q    5BXJ    5DIT    5DIU    5DIV   
PDB (PDBSum)1KT0    3O5D    3O5E    3O5F    3O5G    3O5I    3O5J    3O5K    3O5L    3O5M    3O5O    3O5P    3O5Q    3O5R    4DRH    4DRI    4DRK    4DRM    4DRN    4DRO    4DRP    4DRQ    4JFI    4JFJ    4JFK    4JFL    4JFM    4R0X    4TW6    4TW7    4TX0    4W9O    4W9P    4W9Q    5BXJ    5DIT    5DIU    5DIV   
PDB (IMB)1KT0    3O5D    3O5E    3O5F    3O5G    3O5I    3O5J    3O5K    3O5L    3O5M    3O5O    3O5P    3O5Q    3O5R    4DRH    4DRI    4DRK    4DRM    4DRN    4DRO    4DRP    4DRQ    4JFI    4JFJ    4JFK    4JFL    4JFM    4R0X    4TW6    4TW7    4TX0    4W9O    4W9P    4W9Q    5BXJ    5DIT    5DIU    5DIV   
PDB (RSDB)1KT0    3O5D    3O5E    3O5F    3O5G    3O5I    3O5J    3O5K    3O5L    3O5M    3O5O    3O5P    3O5Q    3O5R    4DRH    4DRI    4DRK    4DRM    4DRN    4DRO    4DRP    4DRQ    4JFI    4JFJ    4JFK    4JFL    4JFM    4R0X    4TW6    4TW7    4TX0    4W9O    4W9P    4W9Q    5BXJ    5DIT    5DIU    5DIV   
Structural Biology KnowledgeBase1KT0    3O5D    3O5E    3O5F    3O5G    3O5I    3O5J    3O5K    3O5L    3O5M    3O5O    3O5P    3O5Q    3O5R    4DRH    4DRI    4DRK    4DRM    4DRN    4DRO    4DRP    4DRQ    4JFI    4JFJ    4JFK    4JFL    4JFM    4R0X    4TW6    4TW7    4TX0    4W9O    4W9P    4W9Q    5BXJ    5DIT    5DIU    5DIV   
SCOP (Structural Classification of Proteins)1KT0    3O5D    3O5E    3O5F    3O5G    3O5I    3O5J    3O5K    3O5L    3O5M    3O5O    3O5P    3O5Q    3O5R    4DRH    4DRI    4DRK    4DRM    4DRN    4DRO    4DRP    4DRQ    4JFI    4JFJ    4JFK    4JFL    4JFM    4R0X    4TW6    4TW7    4TX0    4W9O    4W9P    4W9Q    5BXJ    5DIT    5DIU    5DIV   
CATH (Classification of proteins structures)1KT0    3O5D    3O5E    3O5F    3O5G    3O5I    3O5J    3O5K    3O5L    3O5M    3O5O    3O5P    3O5Q    3O5R    4DRH    4DRI    4DRK    4DRM    4DRN    4DRO    4DRP    4DRQ    4JFI    4JFJ    4JFK    4JFL    4JFM    4R0X    4TW6    4TW7    4TX0    4W9O    4W9P    4W9Q    5BXJ    5DIT    5DIU    5DIV   
Human Protein AtlasENSG00000096060
Peptide AtlasQ13451
IPIIPI00218775   IPI01010266   IPI01015705   IPI01015323   IPI00443474   IPI00556067   
Protein Interaction databases
IntAct (EBI)Q13451
Ontologies - Pathways
Ontology : AmiGOprotein peptidyl-prolyl isomerization  peptidyl-prolyl cis-trans isomerase activity  protein binding  FK506 binding  nucleoplasm  cytoplasm  protein folding  membrane  heat shock protein binding  chaperone-mediated protein folding  extracellular exosome  
Ontology : EGO-EBIprotein peptidyl-prolyl isomerization  peptidyl-prolyl cis-trans isomerase activity  protein binding  FK506 binding  nucleoplasm  cytoplasm  protein folding  membrane  heat shock protein binding  chaperone-mediated protein folding  extracellular exosome  
Pathways : KEGGEstrogen signaling pathway   
NDEx NetworkFKBP5
Atlas of Cancer Signalling NetworkFKBP5
Wikipedia pathwaysFKBP5
Orthology - Evolution
GeneTree (enSembl)ENSG00000096060
Phylogenetic Trees/Animal Genes : TreeFamFKBP5
Homologs : HomoloGeneFKBP5
Homology/Alignments : Family Browser (UCSC)FKBP5
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFKBP5 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FKBP5
Exome Variant ServerFKBP5
ExAC (Exome Aggregation Consortium)FKBP5 (select the gene name)
Genetic variants : HAPMAP2289
Genomic Variants (DGV)FKBP5 [DGVbeta]
DECIPHERFKBP5 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFKBP5 
ICGC Data PortalFKBP5 
TCGA Data PortalFKBP5 
Broad Tumor PortalFKBP5
OASIS PortalFKBP5 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFKBP5  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDFKBP5
intOGen PortalFKBP5
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch FKBP5
DgiDB (Drug Gene Interaction Database)FKBP5
DoCM (Curated mutations)FKBP5 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FKBP5 (select a term)
NCG5 (London)FKBP5
Cancer3DFKBP5(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM602623    608516   
Genetic Testing Registry FKBP5
NextProtQ13451 [Medical]
Target ValidationFKBP5
Huge Navigator FKBP5 [HugePedia]
snp3D : Map Gene to Disease2289
BioCentury BCIQFKBP5
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2289
Chemical/Pharm GKB GenePA28162
Clinical trialFKBP5
canSAR (ICR)FKBP5 (select the gene name)
PubMed209 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Mon May 22 09:11:26 CEST 2017

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