Alternative titles; symbols
HGNC Approved Gene Symbol: FKBPL
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:32,128,707-32,130,288 (from NCBI)
FKBPL is a divergent member of the immunophilin (see FKBP1A, 186945) family of peptidylprolyl isomerases. FKBPL plays roles in cellular stress response (Robson et al., 1999) and steroid hormone signaling (McKeen et al., 2008). When secreted, FKBPL acts as a proangiogenic factor (Valentine et al., 2011).
By differential cDNA library screening of L132 normal human lung epithelial cells exposed to X irradiation of 0.5 Gy and nonirradiated controls, Robson et al. (1997) identified FKBPL, which they called clone 8.6. Northern blot analysis detected a major transcript of 2.4 kb, with lower expression of transcripts of 5.8, 3.9, 1.7, and 0.68 kb.
Robson et al. (1999) cloned full-length human FKBPL, which they called DIR1. The deduced 349-amino acid protein has a calculated molecular mass of 38.2 kD. DIR1 has 3 tetratricopeptide repeats (TPRs) in its C-terminal half and shares significant homology with its mouse ortholog. FKBPL also shares significant similarity with the immunophilins FKBP52 (FKBP4; 600611) and CYP40 (PPID; 601753), particularly in the TPRs.
Jascur et al. (2005) cloned mouse and human FKBPL, which they called WISP39. In addition to the C-terminal TPRs, WISP39 has a divergent prolyl peptidyl isomerase domain that is likely inactive. FKBPL expression was detected in all tissues examined, with highest expression in testis.
Using immunocytochemistry, McKeen et al. (2008) found that FKBPL localized to both the nucleus and cytoplasm of DU145 human prostate carcinoma cells.
Valentine et al. (2011) found that HMEC-1 normal human microvascular endothelial cells and L132 cells secreted high amounts of FKBPL, whereas secretion was not detected from MDA-231 breast tumor cells.
Using ELISA of various human cell lines, Yakkundi et al. (2015) detected highest secretion of FKBPL from HMEC-1 cells, followed by AGO-1552 normal human fibroblasts. Cancer cell lines and MCF10A normal breast epithelial cells secreted lower levels of FKBPL.
Robson et al. (1999) determined that the FKBPL gene has a single coding exon. The 5-prime flanking region lacks a TATA or CCAAT box, but it has several potential transcription factor-binding sites.
Jascur et al. (2005) stated that the FKBPL gene has 2 exons, the first of which is noncoding.
By genomic sequence analysis, Robson et al. (1999) mapped the FKBPL gene immediately proximal to the ATF6B gene (600984) in the major histocompatibility complex class III region of chromosome 6.
Jascur et al. (2005) reported that the FKBPL gene maps to chromosome 6p21.3. The mouse Fkbpl gene maps to chromosome 17.
Robson et al. (1997) found that X irradiation of 0.05 to 1.0 Gy, but not higher doses, repressed expression of FKBPL.
Robson et al. (1999) found that knockdown of DIR1 in L132 cells or UM-UC-3 human bladder carcinoma cells slowed the cell cycle at G2, G1, and S phases and increased cell resistance to X irradiation of 1 Gy by promoting DNA single-strand break repair.
Robson et al. (2000) found that repression of DIR1 increased the rate of DNA repair and cell survival in 3 human cell lines that exhibit hypersensitivity to low-dose X irradiation and induced radioresistance, but not in ATBIVA human fibroblasts, which do not exhibit low-dose hypersensitivity or induced radioresistance.
By yeast 2-hybrid screening of a mouse T-cell lymphoma cDNA library, Jascur et al. (2005) found that the cell cycle regulator p21 (CDKN1A; 116899) interacted with Wisp39. Experiments with human and mouse cells revealed that WISP39 interacted simultaneously with p21 and the chaperone HSP90 (see 140571) via different motifs, and that WISP39 functioned as an adaptor to mediate HSP90-dependent p21 stability against proteasome-mediated degradation. WISP39 had no effect on p21 stability in the absence of HSP90. Knockdown of WISP39 via small interfering RNA (siRNA) prevented accumulation of p21 and cell cycle arrest after exposure of cells to 10 Gy of ionizing radiation.
McKeen et al. (2008) identified FKBPL as an immunofilin in glucocorticoid receptor (GR, or NR3C1; 138040)-HSP90 protein complexes and showed that it mediated interaction of the complexes with the dynein motor protein dynamitin (DCTN2; 607376). In GR-expressing DU145 human prostate carcinoma cells, knockdown of FKBPL via siRNA perturbed translocation of GR complexes along microtubules from the cytoplasm to the nucleus in response to the GR ligand dexamethasone. Overexpression of FKBPL in DU145 cells increased GR protein content and transactivation of a reporter gene in response to dexamethasone, but the effect of FKBPL on GR transcriptional activity was cell-line dependent. In L132 cells, which do not express high levels of GR, FKBPL overexpression reduced GR transcriptional activity, and knockdown of FKBPL increased GR transcriptional activity.
Donley et al. (2014) stated that FKBPL forms cochaperone complexes with androgen receptor (AR; 313700) and estrogen receptor (ER)-alpha (ESR1; 133430), in addition to GR. By yeast 2-hybrid screening of a human fetal brain cDNA library, they found that FKBPL interacted with the transcriptional coregulator RBCK1 (610924). RBCK1 stabilized FKBPL protein, possibly via linear ubiquitination of FKBPL at its N- or C-terminal end. Coimmunoprecipitation and Western blot analysis revealed that RBCK1 and FKBPL interacted in a complex with HSP90. In human breast cancer cell lines, this complex bound ER-alpha in the presence of estradiol and activated an ER-responsive gene.
Valentine et al. (2011) found that expression of full-length recombinant FKBPL inhibited HMEC-1 cell migration, tubule formation, and microvessel formation in vitro and in vivo. Exogenous administration of purified FKBPL also inhibited HMEC-1 cell migration in a dose-dependent manner in a scratch-wound assay. Truncation analysis revealed an antiangiogenic domain in FKBPL between amino acids 34 and 58. A synthetic peptide spanning this region, called AD01, showed similar antiangiogenic activity in vitro and in vivo in xenografts in mice. Homology between AD01 and the CD44 (107269) dimerization domain of CD74 (142790) suggested that AD01 interacts with cell surface CD44. Both full-length recombinant FKBPL and AD01 inhibited cell migration of tumor cell lines in a CD44-dependent manner.
Using ELISA, Yakkundi et al. (2015) found that hypoxia, but not proangiogenic cytokines, inhibited secretion of FKBPL from HMEC-1 cells without altering intracellular FKBPL expression.
Yakkundi et al. (2015) found that knockout of Fkbpl in mice was embryonic lethal, with death occurring before embryonic day 8.5. Fkbpl +/- embryos showed some vasculature irregularities, but they grew and developed normally. Angiogenesis assays revealed that Fkbpl +/- mice exhibited increased vessel recruitment and sprouting and faster tumor growth. In contrast, morpholino-mediated knockdown of Fkbpl in zebrafish embryos reduced vessel formation, with prominent defects in dorsal longitudinal anastomotic vessels and intersegmental vessels. The phenotype was rescued by expression of full-length human FKBPL or N- or C-terminal FKBPL fragments. Vessel disruption was also rescued by co-knockdown of Cd44, supporting dependence of Fkbpl on Cd44.
Donley, C., McClelland, K., McKeen, H. D., Nelson, L., Yakkundi, A., Jithesh, P. V., Burrows, J., McClements, L., Valentine, A., Prise, K. M., McCarthy, H. O., Robson, T. Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen. Oncogene 33: 3441-3450, 2014. [PubMed: 23912458] [Full Text: https://doi.org/10.1038/onc.2013.306]
Jascur, T., Brickner, H., Salles-Passador, I., Barbier, V., El Khissiin, A., Smith, B., Fotedar, R., Fotedar, A. Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR protein. Molec. Cell 17: 237-249, 2005. [PubMed: 15664193] [Full Text: https://doi.org/10.1016/j.molcel.2004.11.049]
McKeen, H. D., McAlpine, K., Valentine, A., Quinn, D. J., McClelland, K., Byrne, C., O'Rourke, M., Young, S., Scott, C. J., McCarthy, H. O., Hirst, D. G., Robson, T. A novel FK506-like binding protein interacts with the glucocorticoid receptor and regulates steroid receptor signaling. Endocrinology 149: 5724-5734, 2008. [PubMed: 18669603] [Full Text: https://doi.org/10.1210/en.2008-0168]
Robson, T. A., Lohrer, H., Bailie, J. R., Hirst, D. G., Joiner, M. C., Arrand, J. E. Gene regulation by low-dose ionizing radiation in a normal human lung epithelial cell line. Biochem. Soc. Trans. 25: 335-342, 1997. [PubMed: 9056895] [Full Text: https://doi.org/10.1042/bst0250335]
Robson, T., Joiner, M. C., Wilson, G. D., McCullough, W., Price, M. E., Logan, I., Jones, H., McKeown, S. R., Hirst, D. G. A novel human stress response-related gene with a potential role in induced radioresistance. Radiat. Res. 152: 451-461, 1999. [PubMed: 10521921]
Robson, T., Price, M. E., Moore, M. L., Joiner, M. C., McKelvey-Martin, V. J., McKeown, S. R., Hirst, D. G. Increased repair and cell survival in cells treated with DIR1 antisense oligonucleotides: implications for induced radioresistance. Int. J. Radiat. Biol. 76: 617-623, 2000. [PubMed: 10866283] [Full Text: https://doi.org/10.1080/095530000138277]
Valentine, A., O'Rourke, M., Yakkundi, A., Worthington, J., Hookham, M., Bicknell, R., McCarthy, H. O., McClelland, K., McCallum, L., Dyer, H., McKeen, H., Waugh, D. J. J., Roberts, J., McGregor, J., Cotton, G., James, I., Harrison, T., Hirst, D. G., Robson, T. FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism. Clin. Cancer Res. 17: 1044-1056, 2011. [PubMed: 21364036] [Full Text: https://doi.org/10.1158/1078-0432.CCR-10-2241]
Yakkundi, A., Bennett, R., Hernandez-Negrete, I., Delalande, J.-M., Hanna, M., Lyumbomska, O., Arthur, K., Short, A., McKeen, H., Nelson, L., McCrudden, C. M., McNally, R., McClements, L., McCarthy, H. O., Burns, A. J., Bicknell, R., Kissenpfennig, A., Robson, T. FKBPL is a critical antiangiogenic regulator of developmental and pathological angiogenesis. Arterioscler. Thromb. Vasc. Biol. 35: 845-854, 2015. [PubMed: 25767277] [Full Text: https://doi.org/10.1161/ATVBAHA.114.304539]