Alternative titles; symbols
HGNC Approved Gene Symbol: PIN1
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:9,835,318-9,849,689 (from NCBI)
Peptidyl-prolyl cis/trans isomerases (PPIases; EC 5.2.1.8), such as PIN1, catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds. PIN1 is the only PPIase that specifically binds to phosphorylated ser/thr-pro motifs to catalytically regulate the post-phosphorylation conformation of its substrates. PIN1-catalyzed conformational regulation has a profound impact on key proteins involved in the regulation of cell growth, genotoxic and other stress responses, the immune response, germ cell development, neuronal differentiation, and survival (review by Lu and Zhou, 2007).
Maleszka et al. (1996) sequenced the region of DNA adjacent to the Drosophila flightless (fli) gene, which is homologous to human FLII (600362). They characterized 4 transcriptional units within this region of the Drosophila genome, including the dod gene. By database analysis, Maleszka et al. (1996) identified human DOD, or PIN1, which encodes a predicted 163-amino acid protein. Both Drosophila and human DOD contain a WW domain for protein-protein interactions and a peptidylprolyl cis-trans isomerase (PPIase; EC 5.2.1.8) domain, and they are related to the Ess1 cell division gene of Saccharomyces cerevisiae. Lu et al. (1996) also described human PIN1.
Maleszka et al. (1996) found that expression of the Drosophila dod gene product in S. cerevisiae rescued the lethal phenotype of Ess1 mutation.
Lu et al. (1996) showed that deletion of PIN1 from HeLa cells induced mitotic arrest, whereas HeLa cells overexpressing PIN1 arrested in G2 phase.
In the frog, Pin1 is implicated in the regulation of cell cycle progression and required for the DNA replication checkpoint. By fluorescence microscopy, Winkler et al. (2000) observed that nuclear extracts from Xenopus eggs depleted of Pin1 inappropriately transited from the G2 to the M phase of the cell cycle in the presence of a DNA replication inhibitor. Immunoblot analysis revealed that inappropriate transition was accompanied by hyperphosphorylation of CDC25 (see CDC25A, 116947), activation of CDC2 (116940)/cyclin B (123836), and mitotic phosphoproteins. Addition of recombinant wildtype, but not mutant, Pin1 reversed the defect in replication checkpoint function.
Liou et al. (2002) demonstrated that loss of Pin1 function in mouse causes phenotypes resembling cyclin D1 (168461)-null phenotypes. Their findings confirmed that Pin1 positively regulates cyclin D1 function at the transcriptional level and also through posttranslational stabilization. The results provided genetic evidence for an essential role of Pin1 in maintaining cell proliferation and regulating cyclin D1 function.
Zacchi et al. (2002) demonstrated that, on DNA damage, p53 (191170) interacts with PIN1, which regulates the function of many proteins involved in cell cycle control and apoptosis. The interaction is strictly dependent on p53 phosphorylation, and requires ser33, thr81, and ser315. On binding, PIN1 generates conformational changes in p53, enhancing its transactivation activity. Stabilization of p53 is impaired in UV-treated Pin1 -/- cells owing to its inability to efficiently dissociate from MDM2 (164785). As a consequence, a reduced p53-dependent response was detected in Pin1 -/- cells, and this correlated with a diminished transcriptional activation of some p53-regulated genes. Zacchi et al. (2002) concluded that following stress-induced phosphorylation, p53 needs to form a complex with PIN1 and to undergo a conformational change to fulfill its biologic roles.
Zheng et al. (2002) demonstrated that DNA damage specifically induces p53 phosphorylation on ser/thr-pro motifs, which facilitates its interaction with PIN1. Furthermore, the interaction of PIN1 with p53 is dependent on the phosphorylation that is induced by DNA damage. Consequently, PIN1 stimulates the DNA-binding activity and transactivation function of p53. The PIN1-mediated p53 activation requires the WW domain, a phosphorylated ser/thr-pro motif interaction module, and the isomerase activity of PIN1. Moreover, Zheng et al. (2002) showed that PIN1-deficient cells were defective in p53 activation and timely accumulation of p53 protein, and exhibited an impaired checkpoint control in response to DNA damage. Zheng et al. (2002) concluded that their data suggested a mechanism for p53 regulation and cellular response to genotoxic stress.
Shen et al. (2005) treated purified eosinophils with hyaluronic acid alone or with various concentrations of cyclosporin A (CsA), which inhibits PPIA (123840), FK506, which inhibits FKBP1A (186945), or juglone, which specifically and irreversibly inhibits PIN1, and assessed CSF2 (138960) secretion and eosinophil survival. Only CsA and juglone caused eosinophil apoptosis, which was mediated by CASP3 (600636) cleavage. Juglone-mediated inhibition of PIN1 accelerated eosinophil apoptosis by preventing CSF2 release, whereas CsA induced apoptosis via a CSF2-independent mechanism. Immunoprecipitation analysis showed that PIN1 associated with AUF1 (HNRNPD; 601324), which, like PIN1, is rapidly degraded in the proteasome. Incubation of eosinophils with hyaluronic acid increased PIN1 activity. Examination of bronchoalveolar lavage fluid from donors after allergen challenge showed PIN1 activation. Shen et al. (2005) proposed that phosphorylated AUF1 p40 and p45 physically associate with phosphorylated PIN1 and unphosphorylated p42 and p37 of AUF1 to form a ribonucleoprotein complex with CSF2 mRNA in resting eosinophils. They concluded that PIN1 is a critical regulator of cytokine mRNA turnover, which controls survival of activated eosinophils in the lungs of asthmatics.
Pulmonary eosinophils are a predominant source of TGF-beta-1 (TGFB1; 190180), which drives fibroblast proliferation and extracellular matrix deposition. Shen et al. (2008) found that PIN1 regulated the decay, accumulation, and translation of TGF-beta-1 mRNA in human and rodent eosinophils activated both in vitro and in vivo. PIN1 controlled the association of a subset of ARE-binding proteins (e.g., HNRNPD; 601324) with TGF-beta-1 mRNA and with the mRNA decay machinery. PIN1 associated with and was regulated by PKC-alpha (PRKCA; 176960) and protein phosphatase-2A (see PPP2CA; 176915). In vivo inhibition of Pin1 selectively and significantly reduced eosinophilic inflammation, TGF-beta-1 mRNA, and collagen (see 120150) mRNA and protein in bronchoalveolar lavage fluid, airways, and total lung of allergen-sensitized and -challenged rats. Similarly, reduced airway collagen deposition was also observed in Pin1-knockout mice after chronic allergen challenge.
The 66-kD isoform of the growth factor adaptor SHC, p66(SHC) (600560), translates oxidative damage into cell death by acting as a reactive oxygen species producer within mitochondria. Pinton et al. (2007) demonstrated that protein kinase C-beta (see 176970), activated by oxidative conditions in the cell, induces phosphorylation of p66(SHC) and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase PIN1. Once imported, p66(SHC) causes alterations of mitochondrial calcium ion responses and 3-dimensional structure, thus causing apoptosis. Pinton et al. (2007) concluded that their data identified a signaling route that activates an apoptotic inducer shortening the life span.
Notch proteins (see NOTCH1; 190198) are ligand-activated membrane receptors. Ligand binding induces cleavage of the receptor, resulting in release of its intracellular domain, which functions as a transcriptional activator in the nucleus. Rustighi et al. (2009) showed that PIN1 enhanced NOTCH1 signaling in human cancer cell lines through its prolyl-isomerase activity. PIN1 interacted directly with phosphorylated NOTCH1 and enhanced NOTCH1 cleavage by gamma-secretase (see 104311). Accordingly, PIN1 contributed to NOTCH1 transforming properties both in vitro and in vivo. NOTCH1 in turn upregulated PIN1, thus establishing a positive feedback loop that amplified NOTCH1 signaling.
By coimmunoprecipitation analysis of HeLa cell lysates, Lee et al. (2009) found that PIN1 interacted with TRF1 (TERF1; 600951), a key regulator of telomere length, during mitosis, but not during interphase. Mutation analysis showed that the WW domain of PIN1 bound the phosphorylated motif thr149-pro150 in TRF1. Inhibitor studies revealed that CDK (see CDK1; 116940) phosphorylated TRF1 on thr149, and this phosphorylation was required for interaction of PIN1 with TRF1. Knockdown or inhibition of PIN1 stabilized TRF1 against degradation, resulting in elevated binding of TRF1 to telomeres and gradual, progressive telomere shortening. Furthermore, Pin1 -/- mice exhibited accelerated aging in association with accelerated telomere loss within a single generation. Lee et al. (2009) concluded that PIN1 functions to protect telomeres by inducing TRF1 instability and degradation.
Manganaro et al. (2010) noted that resting peripheral blood T lymphocytes do not support efficient human immunodeficiency virus (HIV) infection and reverse transcription. They found that JNK (see 601158), which Western blot analysis showed was not expressed in resting lymphocytes, regulated permissiveness to HIV-1 infection. In activated T cells, JNK phosphorylated HIV-1 viral integrase on a highly conserved serine in its core domain. Phosphorylated integrase was a substrate for PIN1, which catalyzed a conformational modification of integrase, increasing its stability. This pathway of protein modification was required for efficient HIV-1 integration and infection and was present in activated, but not nonactivated, primary resting CD4 (186940)-positive T lymphocytes.
Role in Alzheimer Disease
Lu et al. (1999) hypothesized that restoring the function of phosphorylated tau (157140) might prevent or reverse paired helical filament (PHF) formation in Alzheimer disease (AD; 104300). They demonstrated that the WW domain of PIN1 binds to phosphorylated tau at thr231 (T231). The T231 residue is hyperphosphorylated in AD and is phosphorylated to a certain extent in the normal brain. Using a pull-down assay, Lu et al. (1999) demonstrated that PIN1 binds to hyperphosphorylated tau from the brains of people with AD but not to tau from age-matched healthy brains. By immunoblotting, Lu et al. (1999) detected endogenous PIN1 in the PHFs of diseased brains, and using immunohistochemistry, they found that recombinant PIN1 binds to pathologic tau. Using immunohistochemistry, Lu et al. (1999) localized PIN1 to the nucleus in healthy brains. In the brains of people with AD, PIN1 staining was associated with pathologic tau in neuronal cells. Lu et al. (1999) also demonstrated that phosphorylated tau could neither bind microtubules nor promote microtubule assembly. However, PIN1 was able to restore the ability of phosphorylated tau to bind microtubules and promoted microtubule assembly in vitro. The level of soluble PIN1 in the brains of AD patients was greatly reduced compared to that in age-matched control brains. The authors concluded with the hypothesis that since depletion of PIN1 induces mitotic arrest and apoptotic cell death, sequestration of PIN1 into PHFs may contribute to neuronal death.
Phosphorylation of tau and other proteins on serine or threonine residues preceding proline seems to precede tangle formation and neurodegeneration in Alzheimer disease (AD; 104300). These phospho(ser/thr)-pro motifs exist in 2 distinct conformations, whose conversion in some proteins is catalyzed by the Pin1 prolyl isomerase. Pin1 activity can directly restore the conformation and function of phosphorylated tau or it can do so indirectly by promoting its dephosphorylation, which suggests that Pin1 is involved in neurodegeneration. Liou et al. (2003) showed that Pin1 expression is inversely correlated with predicted neuronal vulnerability and actual neurofibrillary degeneration in AD. Pin1 knockout in mice causes progressive age-dependent neuropathy characterized by motor and behavioral deficits, tau hyperphosphorylation, tau filament formation, and neuronal degeneration. Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing insight into the pathogenesis and treatment of AD and other tauopathies.
In hippocampus of normal human subjects, expression of Pin1 was relatively higher in CA4, CA3, CA2, and presubiculum and lower in CA1 and subiculum. In the parietal cortex, expression of Pin1 was relatively higher in layer IIIb-c neurons, and lower in layer V neurons. Liou et al. (2003) noted that the subregions with low expression of Pin1 are prone to neurofibrillary degeneration in AD, whereas those containing high Pin1 expression are spared, suggesting that there is an inverse correlation between Pin1 expression and predicted vulnerability. This was corroborated by immunostaining of 10 AD-affected brain sections with antibodies against Pin1 and a phospho-tau antibody, AT8. Liou et al. (2003) showed that overall, 96% of pyramidal neurons that contained relatively more Pin1 lacked tangles, whereas 71% of neurons that contained relatively less Pin1 had tangles. Liou et al. (2003) concluded that there is an inverse correlation between Pin1 expression and actual neurofibrillary degeneration in AD.
Pastorino et al. (2006) demonstrated that PIN1 has profound effects on APP (104760) processing and amyloid beta production. They found that PIN1 binds to the phosphorylated thr668-to-pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between 2 conformations, as visualized by NMR. Whereas Pin1 overexpression reduces amyloid beta secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble amyloid beta-42, a major toxic species, in brains in an age-dependent manner, with amyloid beta-42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer disease before plaque pathology. Thus, Pastorino et al. (2006) concluded that PIN1-catalyzed prolyl isomerization is a novel mechanism to regulate APP processing and amyloid beta production, and its deregulation may link both tangle and plaque pathologies.
Kap et al. (2007) found that the human PIN1 promoter contains no endoplasmic reticulum stress response element (ERSE), suggesting that it is not induced in the unfolded protein response. In contrast, both mouse and rat genes do contain ERSE motifs. Cell studies showed that PIN1 was downregulated during ER stress in human neuroblastoma cells, in contrast to mouse neuroblastoma cells that showed constant levels of Pin1 during ER stress. Kap et al. (2007) concluded that the decrease in human PIN1 would decrease the potential of the cell to dephosphorylate tau, thereby facilitating tangle formation in Alzheimer disease in humans, whereas mouse neurons may be less prone to form tangles.
Reviews
Lu and Zhou (2007) reviewed the molecular and structural basis for PIN1-catalyzed post-phosphorylation regulation. They discussed the significance of such a regulatory mechanism in human physiology and pathology and explored the potential of this mechanism for disease diagnosis and therapeutic interventions.
Using fluorescence in situ hybridization and somatic cell hybrid analysis, Campbell et al. (1997) mapped the PIN1 gene to chromosome 19p13. They mapped the PIN1L gene (602051) to chromosome 1p31.
Campbell, H. D., Webb, G. C., Fountain, S., Young, I. G. The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31. Genomics 44: 157-162, 1997. [PubMed: 9299231] [Full Text: https://doi.org/10.1006/geno.1997.4854]
Kap, Y. S., Hoozemans, J. J. M., Bodewes, A. J., Zwart, R., Meijer, O. C., Baas, F., Scheper, W. Pin1 levels are downregulated during ER stress in human neuroblastoma cells. Neurogenetics 8: 21-27, 2007. [PubMed: 16972081] [Full Text: https://doi.org/10.1007/s10048-006-0060-2]
Lee, T. H., Tun-Kyi, A., Shi, R., Lim, J., Soohoo, C., Finn, G., Balastik, M., Pastorino, L., Wulf, G., Zhou, X. Z., Lu, K. P. Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance. Nature Cell Biol. 11: 97-105, 2009. [PubMed: 19060891] [Full Text: https://doi.org/10.1038/ncb1818]
Liou, Y.-C., Ryo, A., Huang, H.-K., Lu, P.-J., Bronson, R., Fujimori, F., Uchida, T., Hunter, T., Lu, K. P. Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc. Nat. Acad. Sci. 99: 1335-1340, 2002. [PubMed: 11805292] [Full Text: https://doi.org/10.1073/pnas.032404099]
Liou, Y.-C., Sun, A., Ryo, A., Zhou, X. Z., Yu, Z.-X., Huang, H.-K., Uchida, T., Bronson, R., Bing, G., Li, X., Hunter, T., Lu, K. P. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424: 556-561, 2003. [PubMed: 12891359] [Full Text: https://doi.org/10.1038/nature01832]
Lu, K. P., Hanes, S. D., Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380: 544-547, 1996. [PubMed: 8606777] [Full Text: https://doi.org/10.1038/380544a0]
Lu, K. P., Zhou, X. Z. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nature Rev. Molec. Cell Biol. 8: 904-916, 2007. [PubMed: 17878917] [Full Text: https://doi.org/10.1038/nrm2261]
Lu, P.-J., Wulf, G., Zhou, X. Z., Davies, P., Lu, K. P. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399: 784-788, 1999. [PubMed: 10391244] [Full Text: https://doi.org/10.1038/21650]
Maleszka, R., Hanes, S. D., Hackett, R. L., de Couet, H. G., Gabor Miklos, G. L. The Drosophila melanogaster dodo (dod) gene, conserved in humans, is functionally interchangeable with the ESS1 cell division gene of Saccharomyces cerevisiae. Proc. Nat. Acad. Sci. 93: 447-451, 1996. [PubMed: 8552658] [Full Text: https://doi.org/10.1073/pnas.93.1.447]
Manganaro, L., Lusic, M., Gutierrez, M. I., Cereseto, A., Del Sal, G., Giacca, M. Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4(+) T lymphocytes. Nature Med. 16: 329-333, 2010. [PubMed: 20173753] [Full Text: https://doi.org/10.1038/nm.2102]
Pastorino, L., Sun, A., Lu, P.-J., Zhou, X. Z., Balastik, M., Finn, G., Wulf, G., Lim, J., Li, S.-H., Li, X., Xia, W., Nicholson, L. K., Lu, K. P. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440: 528-534, 2006. Note: Erratum: Nature 446: 342 only, 2007. [PubMed: 16554819] [Full Text: https://doi.org/10.1038/nature04543]
Pinton, P., Rimessi, A., Marchi, S., Orsini, F., Migliaccio, E., Giorgio, M., Contursi, C., Minucci, S., Mantovani, F., Wieckowski, M. R., Del Sal, G., Pelicci, P. G., Rizzuto, R. Protein kinase C-beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66(Shc) Science 315: 659-663, 2007. [PubMed: 17272725] [Full Text: https://doi.org/10.1126/science.1135380]
Rustighi, A., Tiberi, L., Soldano, A., Napoli, M., Nuciforo, P., Rosato, A., Kaplan, F., Capobianco, A., Pece, S., De Fiore, P. P., Del Sal, G. The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nature Cell Biol. 11: 133-142, 2009. [PubMed: 19151708] [Full Text: https://doi.org/10.1038/ncb1822]
Shen, Z.-J., Esnault, S., Malter, J. S. The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nature Immun. 6: 1280-1287, 2005. [PubMed: 16273101] [Full Text: https://doi.org/10.1038/ni1266]
Shen, Z.-J., Esnault, S., Rosenthal, L. A., Szakaly, R. J., Sorkness, R. L., Westmark, P. R., Sandor, M., Malter, J. S. Pin1 regulates TGF-beta-1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J. Clin. Invest. 118: 479-490, 2008. [PubMed: 18188456] [Full Text: https://doi.org/10.1172/JCI32789]
Winkler, K. E., Swenson, K. I., Kornbluth, S., Means, A. R. Requirement of the prolyl isomerase Pin1 for the replication checkpoint. Science 287: 1644-1647, 2000. [PubMed: 10698738] [Full Text: https://doi.org/10.1126/science.287.5458.1644]
Zacchi, P., Gostissa, M., Uchida, T., Salvagno, C., Avolio, F., Volinia, S., Ronai, Z., Blandino, G., Schneider, C., Del Sal, G. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419: 853-857, 2002. [PubMed: 12397362] [Full Text: https://doi.org/10.1038/nature01120]
Zheng, H., You, H., Zhou, X. Z., Murray, S. A., Uchida, T., Wulf, G., Gu, L., Tang, X., Lu, K. P., Xiao, Z.-X. J. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419: 849-853, 2002. Note: Erratum: Nature 420: 445 only, 2002. [PubMed: 12397361] [Full Text: https://doi.org/10.1038/nature01116]