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Gene Review

PIN1  -  peptidylprolyl cis/trans isomerase, NIMA...

Homo sapiens

Synonyms: DOD, PPIase Pin1, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, Peptidyl-prolyl cis-trans isomerase Pin1, Rotamase Pin1, ...
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Disease relevance of PIN1


Psychiatry related information on PIN1

  • Here we show that Pin1 binds to only one pT-P motif in tau and copurifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients [5].
  • Here, Pin1 distribution in AD, and its colocalization with pThr231 tau in AD, FTDP-17 (P301L), Pick's disease (PiD), and PSP was investigated using TG-3, a monoclonal antibody to conformationally altered pThr231 tau [6].

High impact information on PIN1

  • Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent [7].
  • This raises the possibility of phosphorylation-mediated control of Pin1-substrate interactions in cell cycle regulation [7].
  • Pin1 displays a preference for an acidic residue N-terminal to the isomerized proline bond due to interaction of this acidic side chain with a basic cluster [7].
  • Here we report that DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, which facilitates its interaction with Pin1, a member of peptidyl-prolyl isomerase [8].
  • Consequently, Pin1 stimulates the DNA-binding activity and transactivation function of p53 [8].

Chemical compound and disease context of PIN1

  • Depletion of Pin1 in MCF-7 human breast cancer cells reduces the endogenous estrogen-dependent recruitment of p300 to the promoters of estrogen receptor-dependent genes [9].

Biological context of PIN1


Anatomical context of PIN1


Associations of PIN1 with chemical compounds

  • No direct interaction between the PIN1 WW domain or its catalytic proline cis/trans-isomerase domain and p13(SUC1) was detected, but our study showed that in vitro the WW domain of the human PIN1 antagonizes the binding of the p13(SUC1) to the CDC25 phosphopeptide, by binding to the same phosphoepitope [10].
  • Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1 [3].
  • Depletion of Pin1 by small interfering RNA (siRNA) reduces hormone-dependent transcription from both transfected reporters and an endogenous steroid receptor target gene [9].
  • Unlike Pin1-type enzymes it lacks the phosphoserine or phosphothreonine binding WW domain [11].
  • Similar to human Pin1 and yeast Ess1, it exhibits catalytic activity toward substrates containing (Thr(P)/Ser(P))-Pro peptide bonds and comparable inhibition kinetics with juglone [11].

Physical interactions of PIN1


Enzymatic interactions of PIN1

  • Thus, Pin1 likely acts as a general regulator of mitotic proteins that have been phosphorylated by Cdc2 and other mitotic kinases [20].
  • The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9 [21].
  • We show here that the peptidyl prolyl cis-trans isomerase Pin1 interacts specifically with the phosphorylated form of NFAT [22].
  • The X-ray crystal structure of Pin1 bound to a doubly phosphorylated peptide (Tyr-P.Ser-Pro-Thr-P.Ser-Pro-Ser) representing a heptad repeat of the RNA polymerase II large subunit's C-terminal domain (CTD), reveals the residues involved in the recognition of a single P.Ser side chain, the rings of two prolines, and the backbone of the CTD peptide [23].
  • Pin1 binds to the phosphorylated Ser178-Pro motif in the Daxx protein, and Pin1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway [24].

Regulatory relationships of PIN1

  • IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry [1].
  • Together, our results suggest that KRMP1 is a mitotic target regulated by Pin1 and vice versa [15].
  • Thus, Pin1 is up-regulated in human tumors and cooperates with Ras signaling in increasing c-Jun transcriptional activity towards cyclin D1 [25].
  • This aberrant response leading to neurofibrillary degeneration may be triggered by the sequential combination of three partners: the complex Cdk5/p25 induces both apoptosis and the "abnormal mitotic Tau phosphorylation". These mitotic epitopes may allow for the nuclear depletion of Pin1 [26].
  • p53 Protein is activated by Pin1: and also by Cu-SOD prion-like enzyme [27].

Other interactions of PIN1

  • Pin1 is also a critical regulator of the tumor suppressor p53 during DNA damage response [14].
  • Following evaluation of the slides, data were also analyzed by combining several of the groups into three categories: (a) benign/PIN1; (b) PIN2/PIN3/PIN cannot rule out cancer; and (c) PIN plus cancer [28].
  • Furthermore, we found that Cyclin D1 expression and RB phosphorylation are dramatically decreased in Pin1(-/-) MEF cells [1].
  • The induction of Pin1 by IGF-1 is mediated via the phosphatidylinositol 3-kinase as well as the MAP kinase pathways [1].
  • However, the analysis of the relationship between Pin1 and other cyclin genes has not been demonstrated in human OSCC [2].

Analytical, diagnostic and therapeutic context of PIN1

  • In addition, site-directed mutagenesis indicated that the interaction of Pin1 with p54nrb was mediated by three threonine residues located in the proline-rich carboxy-terminal extremity of the protein [29].
  • GST-Pin1 pull-down and immunoprecipitation assay revealed that Pin1 binds phosphorylated Thr668-Pro of C99 [30].
  • Enzyme immunoassay of brains of the Pin1-deficient mice revealed that production of Abeta40 and Abeta42 was lower than that of the wild-type mice, indicating that Pin1 promotes Abeta production in the brain [30].
  • Immunohistochemical assessment with affinity-purified polyclonal Pin1-specific antibodies was performed on formalin-fixed paraffin sections of tissue microarray composed of 580 radical prostatectomy specimens [31].
  • The BEACON gene (also known as UBL5) was identified as differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity, type 2 diabetes, and dyslipidemia [32].


  1. IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry. You, H., Zheng, H., Murray, S.A., Yu, Q., Uchida, T., Fan, D., Xiao, Z.X. J. Cell. Biochem. (2002) [Pubmed]
  2. Expression status of Pin1 and cyclins in oral squamous cell carcinoma: Pin1 correlates with Cyclin D1 mRNA expression and clinical significance of cyclins. Miyashita, H., Uchida, T., Mori, S., Echigo, S., Motegi, K. Oncol. Rep. (2003) [Pubmed]
  3. Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Ryo, A., Nakamura, M., Wulf, G., Liou, Y.C., Lu, K.P. Nat. Cell Biol. (2001) [Pubmed]
  4. Differential histochemical peanut agglutinin stain in benign and malignant human prostate tumors: relationship with prostatic specific antigen immunostain and nuclear DNA content. Janssen, T., Petein, M., Van Velthoven, R., Van Leer, P., Fourmarier, M., Vanegas, J.P., Danguy, A., Schulman, C., Pasteels, J.L., Kiss, R. Hum. Pathol. (1996) [Pubmed]
  5. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Lu, P.J., Wulf, G., Zhou, X.Z., Davies, P., Lu, K.P. Nature (1999) [Pubmed]
  6. Pin1 colocalization with phosphorylated tau in Alzheimer's disease and other tauopathies. Ramakrishnan, P., Dickson, D.W., Davies, P. Neurobiol. Dis. (2003) [Pubmed]
  7. Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Ranganathan, R., Lu, K.P., Hunter, T., Noel, J.P. Cell (1997) [Pubmed]
  8. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Zheng, H., You, H., Zhou, X.Z., Murray, S.A., Uchida, T., Wulf, G., Gu, L., Tang, X., Lu, K.P., Xiao, Z.X. Nature (2002) [Pubmed]
  9. Peptidyl-prolyl isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of phosphorylated steroid receptor coactivator 3 (SRC-3/AIB1). Yi, P., Wu, R.C., Sandquist, J., Wong, J., Tsai, S.Y., Tsai, M.J., Means, A.R., O'Malley, B.W. Mol. Cell. Biol. (2005) [Pubmed]
  10. p13(SUC1) and the WW domain of PIN1 bind to the same phosphothreonine-proline epitope. Landrieu, I., Odaert, B., Wieruszeski, J.M., Drobecq, H., Rousselot-Pailley, P., Inze, D., Lippens, G. J. Biol. Chem. (2001) [Pubmed]
  11. Functional replacement of the essential ESS1 in yeast by the plant parvulin DlPar13. Metzner, M., Stoller, G., Rücknagel, K.P., Lu, K.P., Fischer, G., Luckner, M., Küllertz, G. J. Biol. Chem. (2001) [Pubmed]
  12. PIN1 overexpression and beta-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma. Pang, R., Yuen, J., Yuen, M.F., Lai, C.L., Lee, T.K., Man, K., Poon, R.T., Fan, S.T., Wong, C.M., Ng, I.O., Kwong, Y.L., Tse, E. Oncogene (2004) [Pubmed]
  13. The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31. Campbell, H.D., Webb, G.C., Fountain, S., Young, I.G. Genomics (1997) [Pubmed]
  14. Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer. Ryo, A., Liou, Y.C., Lu, K.P., Wulf, G. J. Cell. Sci. (2003) [Pubmed]
  15. Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1. Kamimoto, T., Zama, T., Aoki, R., Muro, Y., Hagiwara, M. J. Biol. Chem. (2001) [Pubmed]
  16. Accumulation of rab4GTP in the cytoplasm and association with the peptidyl-prolyl isomerase pin1 during mitosis. Gerez, L., Mohrmann, K., van Raak, M., Jongeneelen, M., Zhou, X.Z., Lu, K.P., van Der Sluijs, P. Mol. Biol. Cell (2000) [Pubmed]
  17. Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCF(betatrcp). Bernis, C., Vigneron, S., Burgess, A., Labb??, J.C., Fesquet, D., Castro, A., Lorca, T. EMBO Rep. (2007) [Pubmed]
  18. Interaction of Pin1 with Nek6 and characterization of their expression correlation in Chinese hepatocellular carcinoma patients. Chen, J., Li, L., Zhang, Y., Yang, H., Wei, Y., Zhang, L., Liu, X., Yu, L. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  19. A hyperphosphorylated form of RNA polymerase II is the major interphase antigen of the phosphoprotein antibody MPM-2 and interacts with the peptidyl-prolyl isomerase Pin1. Albert, A., Lavoie, S., Vincent, M. J. Cell. Sci. (1999) [Pubmed]
  20. The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Shen, M., Stukenberg, P.T., Kirschner, M.W., Lu, K.P. Genes Dev. (1998) [Pubmed]
  21. The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9. Lavoie, S.B., Albert, A.L., Handa, H., Vincent, M., Bensaude, O. J. Mol. Biol. (2001) [Pubmed]
  22. Binding and regulation of the transcription factor NFAT by the peptidyl prolyl cis-trans isomerase Pin1. Liu, W., Youn, H.D., Zhou, X.Z., Lu, K.P., Liu, J.O. FEBS Lett. (2001) [Pubmed]
  23. Structural basis for phosphoserine-proline recognition by group IV WW domains. Verdecia, M.A., Bowman, M.E., Lu, K.P., Hunter, T., Noel, J.P. Nat. Struct. Biol. (2000) [Pubmed]
  24. A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. Ryo, A., Hirai, A., Nishi, M., Liou, Y.C., Perrem, K., Lin, S.C., Hirano, H., Lee, S.W., Aoki, I. J. Biol. Chem. (2007) [Pubmed]
  25. Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. Wulf, G.M., Ryo, A., Wulf, G.G., Lee, S.W., Niu, T., Petkova, V., Lu, K.P. EMBO J. (2001) [Pubmed]
  26. Neurofibrillary degeneration of the Alzheimer-type: an alternate pathway to neuronal apoptosis? Hamdane, M., Delobel, P., Sambo, A.V., Smet, C., Bégard, S., Violleau, A., Landrieu, I., Delacourte, A., Lippens, G., Flament, S., Buée, L. Biochem. Pharmacol. (2003) [Pubmed]
  27. p53 Protein is activated by Pin1: and also by Cu-SOD prion-like enzyme. Wiseman, A. Med. Hypotheses (2005) [Pubmed]
  28. Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Epstein, J.I., Grignon, D.J., Humphrey, P.A., McNeal, J.E., Sesterhenn, I.A., Troncoso, P., Wheeler, T.M. Am. J. Surg. Pathol. (1995) [Pubmed]
  29. The multifunctional nuclear protein p54nrb is multiphosphorylated in mitosis and interacts with the mitotic regulator Pin1. Proteau, A., Blier, S., Albert, A.L., Lavoie, S.B., Traish, A.M., Vincent, M. J. Mol. Biol. (2005) [Pubmed]
  30. Pin1 promotes production of Alzheimer's amyloid beta from beta-cleaved amyloid precursor protein. Akiyama, H., Shin, R.W., Uchida, C., Kitamoto, T., Uchida, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  31. The prolyl isomerase Pin1 is a novel prognostic marker in human prostate cancer. Ayala, G., Wang, D., Wulf, G., Frolov, A., Li, R., Sowadski, J., Wheeler, T.M., Lu, K.P., Bao, L. Cancer Res. (2003) [Pubmed]
  32. Genetic variation in BEACON influences quantitative variation in metabolic syndrome-related phenotypes. Jowett, J.B., Elliott, K.S., Curran, J.E., Hunt, N., Walder, K.R., Collier, G.R., Zimmet, P.Z., Blangero, J. Diabetes (2004) [Pubmed]
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