Skip to main content

Peptidyl-prolyl cis–trans isomerase Pin1 in ageing, cancer and Alzheimer disease

  • Tae Ho Lee (a1), Lucia Pastorino (a1) and Kun Ping Lu (a1)

Phosphorylation of proteins on serine or threonine residues preceding proline is a key signalling mechanism in diverse physiological and pathological processes. Pin1 (peptidyl-prolyl cis–trans isomerase) is the only enzyme known that can isomerise specific Ser/Thr-Pro peptide bonds after phosphorylation and regulate their conformational changes with high efficiency. These Pin1-catalysed conformational changes can have profound effects on phosphorylation signalling by regulating a spectrum of target activities. Interestingly, Pin1 deregulation is implicated in a number of diseases, notably ageing and age-related diseases, including cancer and Alzheimer disease. Pin1 is overexpressed in most human cancers; it activates numerous oncogenes or growth enhancers and also inactivates a large number of tumour suppressors or growth inhibitors. By contrast, ablation of Pin1 prevents cancer, but eventually leads to premature ageing and neurodegeneration. Consistent with its neuroprotective role, Pin1 has been shown to be inactivated in neurons of patients with Alzheimer disease. Therefore, Pin1-mediated phosphorylation-dependent prolyl isomerisation represents a unique signalling mechanism that has a pivotal role in the development of human diseases, and might offer an attractive new diagnostic and therapeutic target.

Corresponding author
*Corresponding author: Kun Ping Lu, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA. E-mail:
Hide All
1Blume-Jensen, P. and Hunter, T. (2001) Oncogenic kinase signalling. Nature 411, 355-365
2Lu, K.P. and Zhou, X.Z. (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nature Reviews. Molecular Cell Biology 8, 904-916
3Pawson, T. and Scott, J.D. (2005) Protein phosphorylation in signaling – 50 years and counting. Trends in Biochemical Sciences 30, 286-290
4Nigg, E.A. (2002) Centrosome aberrations: cause or consequence of cancer progression? Nature Reviews. Cancer 2, 815-825
5Lee, M.S. and Tsai, L.H. (2003) Cdk5: one of the links between senile plaques and neurofibrillary tangles? Journal of Alzheimer's Disease 5, 127-137
6Zhu, X. et al. (2002) The role of mitogen-activated protein kinase pathways in Alzheimer's disease. Neurosignals 11, 270-281
7Zhu, X. et al. (2004) Oxidative stress signalling in Alzheimer's disease. Brain Research 1000, 32-39
8Fanghanel, J. and Fischer, G. (2004) Insights into the catalytic mechanism of peptidyl prolyl cis/trans isomerases. Frontiers in Bioscience: A Journal and Virtual Library 9, 3453-3478
9Lu, K.P. et al. (2007) Prolyl cis-trans isomerization as a molecular timer. Nature Chemical Biology 3, 619-629
10Lu, K.P., Hanes, S.D. and Hunter, T. (1996) A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544-547
11Yaffe, M.B. et al. (1997) Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 278, 1957-1960
12Pastorino, L. et al. (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440, 528-534
13Atchison, F.W. and Means, A.R. (2004) A role for Pin1 in mammalian germ cell development and spermatogenesis. Frontiers in Bioscience 9, 3248-3256
14Butterfield, D.A. et al. (2006) Pin1 in Alzheimer's disease. Journal of Neurochemistry 98, 1697-1706
15Lu, K.P. (2004) Pinning down cell signaling, cancer and Alzheimer's disease. Trends in Biochemical Sciences 29, 200-209
16Wulf, G. et al. (2005) Phosphorylation-specific prolyl isomerization: is there an underlying theme? Nature Cell Biology 7, 435-441
17Shen, Z.J., Esnault, S. and Malter, J.S. (2005) The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nature Immunology 6, 1280-1287
18Suizu, F. et al. (2006) Pin1 regulates centrosome duplication, and its overexpression induces centrosome amplification, chromosome instability, and oncogenesis. Molecular and Cellular Biology 26, 1463-1479
19Driver, J.A. and Lu, K.P. (2010) Pin1: a new genetic link between Alzheimer's disease, cancer and aging. Current Aging Science 3, 158-165
20Lee, T.H. et al. (2009) Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance. Nature Cell Biology 11, 97-105
21Wijsman, E.M. et al. (2004) Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2. American Journal of Human Genetics 75, 398-409
22Segat, L., Milanese, M. and Crovella, S. (2007) Pin1 promoter polymorphisms in hepatocellular carcinoma patients. Gastroenterology 132, 2618-2619; author reply 19-20
23Lu, J. et al. (2009) A novel functional variant (-842G > C) in the PIN1 promoter contributes to decreased risk of squamous cell carcinoma of the head and neck by diminishing the promoter activity. Carcinogenesis 30, 1717-1721
24Han, C.H. et al. (2010) The functional promoter polymorphism (-842G > C) in the PIN1 gene is associated with decreased risk of breast cancer in non-Hispanic white women 55 years and younger. Breast Cancer Research and Treatment 122, 243-249
25Roe, C.M. et al. (2005) Alzheimer disease and cancer. Neurology 64, 895-898
26Behrens, M.I., Lendon, C. and Roe, C.M. (2009) A common biological mechanism in cancer and Alzheimer's disease? Current Alzheimer Research 6, 196-204
27Kenyon, C.J. (2010) The genetics of ageing. Nature 464, 504-512
28Liou, Y.C. et al. (2002) Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proceedings of the National Academy of Sciences of the United States of America 99, 1335-1340
29Liou, Y.C. et al. (2003) Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424, 556-561
30Atchison, F.W., Capel, B. and Means, A.R. (2003) Pin1 regulates the timing of mammalian primordial germ cell proliferation. Development 130, 3579-3586
31Atchison, F.W., Means, A.R. and Capel, B. (2003) Spermatogonial depletion in adult Pin1-deficient mice: Pin1 regulates the timing of mammalian primordial germ cell proliferation. Biology of Reproduction 20, 1989-1997
32Blackburn, E.H. (2001) Switching and signaling at the telomere. Cell 106, 661-673
33Smogorzewska, A. and de Lange, T. (2004) Regulation of telomerase by telomeric proteins. Annual Review of Biochemistry 73, 177-208
34Goldstein, S. (1990) Replicative senescence: the human fibroblast comes of age. Science 249, 1129-1133
35Chin, L. et al. (1999) p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527-538
36Blasco, M.A. et al. (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25-34
37Lee, H.W. et al. (1998) Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569-574
38Rudolph, K.L. et al. (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701-712
39de Lange, T. (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes and Development 19, 2100-2110
40van Steensel, B. and de Lange, T. (1997) Control of telomere length by the human telomeric protein Trf1. Nature 385, 740-743
41van Steensel, B., Smogorzewska, A. and de Lange, T. (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401-413
42Ancelin, K. et al. (2002) Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Molecular and Cellular Biology 22, 3474-3487
43Shen, M. et al. (1997) Characterization and cell cycle regulation of related human telomeric proteins Pin2 and TRF1 suggest a role in mitosis. Proceedings of the National Academy of Sciences of the United States of America 94, 13618-13623
44Kishi, K. and Lu, K.P. (2002) A critical role for Pin2/TRF1 in ATM-dependent regulation: inhibition of Pin2/TRF1 function complements telomere shortening, the radiosensitivity and G2/M checkpoint defect of Ataxia-Telangiectasia cells. Journal of Biological Chemistry 277, 7420-7429
45Kishi, S. et al. (2001) Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells containing short telomeres and is down-regulated in breast tumors. Oncogene 20, 1497-1508
46Kishi, S. et al. (2001) Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. Journal of Biological Chemistry 276, 29282-29291
47Lee, T.H. et al. (2006) F-box protein Fbx4 targets Pin2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. Journal of Biological Chemistry 281, 759-768
48Chang, W., Dynek, J.N. and Smith, S. (2003) TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes and Development 17, 1328-1333
49Calabrese, V. et al. (2010) Redox homeostasis and cellular stress response in aging and neurodegeneration. Methods in Molecular Biology 610, 285-308
50Bader, N. and Grune, T. (2006) Protein oxidation and proteolysis. Biological Chemistry 387, 1351-1355
51Brenkman, A.B. et al. (2008) The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors. Cancer Research 68, 7597-7605
52Greer, E.L. and Brunet, A. (2008) FOXO transcription factors in ageing and cancer. Acta Physiologica 192, 19-28
53Pinton, P. et al. (2007) Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 315, 659-663
54Migliaccio, E. et al. (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313
55Butterfield, D.A. et al. (2006) Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. Neurobiology of Disease 22, 223-232
56Sultana, R. et al. (2006) Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: a redox proteomics analysis. Neurobiology of Aging 27, 918-925
57Satoh, K., Nigro, P. and Berk, B.C. (2010) Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin A. Antioxidants & Redox Signaling 12, 675-682
58Slee, E.A., O'Connor, D.J. and Lu, X. (2004) To die or not to die: how does p53 decide? Oncogene 23, 2809-2818
59Harris, S.L. and Levine, A.J. (2005) The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899-2908
60Toledo, F. and Wahl, G.M. (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Reviews. Cancer 6, 909-923
61Lutzker, S.G. and Levine, A.J. (1996) Apoptosis and cancer chemotherapy. Cancer Treatment and Research 87, 345-356
62Zacchi, P. et al. (2002) The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419, 853-857
63Zheng, H. et al. (2002) The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419, 849-853
64Wulf, G.M. et al. (2002) Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. Journal of Biological Chemistry 277, 47976-47979
65Mantovani, F. et al. (2007) The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. Nature Structural and Molecular Biology 14, 912-920
66Melino, G., De Laurenzi, V. and Vousden, K.H. (2002) p73: friend or foe in tumorigenesis. Nature Reviews. Cancer 2, 605-615
67Yang, A. et al. (2002) On the shoulders of giants: p63, p73 and the rise of p53. Trends in Genetics 18, 90-95
68Mantovani, F. et al. (2004) Pin1 links the activities of c-Abl and p300 in regulating p73 function. Molecular Cell 14, 625-636
69Wulf, G.M. et al. (2001) Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards the cyclin D1. EMBO Journal 20, 3459-3472
70Ryo, A. et al. (2001) Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nature Cell Biology 3, 793-801
71Bao, L. et al. (2004) Prevalent overexpression of prolyl isomerase Pin1 in human cancers. American Journal of Pathology 164, 1727-1737
72Ayala, G. et al. (2003) Pin1 is a novel prognostic marker in prostate cancer. Cancer Research 63, 6244-6251
73Sasaki, T. et al. (2006) An immunohistochemical scoring system of prolyl isomerase Pin1 for predicting relapse of prostate carcinoma after radical prostatectomy. Pathology, Research and Practice 202, 357-364
74Yi, P. et al. (2005) 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). Molecular and Cellular Biology 25, 9687-9699
75Liao, Y. et al. (2009) Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation. Oncogene 28, 2436-2445
76Shen, Z.J. et al. (2009) The peptidyl-prolyl isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation. Nature Immunology 10, 257-265
77Basu, A. et al. (2002) Proteasomal degradation of human peptidyl prolyl isomerase pin1-pointing phospho Bcl2 toward dephosphorylation. Neoplasia 4, 218-227
78Yu, L. et al. (2006) Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. Journal of Biological Chemistry 281, 18201-18207
79Pulikkan, J.A. et al. (2010) Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML. Leukemia 24, 914-923
80Ryo, A. et al. (2007) A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. Journal of Biological Chemistry 282, 36671-36681
81Zheng, Y. et al. (2009) FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Molecular Cell 35, 11-25
82Monje, P. et al. (2005) Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1. Journal of Biological Chemistry 280, 35081-35084
83Penela, P. et al. (2010) G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proceedings of the National Academy of Sciences of the United States of America 107, 1118-1123
84Pang, R. et al. (2007) Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. Gastroenterology 132, 1088-1103
85Ding, Q. et al. (2008) Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Research 68, 6109-6117
86Li, Q.M. et al. (2007) Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury. Journal of Neuroscience 27, 8395-8404
87Pani, E. et al. (2008) Pin1 interacts with c-Myb in a phosphorylation-dependent manner and regulates its transactivation activity. Biochimica et Biophysica Acta 1783, 1121-1128
88Lam, P.B. et al. (2008) Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability. Molecular Cancer 7, 91
89Ryo, A. et al. (2003) Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Molecular Cell 12, 1413-1426
90Rustighi, A. et al. (2009) The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nature Cell Biology 11, 133-142
91Lee, N.Y. et al. (2009) The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation. Carcinogenesis 30, 671-681
92Takahashi, K. et al. (2007) Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1. Oncogene 26, 3835-3845
93Crenshaw, D.G. et al. (1998) The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1. EMBO Journal 17, 1315-1327
94Shen, M. et al. (1998) The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes and Development 12, 706-720
95Eckerdt, F. et al. (2005) Polo-like kinase 1-mediated phosphorylation stabilizes Pin1 by inhibiting its ubiquitination in human cells. Journal of Biological Chemistry 280, 36575-36583
96Reineke, E.L. et al. (2008) Degradation of the tumor suppressor PML by Pin1 contributes to the cancer phenotype of breast cancer MDA-MB-231 cells. Molecular and Cellular Biology 28, 997-1006
97Dougherty, M.K. et al. (2005) Regulation of Raf-1 by direct feedback phosphorylation. Molecular Cell 17, 215-224
98Gianni, M. et al. (2009) Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of RARalpha and PML-RARalpha. Cancer Research 69, 1016-1026
99Brondani, V. et al. (2005) The peptidyl-prolyl isomerase Pin1 regulates phospho-Ser77 retinoic acid receptor alpha stability. Biochemical and Biophysical Research Communications 328, 6-13
100Fan, G. et al. (2009) Peptidyl-prolyl isomerase Pin1 markedly enhances the oncogenic activity of the rel proteins in the nuclear factor-kappaB family. Cancer Research 69, 4589-4597
101Nakano, A. et al. (2009) Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins. Journal of Biological Chemistry 284, 6109-6115
102Stanya, K.J. et al. (2008) Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT. Journal of Cell Biology 183, 49-61
103Lufei, C. et al. (2007) Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity. Oncogene 26, 7656-7664
104Peloponese, J.M. Jr et al. (2009) Peptidylproline cis-trans-isomerase Pin1 interacts with human T-cell leukemia virus type 1 tax and modulates its activation of NF-kappaB. Journal of Virology 83, 3238-3248
105Wiegand, S. et al. (2009) The rotamase Pin1 is up-regulated, hypophosphorylated and required for cell cycle progression in head and neck squamous cell carcinomas. Oral Oncology 45, e140-e149
106Lee, T.H. et al. (2011) Death associated protein kinase phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Molecular Cell 42, 147-159
107Wulf, G. et al. (2004) Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO Journal 23, 3397-3407
108Bornens, M. (2002) Centrosome composition and microtubule anchoring mechanisms. Current Opinion in Cell Biology 14, 25-34
109Doxsey, S., McCollum, D. and Theurkauf, W. (2005) Centrosomes in cellular regulation. Annual Review of Cell and Developmental Biology 21, 411-434
110Doxsey, S. (2002) Duplicating dangerously: linking centrosome duplication and aneuploidy. Molecular Cell 10, 439-440
111Ryo, A. et al. (2009) Pinning down HER2-ER crosstalk in SMRT regulation. Trends in Biochemical Sciences 34, 162-165
112Liao, L. et al. (2002) Molecular structure and biological function of the cancer-amplified nuclear receptor coactivator SRC-3/AIB1. Journal of Steroid Biochemistry and Molecular Biology 83, 3-14
113Xu, L., Glass, C.K. and Rosenfeld, M.G. (1999) Coactivator and corepressor complexes in nuclear receptor function. Current Opinion in Genetics and Development 9, 140-147
114Goedert, M. et al. (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159-168
115Glenner, G.G. et al. (1984) The amyloid deposits in Alzheimer's disease: their nature and pathogenesis. Applied Pathology 2, 357-369
116Braak, H. and Braak, E. (1990) Alzheimer's disease: striatal amyloid deposits and neurofibrillary changes. Journal of Neuropathology and Experimental Neurology 49, 215-224
117Lu, P.J. et al. (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784-788
118Thorpe, J.R., Morley, S.J. and Rulten, S.L. (2001) Utilizing the peptidyl-prolyl cis-trans isomerase pin1 as a probe of its phosphorylated target proteins. Examples of binding to nuclear proteins in a human kidney cell line and to tau in Alzheimer's diseased brain. Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society 49, 97-108
119Segat, L. et al. (2007) PIN1 promoter polymorphisms are associated with Alzheimer's disease. Neurobiology of Aging 28, 69-74
120Poli, M. et al. (2005) DNA sequence variations in the prolyl isomerase Pin1 gene and Alzheimer's disease. Neuroscience Letters 389, 66-70
121Nowotny, P. et al. (2007) Association studies between common variants in prolyl isomerase Pin1 and the risk for late-onset. Alzheimer's disease. Neuroscience Letters 419, 15-17
122Ma, S.L. et al. (2011) A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease. Neurobiology of Aging, in press
123Strittmatter, W.J. et al. (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90, 1977-1981
124Corder, E.H. et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923
125Buee, L. et al. (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Research. Brain Research Reviews 33, 95-130
126Iqbal, K. et al. (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathologica 118, 53-69
127Andorfer, C. et al. (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. Journal of Neurochemistry 86, 582-590
128Cruz, J.C. and Tsai, L.H. (2004) Cdk5 deregulation in the pathogenesis of Alzheimer's disease. Trends in Molecular Medicine 10, 452-458
129Noble, W. et al. (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38, 555-565
130Mandelkow, E.M. et al. (1992) Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Letters 314, 315-321
131Sperber, B.R. et al. (1995) Glycogen synthase kinase-3 beta phosphorylates tau protein at multiple sites in intact cells. Neuroscience Letters 197, 149-153
132Vincent, I.J. and Davies, P. (1992) A protein kinase associated with paired helical filaments in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 89, 2878-2882
133Daly, N.L. et al. (2000) Role of phosphorylation in the conformation of tau peptides implicated in Alzheimer's disease. Biochemistry 39, 9039-9046
134Mondragon-Rodriguez, S. et al. (2008) Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer's disease. International Journal of Experimental Pathology 89, 81-90
135Jeganathan, S. et al. (2008) Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC-1) conformation. Journal of Biological Chemistry 283, 32066-32076
136Carmel, G. et al. (1996) The structural basis of monoclonal antibody Alz50's selectivity for Alzheimer's disease pathology. Journal of Biological Chemistry 271, 32789-32795
137Luna-Munoz, J. et al. (2007) Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease. Journal of Alzheimer's Disease 12, 365-375
138Ramakrishnan, P., Dickson, D.W. and Davies, P. (2003) Pin1 colocalization with phosphorylated tau in Alzheimer's disease and other tauopathies. Neurobiology of Disease 14, 251-264
139Holzer, M. et al. (2002) Inverse association of Pin1 and tau accumulation in Alzheimer's disease hippocampus. Acta Neuropathologica 104, 471-481
140Thorpe, J.R. et al. (2004) Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. Neurobiology of Disease 17, 237-249
141Galas, M.C. et al. (2006) The peptidylprolyl cis/trans-isomerase Pin1 modulates stress-induced dephosphorylation of Tau in neurons. Implication in a pathological mechanism related to Alzheimer disease. Journal of Biological Chemistry 281, 19296-19304
142Lim, J. et al. (2008) Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. Journal of Clinical Investigation 118, 1877-1889
143Mirra, S.S. et al. (1999) Tau pathology in a family with dementia and a P301L mutation in tau. Journal of Neuropathology and Experimental Neurology 58, 335-345
144Lewis, J. et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487-1491
145Lewis, J. et al. (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genetics 25, 402-405
146Gotz, J. et al. (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491-1495
147Walsh, D.M. et al. (2000) The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 39, 10831-10839
148Walsh, D.M. et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539
149Shankar, G.M. et al. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Medicine 14, 837-842
150Thinakaran, G. and Koo, E.H. (2008) Amyloid precursor protein trafficking, processing, and function. Journal of Biological Chemistry 283, 29615-29619
151Mattson, M.P. (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiological Reviews 77, 1081-1132
152Young-Pearse, T.L. et al. (2008) Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Development 3, 15
153Suzuki, T. and Nakaya, T. (2008) Regulation of amyloid beta-protein precursor by phosphorylation and protein interactions. Journal of Biological Chemistry 283, 29633-29637
154Lee, M.S. et al. (2003) APP processing is regulated by cytoplasmic phosphorylation. Journal of Cell Biology 163, 83-95
155Cruz, J.C. et al. (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. Journal of Neuroscience 26, 10536-10541
156Phiel, C.J. et al. (2003) GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423, 435-439
157Ramelot, T.A., Gentile, L.N. and Nicholson, L.K. (2000) Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic factors. Biochemistry 39, 2714-2725
158Ramelot, T.A. and Nicholson, L.K. (2001) Phosphorylation-induced structural changes in the amyloid precursor protein cytoplasmic tail detected by NMR. Journal of Molecular Biology 307, 871-884
159Carlson, G.A. et al. (1997) Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Human Molecular Genetics 6, 1951-1959
160Kawarabayashi, T. et al. (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. Journal of Neuroscience 21, 372-381
161Almeida, C.G., Takahashi, R.H. and Gouras, G.K. (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. Journal of Neuroscience 26, 4277-4288
162Akiyama, H. et al. (2005) Pin1 promotes production of Alzheimer's amyloid beta from beta-cleaved amyloid precursor protein. Biochemical and Biophysical Research Communications 336, 521-529
163Bulbarelli, A. et al. (2009) Pin1 affects Tau phosphorylation in response to Abeta oligomers. Molecular and Cellular Neurosciences 42, 75-80
164Wang, S. et al. (2007) The significance of Pin1 in the development of Alzheimer's disease. Journal of Alzheimer's Disease 11, 13-23
165Sultana, R. et al. (2006) Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: a redox proteomics analysis. Neurobiology of Aging 27, 918-925
166Lambert, J.C. et al. (2006) Association study of the PIN1 gene with Alzheimer's disease. Neuroscience Letters 402, 259-261
167Kesavapany, S. et al. (2007) Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons. Molecular Biology of the Cell 18, 3645-3655
168Hashemzadeh-Bonehi, L. et al. (2006) Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Experimental Neurology 199, 328-338
169Fujimori, F. et al. (1999) Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest. Biochemical and Biophysical Research Communications 265, 658-663
170Toledo, F. et al. (2007) Mouse mutants reveal that putative protein interaction sites in the p53 proline-rich domain are dispensable for tumor suppression. Molecular and Cellular Biology 27, 1425-1432
171Rapoport, M. et al. (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America 99, 6364-6369
172Kuramochi, J. et al. (2006) High Pin1 expression is associated with tumor progression in colorectal cancer. Journal of Surgical Oncology 94, 155-160
173Fukuchi, M. et al. (2006) Prolyl isomerase Pin1 expression predicts prognosis in patients with esophageal squamous cell carcinoma and correlates with cyclinD1 expression. International Journal of Oncology 29, 329-334
174Leung, K.W. et al. (2009) Pin1 overexpression is associated with poor differentiation and survival in oral squamous cell carcinoma. Oncology Reports 21, 1097-1104
175Tan, X. et al. (2010) Pin1 expression contributes to lung cancer: prognosis and carcinogenesis. Cancer Biology and Therapy 9, 111-119
176Ryo, A. et al. (2002) Pin1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Molecular and Cellular Biology 22, 5281-5295
177Ryo, A. et al. (2005) Stable suppression of tumorigenicity by Pin1-targeted RNA interference in prostate cancer. Clinical Cancer Research 11, 7523-7531
178Hennig, L. et al. (1998) Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone. Biochemistry 37, 5953-5960
179Uchida, T. et al. (2003) Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation. Chemistry and Biology 10, 15-24
180Wildemann, D. et al. (2006) Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries. Journal of Medicinal Chemistry 49, 2147-2150
181Potter, A.J. et al. (2010) Structure-guided design of alpha-amino acid-derived Pin1 inhibitors. Bioorganic and Medicinal Chemistry Letters 20, 586-590
182Guo, C. et al. (2009) Structure-based design of novel human Pin1 inhibitors (I). Bioorganic and Medicinal Chemistry Letters 19, 5613-5616
183Zhao, S. and Etzkorn, F.A. (2007) A phosphorylated prodrug for the inhibition of Pin1. Bioorganic and Medicinal Chemistry Letters 17, 6615-6618
184Xu, G.G. and Etzkorn, F.A. (2009) Pin1 as an anticancer drug target. Drug News and Perspectives 22, 399-407
185Wildemann, D. et al. (2007) An essential role for Pin1 in Xenopus laevis embryonic development revealed by specific inhibitors. Biological Chemistry 388, 1103-1111
186Zhang, Y. et al. (2007) Structural basis for high-affinity peptide inhibition of human Pin1. ACS Chemical Biology 2, 320-328
187Liu, T. et al. (2010) Membrane permeable cyclic peptidyl inhibitors against human Peptidylprolyl Isomerase Pin1. Journal of Medicinal Chemistry 53, 2494-2501
188Wulf, G. et al. (2003) The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Research 5, 76-82

The following papers describe in detail the mechanisms of prolyl cis–trans isomerisation that are not discussed in this review. Other diseases involving Pin1 deregulation are also reviewed.

Behrens, M.I. et al. (2009) A common biological mechanism in cancer and Alzheimer's disease? Current Alzheimer Research 6, 196-204
Lu, K.P. and Zhou, X.Z. (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nature Reviews. Molecular Cell Biology 8, 904-916
Lu, K.P. et al. (2007) Prolyl cis-trans isomerization as a molecular timer. Nature Chemical Biology 3, 619-629
Wulf, G. et al. (2005) Phosphorylation-specific prolyl isomerization: is there an underlying theme? Nature Cell Biology 7, 435-441
The UCSD-Nature Signaling Gateway Molecule Pages provide general information about Pin1, its regulation and interacting proteins:
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *