Abstract
The prolyl isomerase Pin1 is a conserved enzyme that is intimately involved in diverse biological processes and pathological conditions such as cancer and Alzheimer's disease. By catalysing cis–trans interconversion of certain motifs containing phosphorylated serine or threonine residues followed by a proline residue (pSer/Thr-Pro), Pin1 can have profound effects on phosphorylation signalling. The structural and functional differences that result from cis–trans isomerization of specific pSer/Thr-Pro motifs probably underlie most, if not all, Pin1-dependent actions. Phosphorylation-dependent prolyl isomerization by Pin1 remains a unique mode for the modulation of signal transduction. Here, we provide an overview of the plethora of regulatory events that involve this unique enzyme, with a particular focus on oncogenic signalling and neurodegeneration.
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References
Lu, K. P., Hanes, S. D. & Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544–547 (1996).
Ye, X. S. et al. The NIMA protein kinase is hyperphosphorylated and activated downstream of p34cdc2/cyclin B: coordination of two mitosis promoting kinases. EMBO J. 14, 986–994 (1995).
Lu, K. P. & Hunter, T. Evidence for a NIMA-like mitotic pathway in vertebrate cells. Cell 81, 413–424 (1995).
Yaffe, M. B. et al. Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism. Science 278, 1957–1960 (1997).
Ranganathan, R., Lu, K. P., Hunter, T. & Noel, J. P. Structural and functional analysis of the mitotic peptidyl-prolyl isomerase Pin1 suggests that substrate recognition is phosphorylation dependent. Cell 89, 875–886 (1997).
Lu, K. P., Liou, Y. C. & Zhou, X. Z. Pinning down the proline-directed phosphorylation signaling. Trends Cell Biol. 12, 164–172 (2002).
Lu, K. P. Pinning down cell signaling, cancer and Alzheimer's disease. Trends Biochem. Sci. 29, 200–209 (2004).
Lu, P. J., Zhou, X. Z., Shen, M. & Lu, K. P. A function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 283, 1325–1328 (1999).
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).
Zhou, X. Z. et al. Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol. Cell 6, 873–883 (2000).
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).
Wu, X. et al. The Ess1 prolyl isomerase is linked to chromatin remodeling complexes and the general transcription machinery. EMBO J. 19, 3727–3738 (2000).
Wulf, G. M. et al. Pin1 is overexpressed in breast cancer and potentiates the transcriptional activity of phosphorylated c-Jun towards the cyclin D1 gene. EMBO J. 20, 3459–3472 (2001).
Ryo, A., Nakamura, N., Wulf, G., Liou, Y. C. & Lu, K. P. Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nature Cell Biol. 3, 793–801 (2001).
Stukenberg, P. T. & Kirschner, M. W. Pin1 acts catalytically to promote a conformational change in Cdc25. Mol. Cell 7, 1071–1083 (2001).
Liou, Y. C. et al. Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc. Natl Acad. Sci. USA 99, 1335–1340 (2002).
Ryo, A. et al. Pin1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Mol. Cell Biol. 22, 5281–5295 (2002).
Wulf, G. M., Liou, Y. C., Ryo, A., Lee, S. W. & Lu, K. P. Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. J. Biol. Chem. 277, 47976–47979 (2002).
Zheng, H. et al. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419, 849–853 (2002).
Zacchi, P. et al. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419, 853–857 (2002).
Ryo, A. et al. Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol. Cell 12, 1413–1426 (2003).
Atchison, F. W., Capel, B. & Means, A. R. Pin1 regulates the timing of mammalian primordial germ cell proliferation. Development 130, 3579–3586 (2003).
Xu, Y. X., Hirose, Y., Zhou, X. Z., Lu, K. P. & Manley, J. L. Pin1 modulates the structure and function of human RNA polymerase II. Genes Dev. 17, 2765–2776 (2003).
Liou, Y.-C. et al. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424, 556–561 (2003).
Yeh, E. et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nature Cell Biol. 6, 308–318 (2004).
Mantovani, F. et al. Pin1 links the activities of c-Abl and p300 in regulating p73 function. Mol. Cell 14, 625–636 (2004).
Wilcox, C. B., Rossettini, A. & Hanes, S. D. Genetic interactions with C-terminal domain (CTD) kinases and the CTD of RNA Pol II suggest a role for ESS1 in transcription initiation and elongation in Saccharomyces cerevisiae. Genetics 167, 93–105 (2004).
Dougherty, M. K. et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215–224 (2005).
Thorpe, J. R. et al. Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. Neurobiol. Dis. 17, 237–249 (2004).
Ayala, G. et al. Pin1 is a novel prognostic marker in prostate cancer. Cancer Res. 63, 6244–6251 (2003).
Bao, L., Sauter, G., Sowadski, J., Lu, K. P. & Wang, D. Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am. J. Pathol. 164, 1727–1737 (2004).
Pang, R. et al. PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma. Oncogene 23, 4182–4186 (2004).
Wulf, G., Garg, P., Liou, Y. C., Iglehart, D. & Lu, K. P. Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J. 23, 3397–3407 (2004).
Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).
Lu, K. P. Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics. Cancer Cell 4, 175–180 (2003).
Fischer, G. & Aumuller, T. Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes. Rev. Physiol. Biochem. Pharmacol. 148, 105–150 (2003).
Uchida, T., Fujimori, F., Tradler, T., Fischer, G. & Rahfeld, J. U. Identification and characterization of a 14 kDa human protein as a novel parvulin-like peptidyl prolyl cis/trans isomerase. FEBS Lett. 446, 278–282 (1999).
Weiwad, M., Kullertz, G., Schutkowski, M. & Fischer, G. Evidence that the substrate backbone conformation is critical to phosphorylation by p42 MAP kinase. FEBS Lett. 478, 39–42 (2000).
Brown, N. R., Noble, M. E., Endicott, J. A. & Johnson, L. N. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nature Cell Biol. 1, 438–443 (1999).
Verdecia, M. A., Bowman, M. E., Lu, K. P., Hunter, T. & Noel, J. P. Structural basis for phosphoserine-proline recognition by group IV WW domains. Nature Struct. Biol. 7, 639–643 (2000).
Shen, M., Stukenberg, P. T., Kirschner, M. W. & Lu, K. P. The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes Dev. 12, 706–720 (1998).
You, H. et al. IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry. J. Cell. Biochem. 84, 211–216 (2002).
Lu, P. J., Zhou, X. Z., Liou, Y. C., Noel, J. P. & Lu, K. P. Critical role of WW domain phosphorylation in regulating its phosphoserine-binding activity and the Pin1 function. J. Biol. Chem. 277, 2381–2384 (2002).
Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).
Lamb, J. et al. A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114, 323–334 (2003).
Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998).
Alt, J. R., Cleveland, J. L., Hannink, M. & Diehl, J. A. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 14, 3102–3114 (2000).
Gao, M. et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306, 271–275 (2004).
Moon, R. T., Bowerman, B., Boutros, M. & Perrimon, N. The promise and perils of Wnt signaling through β-catenin. Science 296, 1644–1646 (2002).
Bienz, M. The subcellular destinations of APC proteins. Nature Rev. Mol. Cell Biol. 3, 328–338 (2002).
Karin, M., Cao, Y., Greten, F. R. & Li, Z. W. NF-κB in cancer: from innocent bystander to major culprit. Nature Rev. Cancer 2, 301–310 (2002).
Wahl, G. M. & Carr, A. M. The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature Cell Biol. 3, E277–E286 (2001).
Lu, K. P., Liou, Y. C. & Vincent, I. Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's disease. Bioessays 25, 174–181 (2003).
Lee, M. S. & Tsai, L. H. Cdk5: one of the links between senile plaques and neurofibrillary tangles? J. Alzheimers Dis. 5, 127–137 (2003).
Zhu, X. et al. Oxidative stress signalling in Alzheimer's disease. Brain Res. 1000, 32–39 (2004).
Lee, M. S. et al. APP processing is regulated by cytoplasmic phosphorylation. J. Cell Biol. 163, 83–95 (2003).
Zhang, Z. et al. Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 395, 698–702 (1998).
Geschwind, D. H. Tau phosphorylation, tangles, and neurodegeneration: the chicken or the egg. Neuron 40, 457–460 (2003).
Kops, O., Zhou, X. Z. & Lu, K. P. Pin1 enhances the dephosphorylation of the C-terminal domain of the RNA polymerase II by Fcp1. FEBS Lett. 513, 305–311 (2002).
Orlicky, S., Tang, X., Willems, A., Tyers, M. & Sicheri, F. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell 112, 243–256 (2003).
Acknowledgements
Owing to space limitations we could not include all relevant references, for which we apologise. We are grateful to B. Neel, L. Cantley, T. Hunter and to the members of the Lu laboratory for stimulating discussions. K.P.L. is a Pew Scholar and a Leukemia and Lymphoma Society Scholar. Work done in the authors' laboratory is supported by NIH grants Mentored Clinician Scientist Award CA093655 to G. W. and GM56230, GM58556, AG17870 and AG22082 to K.P.L.
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K. P. Lu is a member of the Scientific Advisory Board and a Consultant for Pintex Pharmaceutical, Inc. However, the work described in this review was not supported by Pintex or any other pharmaceutical company.
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Wulf, G., Finn, G., Suizu, F. et al. Phosphorylation-specific prolyl isomerization: is there an underlying theme?. Nat Cell Biol 7, 435–441 (2005). https://doi.org/10.1038/ncb0505-435
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DOI: https://doi.org/10.1038/ncb0505-435
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