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Not to be confused with PIN1, an auxin transport protein in plants..
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1gene.[1][2]
Pin 1, or peptidyl-prolyl cis/trans isomerase (PPIase), isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function. Studies have shown that the deregulation of Pin1 may play a pivotal role in various diseases. Notably, the up-regulation of Pin1 is implicated in certain cancers, and the down-regulation of Pin1 is implicated in Alzheimer's disease. Inhibitors of Pin1 may have therapeutic implications for cancer and immune disorders.
The gene encoding Pin1 was identified in 1996 as a result of a genetic/biochemical screen for proteins involved in mitoticregulation. It was found to be essential for cell division in some organisms. By 1999, however, it was apparent that Pin1 knockout mice had a surprisingly mild phenotype, indicating that the enzyme was not required for cell division per se. Further studies later found that loss of Pin1 in mice displays are not only neuronal degenerative phenotypes but also several abnormalities, similar to those of cyclin D1-null mice, suggesting the conformation changes mediated by Pin1 may be crucial for cell normal function.
Activation
Phosphorylation of Ser/Thr-Pro motifs in substrates is required for recognition by Pin1. Pin is a small protein at 18 kDa and does not have a nuclear localization or export signal. However, 2009, Lufei et al. reported that Pin1 has putative novel nuclear localization signal (NLS) and Pin1 interacts with importin α5 (KPNA1).[3] Substrate interactions and a WW domain determine subcellular distribution. Expression is induced by growth signals from E2F transcription factors. Expression levels fluctuate in normal, but not in cancerous cells. Expression is often associated with cell proliferation. Postranslational modifications such as phosphorylation on Ser16 inhibit the ability of Pin1 to bind substrate, and this inhibitory process may be altered during oncogenesis. It is hypothesized, but not proven, that Pin1 might also be regulated by proteolytic pathways.
Function
Pin1 activity regulates the outcome of proline-directed kinase (e.g. MAPK, CDK or GSK3) signalling and consequently regulates cell proliferation (in part through control of cyclin D1 levels and stability) and cell survival. The precise effects of Pin1 depend upon the system: Pin1 accelerates dephosphorylation of Cdc25 and Tau, but protects phosphorylated cyclin D from ubiquitination and proteolysis. Recent data also implicate Pin1 as playing an important role in immune responses, at least in part by increasing the stability of cytokinemRNAs by influencing the protein complexes to which they bind. Pin1 has been hypothesized to act as a molecular timer.[4]
↑Lu KP, Hanes SD, Hunter T (Apr 1996). "A human peptidyl-prolyl isomerase essential for regulation of mitosis". Nature. 380 (6574): 544–7. doi:10.1038/380544a0. PMID8606777.
↑Lu KP, Finn G, Lee TH, Nicholson LK (Oct 2007). "Prolyl cis-trans isomerization as a molecular timer". Nature Chemical Biology. 3 (10): 619–29. doi:10.1038/nchembio.2007.35. PMID17876319.
↑Brenkman AB, de Keizer PL, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM (Sep 2008). "The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors". Cancer Research. 68 (18): 7597–605. doi:10.1158/0008-5472.CAN-08-1059. PMID18794148.
↑Kamimoto T, Zama T, Aoki R, Muro Y, Hagiwara M (Oct 2001). "Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1". The Journal of Biological Chemistry. 276 (40): 37520–8. doi:10.1074/jbc.M106207200. PMID11470801.
↑Wells NJ, Watanabe N, Tokusumi T, Jiang W, Verdecia MA, Hunter T (Oct 1999). "The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G(2)/M progression". Journal of Cell Science. 112 (19): 3361–71. PMID10504341.
↑ 15.015.1Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, Hanai J, Akiyama H, Abe M, Miyazono K, Matsumoto T, Imamura T (Mar 2009). "Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins". The Journal of Biological Chemistry. 284 (10): 6109–15. doi:10.1074/jbc.M804659200. PMID19122240.
↑Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP (Dec 2002). "Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage". The Journal of Biological Chemistry. 277 (50): 47976–9. doi:10.1074/jbc.C200538200. PMID12388558.
↑Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S, Ronai Z, Blandino G, Schneider C, Del Sal G (Oct 2002). "The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults". Nature. 419 (6909): 853–7. doi:10.1038/nature01120. PMID12397362.
↑Lavoie SB, Albert AL, Handa H, Vincent M, Bensaude O (Sep 2001). "The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9". Journal of Molecular Biology. 312 (4): 675–85. doi:10.1006/jmbi.2001.4991. PMID11575923.
Further reading
Lu KP, Liou YC, Zhou XZ (Apr 2002). "Pinning down proline-directed phosphorylation signaling". Trends in Cell Biology. 12 (4): 164–72. doi:10.1016/S0962-8924(02)02253-5. PMID11978535.
Wulf G, Finn G, Suizu F, Lu KP (May 2005). "Phosphorylation-specific prolyl isomerization: is there an underlying theme?". Nature Cell Biology. 7 (5): 435–41. doi:10.1038/ncb0505-435. PMID15867923.
Etzkorn FA (May 2006). "Pin1 flips Alzheimer's switch". ACS Chemical Biology. 1 (4): 214–6. doi:10.1021/cb600171g. PMID17163675.
Ranganathan R, Lu KP, Hunter T, Noel JP (Jun 1997). "Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent". Cell. 89 (6): 875–86. doi:10.1016/S0092-8674(00)80273-1. PMID9200606.
Campbell HD, Webb GC, Fountain S, Young IG (Sep 1997). "The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31". Genomics. 44 (2): 157–62. doi:10.1006/geno.1997.4854. PMID9299231.
Lu PJ, Zhou XZ, Shen M, Lu KP (Feb 1999). "Function of WW domains as phosphoserine- or phosphothreonine-binding modules". Science. 283 (5406): 1325–8. doi:10.1126/science.283.5406.1325. PMID10037602.
Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP (Jun 1999). "The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein". Nature. 399 (6738): 784–8. doi:10.1038/21650. PMID10391244.
Albert A, Lavoie S, Vincent M (Aug 1999). "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". Journal of Cell Science. 112. 112 (15): 2493–500. PMID10393805.
Wells NJ, Watanabe N, Tokusumi T, Jiang W, Verdecia MA, Hunter T (Oct 1999). "The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G(2)/M progression". Journal of Cell Science. 112. 112 (19): 3361–71. PMID10504341.
Verdecia MA, Bowman ME, Lu KP, Hunter T, Noel JP (Aug 2000). "Structural basis for phosphoserine-proline recognition by group IV WW domains". Nature Structural Biology. 7 (8): 639–43. doi:10.1038/77929. PMID10932246.
Rippmann JF, Hobbie S, Daiber C, Guilliard B, Bauer M, Birk J, Nar H, Garin-Chesa P, Rettig WJ, Schnapp A (Jul 2000). "Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis". Cell Growth & Differentiation. 11 (7): 409–16. PMID10939594.
Liu W, Youn HD, Zhou XZ, Lu KP, Liu JO (May 2001). "Binding and regulation of the transcription factor NFAT by the peptidyl prolyl cis-trans isomerase Pin1". FEBS Letters. 496 (2–3): 105–8. doi:10.1016/S0014-5793(01)02411-5. PMID11356192.
Kamimoto T, Zama T, Aoki R, Muro Y, Hagiwara M (Oct 2001). "Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1". The Journal of Biological Chemistry. 276 (40): 37520–8. doi:10.1074/jbc.M106207200. PMID11470801.
