Full text data of PIN1
PIN1
[Confidence: low (only semi-automatic identification from reviews)]
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; 5.2.1.8 (Peptidyl-prolyl cis-trans isomerase Pin1; PPIase Pin1; Rotamase Pin1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; 5.2.1.8 (Peptidyl-prolyl cis-trans isomerase Pin1; PPIase Pin1; Rotamase Pin1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q13526
ID PIN1_HUMAN Reviewed; 163 AA.
AC Q13526; A8K4V9; Q53X75;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1;
DE EC=5.2.1.8;
DE AltName: Full=Peptidyl-prolyl cis-trans isomerase Pin1;
DE Short=PPIase Pin1;
DE AltName: Full=Rotamase Pin1;
GN Name=PIN1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8606777; DOI=10.1038/380544a0;
RA Lu K.P., Hanes S.D., Hunter T.;
RT "A human peptidyl-prolyl isomerase essential for regulation of
RT mitosis.";
RL Nature 380:544-547(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP INTERACTION WITH KIF20B, AND MUTAGENESIS OF TYR-23.
RX PubMed=11470801; DOI=10.1074/jbc.M106207200;
RA Kamimoto T., Zama T., Aoki R., Muro Y., Hagiwara M.;
RT "Identification of a novel kinesin-related protein, KRMP1, as a target
RT for mitotic peptidyl-prolyl isomerase Pin1.";
RL J. Biol. Chem. 276:37520-37528(2001).
RN [8]
RP FUNCTION, AND INTERACTION WITH RAF1.
RX PubMed=15664191; DOI=10.1016/j.molcel.2004.11.055;
RA Dougherty M.K., Muller J., Ritt D.A., Zhou M., Zhou X.Z.,
RA Copeland T.D., Conrads T.P., Veenstra T.D., Lu K.P., Morrison D.K.;
RT "Regulation of Raf-1 by direct feedback phosphorylation.";
RL Mol. Cell 17:215-224(2005).
RN [9]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH NEK6.
RX PubMed=16476580; DOI=10.1016/j.bbrc.2005.12.228;
RA Chen J., Li L., Zhang Y., Yang H., Wei Y., Zhang L., Liu X., Yu L.;
RT "Interaction of Pin1 with Nek6 and characterization of their
RT expression correlation in Chinese hepatocellular carcinoma patients.";
RL Biochem. Biophys. Res. Commun. 341:1059-1065(2006).
RN [10]
RP INTERACTION WITH BTX, AND FUNCTION.
RX PubMed=16644721; DOI=10.1074/jbc.M603090200;
RA Yu L., Mohamed A.J., Vargas L., Berglof A., Finn G., Lu K.P.,
RA Smith C.I.;
RT "Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase
RT Pin1.";
RL J. Biol. Chem. 281:18201-18207(2006).
RN [11]
RP FUNCTION IN BCL6 STABILITY REGULATION, INTERACTION WITH BCL6, AND
RP TISSUE SPECIFICITY.
RX PubMed=17828269; DOI=10.1038/ni1508;
RA Phan R.T., Saito M., Kitagawa Y., Means A.R., Dalla-Favera R.;
RT "Genotoxic stress regulates expression of the proto-oncogene Bcl6 in
RT germinal center B cells.";
RL Nat. Immunol. 8:1132-1139(2007).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [13]
RP INTERACTION WITH ATCAY.
RX PubMed=18628984; DOI=10.1371/journal.pone.0002686;
RA Buschdorf J.P., Chew L.L., Soh U.J., Liou Y.C., Low B.C.;
RT "Nerve growth factor stimulates interaction of Cayman ataxia protein
RT BNIP-H/Caytaxin with peptidyl-prolyl isomerase Pin1 in differentiating
RT neurons.";
RL PLoS ONE 3:E2686-E2686(2008).
RN [14]
RP INTERACTION WITH PRKX.
RX PubMed=19367327; DOI=10.1038/ki.2009.95;
RA Li X., Hyink D.P., Radbill B., Sudol M., Zhang H., Zheleznova N.N.,
RA Wilson P.D.;
RT "Protein kinase-X interacts with Pin-1 and Polycystin-1 during mouse
RT kidney development.";
RL Kidney Int. 76:54-62(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-46, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP FUNCTION, AND INTERACTION WITH PML.
RX PubMed=22033920; DOI=10.1074/jbc.M111.289512;
RA Lim J.H., Liu Y., Reineke E., Kao H.Y.;
RT "Mitogen-activated protein kinase extracellular signal-regulated
RT kinase 2 phosphorylates and promotes Pin1 protein-dependent
RT promyelocytic leukemia protein turnover.";
RL J. Biol. Chem. 286:44403-44411(2011).
RN [18]
RP FUNCTION, PHOSPHORYLATION AT SER-71, INTERACTION WITH DAPK1,
RP SUBCELLULAR LOCATION, MUTAGENESIS OF SER-71, AND TISSUE SPECIFICITY.
RX PubMed=21497122; DOI=10.1016/j.molcel.2011.03.005;
RA Lee T.H., Chen C.H., Suizu F., Huang P., Schiene-Fischer C., Daum S.,
RA Zhang Y.J., Goate A., Chen R.H., Zhou X.Z., Lu K.P.;
RT "Death-associated protein kinase 1 phosphorylates Pin1 and inhibits
RT its prolyl isomerase activity and cellular function.";
RL Mol. Cell 42:147-159(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS).
RX PubMed=9200606; DOI=10.1016/S0092-8674(00)80273-1;
RA Ranganathan R., Lu K.P., Hunter T., Noel J.P.;
RT "Structural and functional analysis of the mitotic rotamase Pin1
RT suggests substrate recognition is phosphorylation dependent.";
RL Cell 89:875-886(1997).
CC -!- FUNCTION: Essential PPIase that regulates mitosis presumably by
CC interacting with NIMA and attenuating its mitosis-promoting
CC activity. Displays a preference for an acidic residue N-terminal
CC to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans
CC isomerizations. Down-regulates kinase activity of BTK. Can
CC transactivate multiple oncogenes and induce centrosome
CC amplification, chromosome instability and cell transformation.
CC Required for the efficient dephosphorylation and recycling of RAF1
CC after mitogen activation. Binds and targets PML and BCL6 for
CC degradation in a phosphorylation-dependent manner.
CC -!- CATALYTIC ACTIVITY: Peptidylproline (omega=180) = peptidylproline
CC (omega=0).
CC -!- SUBUNIT: Interacts with STIL. Interacts with KIF20B. Interacts
CC with NEK6. Interacts (via WW domain) with PRKX. Interacts with
CC BTK. Interacts (via PpiC domain) with DAPK1. Interacts with the
CC phosphorylated form of RAF1. Interacts (via WW domain) with ATCAY;
CC upon NGF stimulation. Interacts with PML (isoform PML-4) and BCL-
CC 6.
CC -!- INTERACTION:
CC P78563:ADARB1; NbExp=12; IntAct=EBI-714158, EBI-2967304;
CC P05067-4:APP; NbExp=2; IntAct=EBI-714158, EBI-302641;
CC Q15131:CDK10; NbExp=5; IntAct=EBI-714158, EBI-1646959;
CC P51617:IRAK1; NbExp=10; IntAct=EBI-714158, EBI-358664;
CC Q9HC98:NEK6; NbExp=3; IntAct=EBI-714158, EBI-740364;
CC P46531:NOTCH1; NbExp=9; IntAct=EBI-714158, EBI-636374;
CC Q13950:RUNX2; NbExp=7; IntAct=EBI-714158, EBI-976402;
CC Q9BR01:SULT4A1; NbExp=4; IntAct=EBI-714158, EBI-6690555;
CC P04637:TP53; NbExp=12; IntAct=EBI-714158, EBI-366083;
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus speckle. Cytoplasm.
CC Note=Colocalizes with NEK6 in the nucleus. Mainly localized in the
CC nucleus but phosphorylation at Ser-71 by DAPK1 results in
CC inhibition of its nuclear localization.
CC -!- TISSUE SPECIFICITY: The phosphorylated form at Ser-71 is expressed
CC in normal breast tissue cells but not in breast cancer cells.
CC -!- DOMAIN: The WW domain is required for the interaction with STIL
CC and KIF20B.
CC -!- PTM: Phosphorylation at Ser-71 by DAPK1 results in inhibition of
CC its catalytic activity, nuclear localization, and its ability to
CC induce centrosome amplification, chromosome instability and cell
CC transformation.
CC -!- SIMILARITY: Contains 1 PpiC domain.
CC -!- SIMILARITY: Contains 1 WW domain.
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DR EMBL; U49070; AAC50492.1; -; mRNA.
DR EMBL; CR407654; CAG28582.1; -; mRNA.
DR EMBL; BT019331; AAV38138.1; -; mRNA.
DR EMBL; AK291074; BAF83763.1; -; mRNA.
DR EMBL; CH471106; EAW84057.1; -; Genomic_DNA.
DR EMBL; BC002899; AAH02899.1; -; mRNA.
DR PIR; S68520; S68520.
DR RefSeq; NP_006212.1; NM_006221.3.
DR UniGene; Hs.465849; -.
DR PDB; 1F8A; X-ray; 1.84 A; B=1-163.
DR PDB; 1I6C; NMR; -; A=6-44.
DR PDB; 1I8G; NMR; -; B=6-44.
DR PDB; 1I8H; NMR; -; B=6-44.
DR PDB; 1NMV; NMR; -; A=1-163.
DR PDB; 1NMW; NMR; -; A=50-163.
DR PDB; 1PIN; X-ray; 1.35 A; A=1-163.
DR PDB; 1ZCN; X-ray; 1.90 A; A=1-161.
DR PDB; 2F21; X-ray; 1.50 A; A=1-162.
DR PDB; 2ITK; X-ray; 1.45 A; A=1-163.
DR PDB; 2KBU; NMR; -; A=6-39.
DR PDB; 2KCF; NMR; -; A=6-39.
DR PDB; 2LB3; NMR; -; A=6-41.
DR PDB; 2M9E; NMR; -; A=6-39.
DR PDB; 2M9F; NMR; -; A=6-39.
DR PDB; 2M9I; NMR; -; A=6-39.
DR PDB; 2M9J; NMR; -; A=6-39.
DR PDB; 2Q5A; X-ray; 1.50 A; A=1-163.
DR PDB; 2XP3; X-ray; 2.00 A; A=1-163.
DR PDB; 2XP4; X-ray; 1.80 A; A=1-163.
DR PDB; 2XP5; X-ray; 1.90 A; A=1-163.
DR PDB; 2XP6; X-ray; 1.90 A; A=1-163.
DR PDB; 2XP7; X-ray; 2.00 A; A=1-163.
DR PDB; 2XP8; X-ray; 2.10 A; A=1-163.
DR PDB; 2XP9; X-ray; 1.90 A; A=1-163.
DR PDB; 2XPA; X-ray; 1.90 A; A=1-163.
DR PDB; 2XPB; X-ray; 2.00 A; A=1-163.
DR PDB; 2ZQS; X-ray; 1.90 A; A=1-163.
DR PDB; 2ZQT; X-ray; 1.46 A; A=1-163.
DR PDB; 2ZQU; X-ray; 2.50 A; A=1-163.
DR PDB; 2ZQV; X-ray; 2.50 A; A=1-163.
DR PDB; 2ZR4; X-ray; 2.00 A; A=1-163.
DR PDB; 2ZR5; X-ray; 2.60 A; A=1-163.
DR PDB; 2ZR6; X-ray; 3.20 A; A=1-163.
DR PDB; 3I6C; X-ray; 1.30 A; A/B=45-163.
DR PDB; 3IK8; X-ray; 1.85 A; A/B=45-163.
DR PDB; 3IKD; X-ray; 2.00 A; A/B=45-163.
DR PDB; 3IKG; X-ray; 1.86 A; A/B=45-163.
DR PDB; 3JYJ; X-ray; 1.87 A; A/B=45-163.
DR PDB; 3KAB; X-ray; 2.19 A; A=1-163.
DR PDB; 3KAC; X-ray; 2.00 A; A/B=44-163.
DR PDB; 3KAD; X-ray; 1.95 A; A=1-163.
DR PDB; 3KAF; X-ray; 2.30 A; A=1-163.
DR PDB; 3KAG; X-ray; 1.90 A; A=1-163.
DR PDB; 3KAH; X-ray; 2.30 A; A=1-163.
DR PDB; 3KAI; X-ray; 1.90 A; A=1-163.
DR PDB; 3KCE; X-ray; 1.90 A; A=1-163.
DR PDB; 3NTP; X-ray; 1.76 A; A=1-163.
DR PDB; 3ODK; X-ray; 2.30 A; A=1-163.
DR PDB; 3OOB; X-ray; 1.89 A; A=1-163.
DR PDB; 3TC5; X-ray; 1.40 A; A=1-163.
DR PDB; 3TCZ; X-ray; 2.10 A; A=6-163.
DR PDB; 3TDB; X-ray; 2.27 A; A=6-163.
DR PDB; 4GWT; X-ray; 2.25 A; A=6-39.
DR PDB; 4GWV; X-ray; 3.05 A; A=6-39.
DR PDBsum; 1F8A; -.
DR PDBsum; 1I6C; -.
DR PDBsum; 1I8G; -.
DR PDBsum; 1I8H; -.
DR PDBsum; 1NMV; -.
DR PDBsum; 1NMW; -.
DR PDBsum; 1PIN; -.
DR PDBsum; 1ZCN; -.
DR PDBsum; 2F21; -.
DR PDBsum; 2ITK; -.
DR PDBsum; 2KBU; -.
DR PDBsum; 2KCF; -.
DR PDBsum; 2LB3; -.
DR PDBsum; 2M9E; -.
DR PDBsum; 2M9F; -.
DR PDBsum; 2M9I; -.
DR PDBsum; 2M9J; -.
DR PDBsum; 2Q5A; -.
DR PDBsum; 2XP3; -.
DR PDBsum; 2XP4; -.
DR PDBsum; 2XP5; -.
DR PDBsum; 2XP6; -.
DR PDBsum; 2XP7; -.
DR PDBsum; 2XP8; -.
DR PDBsum; 2XP9; -.
DR PDBsum; 2XPA; -.
DR PDBsum; 2XPB; -.
DR PDBsum; 2ZQS; -.
DR PDBsum; 2ZQT; -.
DR PDBsum; 2ZQU; -.
DR PDBsum; 2ZQV; -.
DR PDBsum; 2ZR4; -.
DR PDBsum; 2ZR5; -.
DR PDBsum; 2ZR6; -.
DR PDBsum; 3I6C; -.
DR PDBsum; 3IK8; -.
DR PDBsum; 3IKD; -.
DR PDBsum; 3IKG; -.
DR PDBsum; 3JYJ; -.
DR PDBsum; 3KAB; -.
DR PDBsum; 3KAC; -.
DR PDBsum; 3KAD; -.
DR PDBsum; 3KAF; -.
DR PDBsum; 3KAG; -.
DR PDBsum; 3KAH; -.
DR PDBsum; 3KAI; -.
DR PDBsum; 3KCE; -.
DR PDBsum; 3NTP; -.
DR PDBsum; 3ODK; -.
DR PDBsum; 3OOB; -.
DR PDBsum; 3TC5; -.
DR PDBsum; 3TCZ; -.
DR PDBsum; 3TDB; -.
DR PDBsum; 4GWT; -.
DR PDBsum; 4GWV; -.
DR ProteinModelPortal; Q13526; -.
DR SMR; Q13526; 1-163.
DR DIP; DIP-29306N; -.
DR IntAct; Q13526; 76.
DR MINT; MINT-86298; -.
DR STRING; 9606.ENSP00000247970; -.
DR BindingDB; Q13526; -.
DR ChEMBL; CHEMBL2288; -.
DR PhosphoSite; Q13526; -.
DR DMDM; 3024406; -.
DR PaxDb; Q13526; -.
DR PeptideAtlas; Q13526; -.
DR PRIDE; Q13526; -.
DR DNASU; 5300; -.
DR Ensembl; ENST00000247970; ENSP00000247970; ENSG00000127445.
DR Ensembl; ENST00000588695; ENSP00000466962; ENSG00000127445.
DR GeneID; 5300; -.
DR KEGG; hsa:5300; -.
DR UCSC; uc002mmk.2; human.
DR CTD; 5300; -.
DR GeneCards; GC19P009945; -.
DR HGNC; HGNC:8988; PIN1.
DR HPA; CAB004528; -.
DR HPA; CAB009326; -.
DR MIM; 601052; gene.
DR neXtProt; NX_Q13526; -.
DR PharmGKB; PA33320; -.
DR eggNOG; COG0760; -.
DR HOGENOM; HOG000275331; -.
DR HOVERGEN; HBG002101; -.
DR InParanoid; Q13526; -.
DR KO; K09578; -.
DR OMA; FALKVGD; -.
DR PhylomeDB; Q13526; -.
DR BRENDA; 5.2.1.8; 2681.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13526; -.
DR EvolutionaryTrace; Q13526; -.
DR GeneWiki; PIN1; -.
DR GenomeRNAi; 5300; -.
DR NextBio; 20486; -.
DR PRO; PR:Q13526; -.
DR ArrayExpress; Q13526; -.
DR Bgee; Q13526; -.
DR CleanEx; HS_PIN1; -.
DR Genevestigator; Q13526; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0030496; C:midbody; IDA:MGI.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0003755; F:peptidyl-prolyl cis-trans isomerase activity; IDA:BHF-UCL.
DR GO; GO:0050815; F:phosphoserine binding; IDA:BHF-UCL.
DR GO; GO:0050816; F:phosphothreonine binding; IDA:BHF-UCL.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:2000146; P:negative regulation of cell motility; IDA:BHF-UCL.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IGI:MGI.
DR GO; GO:0032321; P:positive regulation of Rho GTPase activity; IMP:BHF-UCL.
DR GO; GO:0051443; P:positive regulation of ubiquitin-protein ligase activity; IDA:BHF-UCL.
DR GO; GO:0006457; P:protein folding; IEA:UniProtKB-KW.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0032465; P:regulation of cytokinesis; IMP:MGI.
DR GO; GO:0007088; P:regulation of mitosis; TAS:ProtInc.
DR GO; GO:0060393; P:regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR InterPro; IPR000297; PPIase_PpiC.
DR InterPro; IPR023058; PPIase_PpiC_CS.
DR InterPro; IPR001202; WW_dom.
DR Pfam; PF00639; Rotamase; 1.
DR Pfam; PF00397; WW; 1.
DR SMART; SM00456; WW; 1.
DR SUPFAM; SSF51045; SSF51045; 1.
DR PROSITE; PS01096; PPIC_PPIASE_1; 1.
DR PROSITE; PS50198; PPIC_PPIASE_2; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 1.
DR PROSITE; PS50020; WW_DOMAIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell cycle; Complete proteome; Cytoplasm;
KW Isomerase; Nucleus; Phosphoprotein; Reference proteome; Rotamase.
FT CHAIN 1 163 Peptidyl-prolyl cis-trans isomerase NIMA-
FT interacting 1.
FT /FTId=PRO_0000193435.
FT DOMAIN 5 39 WW.
FT DOMAIN 52 163 PpiC.
FT MOD_RES 46 46 N6-acetyllysine.
FT MOD_RES 71 71 Phosphoserine; by DAPK1.
FT MOD_RES 108 108 Phosphoserine.
FT MUTAGEN 23 23 Y->A: Reduced affinity for KIF20B.
FT MUTAGEN 71 71 S->D,E: Loss of activity, nuclear
FT localization and cellular function.
FT STRAND 11 15
FT TURN 17 19
FT STRAND 22 26
FT TURN 27 29
FT STRAND 32 35
FT STRAND 39 41
FT STRAND 53 62
FT STRAND 67 69
FT STRAND 75 77
FT HELIX 82 98
FT STRAND 99 101
FT HELIX 103 110
FT HELIX 114 118
FT STRAND 121 126
FT HELIX 132 140
FT STRAND 150 152
FT STRAND 155 163
SQ SEQUENCE 163 AA; 18243 MW; 35391AF40B7D1E13 CRC64;
MADEEKLPPG WEKRMSRSSG RVYYFNHITN ASQWERPSGN SSSGGKNGQG EPARVRCSHL
LVKHSQSRRP SSWRQEKITR TKEEALELIN GYIQKIKSGE EDFESLASQF SDCSSAKARG
DLGAFSRGQM QKPFEDASFA LRTGEMSGPV FTDSGIHIIL RTE
//
ID PIN1_HUMAN Reviewed; 163 AA.
AC Q13526; A8K4V9; Q53X75;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1;
DE EC=5.2.1.8;
DE AltName: Full=Peptidyl-prolyl cis-trans isomerase Pin1;
DE Short=PPIase Pin1;
DE AltName: Full=Rotamase Pin1;
GN Name=PIN1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8606777; DOI=10.1038/380544a0;
RA Lu K.P., Hanes S.D., Hunter T.;
RT "A human peptidyl-prolyl isomerase essential for regulation of
RT mitosis.";
RL Nature 380:544-547(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP INTERACTION WITH KIF20B, AND MUTAGENESIS OF TYR-23.
RX PubMed=11470801; DOI=10.1074/jbc.M106207200;
RA Kamimoto T., Zama T., Aoki R., Muro Y., Hagiwara M.;
RT "Identification of a novel kinesin-related protein, KRMP1, as a target
RT for mitotic peptidyl-prolyl isomerase Pin1.";
RL J. Biol. Chem. 276:37520-37528(2001).
RN [8]
RP FUNCTION, AND INTERACTION WITH RAF1.
RX PubMed=15664191; DOI=10.1016/j.molcel.2004.11.055;
RA Dougherty M.K., Muller J., Ritt D.A., Zhou M., Zhou X.Z.,
RA Copeland T.D., Conrads T.P., Veenstra T.D., Lu K.P., Morrison D.K.;
RT "Regulation of Raf-1 by direct feedback phosphorylation.";
RL Mol. Cell 17:215-224(2005).
RN [9]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH NEK6.
RX PubMed=16476580; DOI=10.1016/j.bbrc.2005.12.228;
RA Chen J., Li L., Zhang Y., Yang H., Wei Y., Zhang L., Liu X., Yu L.;
RT "Interaction of Pin1 with Nek6 and characterization of their
RT expression correlation in Chinese hepatocellular carcinoma patients.";
RL Biochem. Biophys. Res. Commun. 341:1059-1065(2006).
RN [10]
RP INTERACTION WITH BTX, AND FUNCTION.
RX PubMed=16644721; DOI=10.1074/jbc.M603090200;
RA Yu L., Mohamed A.J., Vargas L., Berglof A., Finn G., Lu K.P.,
RA Smith C.I.;
RT "Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase
RT Pin1.";
RL J. Biol. Chem. 281:18201-18207(2006).
RN [11]
RP FUNCTION IN BCL6 STABILITY REGULATION, INTERACTION WITH BCL6, AND
RP TISSUE SPECIFICITY.
RX PubMed=17828269; DOI=10.1038/ni1508;
RA Phan R.T., Saito M., Kitagawa Y., Means A.R., Dalla-Favera R.;
RT "Genotoxic stress regulates expression of the proto-oncogene Bcl6 in
RT germinal center B cells.";
RL Nat. Immunol. 8:1132-1139(2007).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [13]
RP INTERACTION WITH ATCAY.
RX PubMed=18628984; DOI=10.1371/journal.pone.0002686;
RA Buschdorf J.P., Chew L.L., Soh U.J., Liou Y.C., Low B.C.;
RT "Nerve growth factor stimulates interaction of Cayman ataxia protein
RT BNIP-H/Caytaxin with peptidyl-prolyl isomerase Pin1 in differentiating
RT neurons.";
RL PLoS ONE 3:E2686-E2686(2008).
RN [14]
RP INTERACTION WITH PRKX.
RX PubMed=19367327; DOI=10.1038/ki.2009.95;
RA Li X., Hyink D.P., Radbill B., Sudol M., Zhang H., Zheleznova N.N.,
RA Wilson P.D.;
RT "Protein kinase-X interacts with Pin-1 and Polycystin-1 during mouse
RT kidney development.";
RL Kidney Int. 76:54-62(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-46, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP FUNCTION, AND INTERACTION WITH PML.
RX PubMed=22033920; DOI=10.1074/jbc.M111.289512;
RA Lim J.H., Liu Y., Reineke E., Kao H.Y.;
RT "Mitogen-activated protein kinase extracellular signal-regulated
RT kinase 2 phosphorylates and promotes Pin1 protein-dependent
RT promyelocytic leukemia protein turnover.";
RL J. Biol. Chem. 286:44403-44411(2011).
RN [18]
RP FUNCTION, PHOSPHORYLATION AT SER-71, INTERACTION WITH DAPK1,
RP SUBCELLULAR LOCATION, MUTAGENESIS OF SER-71, AND TISSUE SPECIFICITY.
RX PubMed=21497122; DOI=10.1016/j.molcel.2011.03.005;
RA Lee T.H., Chen C.H., Suizu F., Huang P., Schiene-Fischer C., Daum S.,
RA Zhang Y.J., Goate A., Chen R.H., Zhou X.Z., Lu K.P.;
RT "Death-associated protein kinase 1 phosphorylates Pin1 and inhibits
RT its prolyl isomerase activity and cellular function.";
RL Mol. Cell 42:147-159(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS).
RX PubMed=9200606; DOI=10.1016/S0092-8674(00)80273-1;
RA Ranganathan R., Lu K.P., Hunter T., Noel J.P.;
RT "Structural and functional analysis of the mitotic rotamase Pin1
RT suggests substrate recognition is phosphorylation dependent.";
RL Cell 89:875-886(1997).
CC -!- FUNCTION: Essential PPIase that regulates mitosis presumably by
CC interacting with NIMA and attenuating its mitosis-promoting
CC activity. Displays a preference for an acidic residue N-terminal
CC to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans
CC isomerizations. Down-regulates kinase activity of BTK. Can
CC transactivate multiple oncogenes and induce centrosome
CC amplification, chromosome instability and cell transformation.
CC Required for the efficient dephosphorylation and recycling of RAF1
CC after mitogen activation. Binds and targets PML and BCL6 for
CC degradation in a phosphorylation-dependent manner.
CC -!- CATALYTIC ACTIVITY: Peptidylproline (omega=180) = peptidylproline
CC (omega=0).
CC -!- SUBUNIT: Interacts with STIL. Interacts with KIF20B. Interacts
CC with NEK6. Interacts (via WW domain) with PRKX. Interacts with
CC BTK. Interacts (via PpiC domain) with DAPK1. Interacts with the
CC phosphorylated form of RAF1. Interacts (via WW domain) with ATCAY;
CC upon NGF stimulation. Interacts with PML (isoform PML-4) and BCL-
CC 6.
CC -!- INTERACTION:
CC P78563:ADARB1; NbExp=12; IntAct=EBI-714158, EBI-2967304;
CC P05067-4:APP; NbExp=2; IntAct=EBI-714158, EBI-302641;
CC Q15131:CDK10; NbExp=5; IntAct=EBI-714158, EBI-1646959;
CC P51617:IRAK1; NbExp=10; IntAct=EBI-714158, EBI-358664;
CC Q9HC98:NEK6; NbExp=3; IntAct=EBI-714158, EBI-740364;
CC P46531:NOTCH1; NbExp=9; IntAct=EBI-714158, EBI-636374;
CC Q13950:RUNX2; NbExp=7; IntAct=EBI-714158, EBI-976402;
CC Q9BR01:SULT4A1; NbExp=4; IntAct=EBI-714158, EBI-6690555;
CC P04637:TP53; NbExp=12; IntAct=EBI-714158, EBI-366083;
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus speckle. Cytoplasm.
CC Note=Colocalizes with NEK6 in the nucleus. Mainly localized in the
CC nucleus but phosphorylation at Ser-71 by DAPK1 results in
CC inhibition of its nuclear localization.
CC -!- TISSUE SPECIFICITY: The phosphorylated form at Ser-71 is expressed
CC in normal breast tissue cells but not in breast cancer cells.
CC -!- DOMAIN: The WW domain is required for the interaction with STIL
CC and KIF20B.
CC -!- PTM: Phosphorylation at Ser-71 by DAPK1 results in inhibition of
CC its catalytic activity, nuclear localization, and its ability to
CC induce centrosome amplification, chromosome instability and cell
CC transformation.
CC -!- SIMILARITY: Contains 1 PpiC domain.
CC -!- SIMILARITY: Contains 1 WW domain.
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DR EMBL; U49070; AAC50492.1; -; mRNA.
DR EMBL; CR407654; CAG28582.1; -; mRNA.
DR EMBL; BT019331; AAV38138.1; -; mRNA.
DR EMBL; AK291074; BAF83763.1; -; mRNA.
DR EMBL; CH471106; EAW84057.1; -; Genomic_DNA.
DR EMBL; BC002899; AAH02899.1; -; mRNA.
DR PIR; S68520; S68520.
DR RefSeq; NP_006212.1; NM_006221.3.
DR UniGene; Hs.465849; -.
DR PDB; 1F8A; X-ray; 1.84 A; B=1-163.
DR PDB; 1I6C; NMR; -; A=6-44.
DR PDB; 1I8G; NMR; -; B=6-44.
DR PDB; 1I8H; NMR; -; B=6-44.
DR PDB; 1NMV; NMR; -; A=1-163.
DR PDB; 1NMW; NMR; -; A=50-163.
DR PDB; 1PIN; X-ray; 1.35 A; A=1-163.
DR PDB; 1ZCN; X-ray; 1.90 A; A=1-161.
DR PDB; 2F21; X-ray; 1.50 A; A=1-162.
DR PDB; 2ITK; X-ray; 1.45 A; A=1-163.
DR PDB; 2KBU; NMR; -; A=6-39.
DR PDB; 2KCF; NMR; -; A=6-39.
DR PDB; 2LB3; NMR; -; A=6-41.
DR PDB; 2M9E; NMR; -; A=6-39.
DR PDB; 2M9F; NMR; -; A=6-39.
DR PDB; 2M9I; NMR; -; A=6-39.
DR PDB; 2M9J; NMR; -; A=6-39.
DR PDB; 2Q5A; X-ray; 1.50 A; A=1-163.
DR PDB; 2XP3; X-ray; 2.00 A; A=1-163.
DR PDB; 2XP4; X-ray; 1.80 A; A=1-163.
DR PDB; 2XP5; X-ray; 1.90 A; A=1-163.
DR PDB; 2XP6; X-ray; 1.90 A; A=1-163.
DR PDB; 2XP7; X-ray; 2.00 A; A=1-163.
DR PDB; 2XP8; X-ray; 2.10 A; A=1-163.
DR PDB; 2XP9; X-ray; 1.90 A; A=1-163.
DR PDB; 2XPA; X-ray; 1.90 A; A=1-163.
DR PDB; 2XPB; X-ray; 2.00 A; A=1-163.
DR PDB; 2ZQS; X-ray; 1.90 A; A=1-163.
DR PDB; 2ZQT; X-ray; 1.46 A; A=1-163.
DR PDB; 2ZQU; X-ray; 2.50 A; A=1-163.
DR PDB; 2ZQV; X-ray; 2.50 A; A=1-163.
DR PDB; 2ZR4; X-ray; 2.00 A; A=1-163.
DR PDB; 2ZR5; X-ray; 2.60 A; A=1-163.
DR PDB; 2ZR6; X-ray; 3.20 A; A=1-163.
DR PDB; 3I6C; X-ray; 1.30 A; A/B=45-163.
DR PDB; 3IK8; X-ray; 1.85 A; A/B=45-163.
DR PDB; 3IKD; X-ray; 2.00 A; A/B=45-163.
DR PDB; 3IKG; X-ray; 1.86 A; A/B=45-163.
DR PDB; 3JYJ; X-ray; 1.87 A; A/B=45-163.
DR PDB; 3KAB; X-ray; 2.19 A; A=1-163.
DR PDB; 3KAC; X-ray; 2.00 A; A/B=44-163.
DR PDB; 3KAD; X-ray; 1.95 A; A=1-163.
DR PDB; 3KAF; X-ray; 2.30 A; A=1-163.
DR PDB; 3KAG; X-ray; 1.90 A; A=1-163.
DR PDB; 3KAH; X-ray; 2.30 A; A=1-163.
DR PDB; 3KAI; X-ray; 1.90 A; A=1-163.
DR PDB; 3KCE; X-ray; 1.90 A; A=1-163.
DR PDB; 3NTP; X-ray; 1.76 A; A=1-163.
DR PDB; 3ODK; X-ray; 2.30 A; A=1-163.
DR PDB; 3OOB; X-ray; 1.89 A; A=1-163.
DR PDB; 3TC5; X-ray; 1.40 A; A=1-163.
DR PDB; 3TCZ; X-ray; 2.10 A; A=6-163.
DR PDB; 3TDB; X-ray; 2.27 A; A=6-163.
DR PDB; 4GWT; X-ray; 2.25 A; A=6-39.
DR PDB; 4GWV; X-ray; 3.05 A; A=6-39.
DR PDBsum; 1F8A; -.
DR PDBsum; 1I6C; -.
DR PDBsum; 1I8G; -.
DR PDBsum; 1I8H; -.
DR PDBsum; 1NMV; -.
DR PDBsum; 1NMW; -.
DR PDBsum; 1PIN; -.
DR PDBsum; 1ZCN; -.
DR PDBsum; 2F21; -.
DR PDBsum; 2ITK; -.
DR PDBsum; 2KBU; -.
DR PDBsum; 2KCF; -.
DR PDBsum; 2LB3; -.
DR PDBsum; 2M9E; -.
DR PDBsum; 2M9F; -.
DR PDBsum; 2M9I; -.
DR PDBsum; 2M9J; -.
DR PDBsum; 2Q5A; -.
DR PDBsum; 2XP3; -.
DR PDBsum; 2XP4; -.
DR PDBsum; 2XP5; -.
DR PDBsum; 2XP6; -.
DR PDBsum; 2XP7; -.
DR PDBsum; 2XP8; -.
DR PDBsum; 2XP9; -.
DR PDBsum; 2XPA; -.
DR PDBsum; 2XPB; -.
DR PDBsum; 2ZQS; -.
DR PDBsum; 2ZQT; -.
DR PDBsum; 2ZQU; -.
DR PDBsum; 2ZQV; -.
DR PDBsum; 2ZR4; -.
DR PDBsum; 2ZR5; -.
DR PDBsum; 2ZR6; -.
DR PDBsum; 3I6C; -.
DR PDBsum; 3IK8; -.
DR PDBsum; 3IKD; -.
DR PDBsum; 3IKG; -.
DR PDBsum; 3JYJ; -.
DR PDBsum; 3KAB; -.
DR PDBsum; 3KAC; -.
DR PDBsum; 3KAD; -.
DR PDBsum; 3KAF; -.
DR PDBsum; 3KAG; -.
DR PDBsum; 3KAH; -.
DR PDBsum; 3KAI; -.
DR PDBsum; 3KCE; -.
DR PDBsum; 3NTP; -.
DR PDBsum; 3ODK; -.
DR PDBsum; 3OOB; -.
DR PDBsum; 3TC5; -.
DR PDBsum; 3TCZ; -.
DR PDBsum; 3TDB; -.
DR PDBsum; 4GWT; -.
DR PDBsum; 4GWV; -.
DR ProteinModelPortal; Q13526; -.
DR SMR; Q13526; 1-163.
DR DIP; DIP-29306N; -.
DR IntAct; Q13526; 76.
DR MINT; MINT-86298; -.
DR STRING; 9606.ENSP00000247970; -.
DR BindingDB; Q13526; -.
DR ChEMBL; CHEMBL2288; -.
DR PhosphoSite; Q13526; -.
DR DMDM; 3024406; -.
DR PaxDb; Q13526; -.
DR PeptideAtlas; Q13526; -.
DR PRIDE; Q13526; -.
DR DNASU; 5300; -.
DR Ensembl; ENST00000247970; ENSP00000247970; ENSG00000127445.
DR Ensembl; ENST00000588695; ENSP00000466962; ENSG00000127445.
DR GeneID; 5300; -.
DR KEGG; hsa:5300; -.
DR UCSC; uc002mmk.2; human.
DR CTD; 5300; -.
DR GeneCards; GC19P009945; -.
DR HGNC; HGNC:8988; PIN1.
DR HPA; CAB004528; -.
DR HPA; CAB009326; -.
DR MIM; 601052; gene.
DR neXtProt; NX_Q13526; -.
DR PharmGKB; PA33320; -.
DR eggNOG; COG0760; -.
DR HOGENOM; HOG000275331; -.
DR HOVERGEN; HBG002101; -.
DR InParanoid; Q13526; -.
DR KO; K09578; -.
DR OMA; FALKVGD; -.
DR PhylomeDB; Q13526; -.
DR BRENDA; 5.2.1.8; 2681.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13526; -.
DR EvolutionaryTrace; Q13526; -.
DR GeneWiki; PIN1; -.
DR GenomeRNAi; 5300; -.
DR NextBio; 20486; -.
DR PRO; PR:Q13526; -.
DR ArrayExpress; Q13526; -.
DR Bgee; Q13526; -.
DR CleanEx; HS_PIN1; -.
DR Genevestigator; Q13526; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0030496; C:midbody; IDA:MGI.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0003755; F:peptidyl-prolyl cis-trans isomerase activity; IDA:BHF-UCL.
DR GO; GO:0050815; F:phosphoserine binding; IDA:BHF-UCL.
DR GO; GO:0050816; F:phosphothreonine binding; IDA:BHF-UCL.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:2000146; P:negative regulation of cell motility; IDA:BHF-UCL.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IGI:MGI.
DR GO; GO:0032321; P:positive regulation of Rho GTPase activity; IMP:BHF-UCL.
DR GO; GO:0051443; P:positive regulation of ubiquitin-protein ligase activity; IDA:BHF-UCL.
DR GO; GO:0006457; P:protein folding; IEA:UniProtKB-KW.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0032465; P:regulation of cytokinesis; IMP:MGI.
DR GO; GO:0007088; P:regulation of mitosis; TAS:ProtInc.
DR GO; GO:0060393; P:regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR InterPro; IPR000297; PPIase_PpiC.
DR InterPro; IPR023058; PPIase_PpiC_CS.
DR InterPro; IPR001202; WW_dom.
DR Pfam; PF00639; Rotamase; 1.
DR Pfam; PF00397; WW; 1.
DR SMART; SM00456; WW; 1.
DR SUPFAM; SSF51045; SSF51045; 1.
DR PROSITE; PS01096; PPIC_PPIASE_1; 1.
DR PROSITE; PS50198; PPIC_PPIASE_2; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 1.
DR PROSITE; PS50020; WW_DOMAIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell cycle; Complete proteome; Cytoplasm;
KW Isomerase; Nucleus; Phosphoprotein; Reference proteome; Rotamase.
FT CHAIN 1 163 Peptidyl-prolyl cis-trans isomerase NIMA-
FT interacting 1.
FT /FTId=PRO_0000193435.
FT DOMAIN 5 39 WW.
FT DOMAIN 52 163 PpiC.
FT MOD_RES 46 46 N6-acetyllysine.
FT MOD_RES 71 71 Phosphoserine; by DAPK1.
FT MOD_RES 108 108 Phosphoserine.
FT MUTAGEN 23 23 Y->A: Reduced affinity for KIF20B.
FT MUTAGEN 71 71 S->D,E: Loss of activity, nuclear
FT localization and cellular function.
FT STRAND 11 15
FT TURN 17 19
FT STRAND 22 26
FT TURN 27 29
FT STRAND 32 35
FT STRAND 39 41
FT STRAND 53 62
FT STRAND 67 69
FT STRAND 75 77
FT HELIX 82 98
FT STRAND 99 101
FT HELIX 103 110
FT HELIX 114 118
FT STRAND 121 126
FT HELIX 132 140
FT STRAND 150 152
FT STRAND 155 163
SQ SEQUENCE 163 AA; 18243 MW; 35391AF40B7D1E13 CRC64;
MADEEKLPPG WEKRMSRSSG RVYYFNHITN ASQWERPSGN SSSGGKNGQG EPARVRCSHL
LVKHSQSRRP SSWRQEKITR TKEEALELIN GYIQKIKSGE EDFESLASQF SDCSSAKARG
DLGAFSRGQM QKPFEDASFA LRTGEMSGPV FTDSGIHIIL RTE
//
MIM
601052
*RECORD*
*FIELD* NO
601052
*FIELD* TI
*601052 PEPTIDYL-PROLYL CIS/TRANS ISOMERASE, NIMA-INTERACTING, 1; PIN1
;;DODO, DROSOPHILA, HOMOLOG OF; DOD
read more*FIELD* TX
DESCRIPTION
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).
CLONING
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.
GENE FUNCTION
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.
MAPPING
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.
*FIELD* RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Lu, K. P.; Hanes, S. D.; Hunter, T.: A human peptidyl-prolyl isomerase
essential for regulation of mitosis. Nature 380: 544-547, 1996.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Winkler, K. E.; Swanson, K. I.; Kornbluth, S.; Means, A. R.:
Requirement of the prolyl isomerase Pin1 for the replication checkpoint. Science 287:
1644-1647, 2000.
17. 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.
18. 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.
*FIELD* CN
Matthew B. Gross - updated: 5/20/2010
Patricia A. Hartz - updated: 5/19/2010
Paul J. Converse - updated: 5/18/2010
Patricia A. Hartz - updated: 1/15/2010
Patricia A. Hartz - updated: 4/18/2008
Ada Hamosh - updated: 4/25/2007
Cassandra L. Kniffin - updated: 2/28/2007
Paul J. Converse - updated: 8/4/2006
Ada Hamosh - updated: 5/26/2006
Ada Hamosh - updated: 7/31/2003
Ada Hamosh - updated: 11/19/2002
Victor A. McKusick - updated: 3/5/2002
Paul J. Converse - updated: 3/2/2000
Ada Hamosh - updated: 6/24/1999
*FIELD* CD
Victor A. McKusick: 2/8/1996
*FIELD* ED
terry: 09/25/2012
terry: 9/9/2010
mgross: 5/20/2010
terry: 5/19/2010
mgross: 5/18/2010
terry: 5/18/2010
mgross: 1/20/2010
terry: 1/15/2010
wwang: 4/20/2009
wwang: 8/27/2008
mgross: 4/25/2008
terry: 4/18/2008
alopez: 5/8/2007
alopez: 5/1/2007
terry: 4/25/2007
wwang: 3/5/2007
ckniffin: 2/28/2007
mgross: 8/29/2006
terry: 8/4/2006
alopez: 6/2/2006
terry: 5/26/2006
terry: 2/3/2006
alopez: 8/4/2003
terry: 7/31/2003
alopez: 11/19/2002
terry: 11/18/2002
mgross: 3/8/2002
terry: 3/5/2002
carol: 7/10/2001
alopez: 3/2/2000
alopez: 6/24/1999
mark: 10/14/1997
mark: 2/8/1996
*RECORD*
*FIELD* NO
601052
*FIELD* TI
*601052 PEPTIDYL-PROLYL CIS/TRANS ISOMERASE, NIMA-INTERACTING, 1; PIN1
;;DODO, DROSOPHILA, HOMOLOG OF; DOD
read more*FIELD* TX
DESCRIPTION
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).
CLONING
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.
GENE FUNCTION
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.
MAPPING
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.
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*FIELD* CN
Matthew B. Gross - updated: 5/20/2010
Patricia A. Hartz - updated: 5/19/2010
Paul J. Converse - updated: 5/18/2010
Patricia A. Hartz - updated: 1/15/2010
Patricia A. Hartz - updated: 4/18/2008
Ada Hamosh - updated: 4/25/2007
Cassandra L. Kniffin - updated: 2/28/2007
Paul J. Converse - updated: 8/4/2006
Ada Hamosh - updated: 5/26/2006
Ada Hamosh - updated: 7/31/2003
Ada Hamosh - updated: 11/19/2002
Victor A. McKusick - updated: 3/5/2002
Paul J. Converse - updated: 3/2/2000
Ada Hamosh - updated: 6/24/1999
*FIELD* CD
Victor A. McKusick: 2/8/1996
*FIELD* ED
terry: 09/25/2012
terry: 9/9/2010
mgross: 5/20/2010
terry: 5/19/2010
mgross: 5/18/2010
terry: 5/18/2010
mgross: 1/20/2010
terry: 1/15/2010
wwang: 4/20/2009
wwang: 8/27/2008
mgross: 4/25/2008
terry: 4/18/2008
alopez: 5/8/2007
alopez: 5/1/2007
terry: 4/25/2007
wwang: 3/5/2007
ckniffin: 2/28/2007
mgross: 8/29/2006
terry: 8/4/2006
alopez: 6/2/2006
terry: 5/26/2006
terry: 2/3/2006
alopez: 8/4/2003
terry: 7/31/2003
alopez: 11/19/2002
terry: 11/18/2002
mgross: 3/8/2002
terry: 3/5/2002
carol: 7/10/2001
alopez: 3/2/2000
alopez: 6/24/1999
mark: 10/14/1997
mark: 2/8/1996