Full text data of PTPN6
PTPN6
(HCP, PTP1C)
[Confidence: low (only semi-automatic identification from reviews)]
Tyrosine-protein phosphatase non-receptor type 6; 3.1.3.48 (Hematopoietic cell protein-tyrosine phosphatase; Protein-tyrosine phosphatase 1C; PTP-1C; Protein-tyrosine phosphatase SHP-1; SH-PTP1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Tyrosine-protein phosphatase non-receptor type 6; 3.1.3.48 (Hematopoietic cell protein-tyrosine phosphatase; Protein-tyrosine phosphatase 1C; PTP-1C; Protein-tyrosine phosphatase SHP-1; SH-PTP1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P29350
ID PTN6_HUMAN Reviewed; 595 AA.
AC P29350; A8K306; G3V0F8; Q969V8; Q9UK67;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-1992, sequence version 1.
DT 22-JAN-2014, entry version 168.
DE RecName: Full=Tyrosine-protein phosphatase non-receptor type 6;
DE EC=3.1.3.48;
DE AltName: Full=Hematopoietic cell protein-tyrosine phosphatase;
DE AltName: Full=Protein-tyrosine phosphatase 1C;
DE Short=PTP-1C;
DE AltName: Full=Protein-tyrosine phosphatase SHP-1;
DE AltName: Full=SH-PTP1;
GN Name=PTPN6; Synonyms=HCP, PTP1C;
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] (ISOFORM 1).
RX PubMed=1732748;
RA Yi T., Cleveland J.L., Ihle J.N.;
RT "Protein tyrosine phosphatase containing SH2 domains:
RT characterization, preferential expression in hematopoietic cells, and
RT localization to human chromosome 12p12-p13.";
RL Mol. Cell. Biol. 12:836-846(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Mammary gland;
RX PubMed=1652101; DOI=10.1038/352736a0;
RA Shen S.H., Bastien L., Posner B.I., Chretien P.;
RT "A protein-tyrosine phosphatase with sequence similarity to the SH2
RT domain of the protein-tyrosine kinases.";
RL Nature 352:736-739(1991).
RN [3]
RP ERRATUM, AND SEQUENCE REVISION.
RA Shen S.H., Bastien L., Posner B.I., Chretien P.;
RL Nature 353:868-868(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1736296; DOI=10.1073/pnas.89.3.1123;
RA Plutzky J., Neel B.G., Rosenberg R.D.;
RT "Isolation of a src homology 2-containing tyrosine phosphatase.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:1123-1127(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 2 AND 3).
RX PubMed=7665165; DOI=10.1006/geno.1995.1020;
RA Banville D., Stocco R., Shen S.H.;
RT "Human protein tyrosine phosphatase 1C (PTPN6) gene structure:
RT alternate promoter usage and exon skipping generate multiple
RT transcripts.";
RL Genomics 27:165-173(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9074930;
RA Ansari-Lari M.A., Shen Y., Muzny D.M., Lee W., Gibbs R.A.;
RT "Large-scale sequencing in human chromosome 12p13: experimental and
RT computational gene structure determination.";
RL Genome Res. 7:268-280(1997).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RX PubMed=10497187; DOI=10.1074/jbc.274.40.28301;
RA Jin Y.J., Yu C.L., Burakoff S.J.;
RT "Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-terminal
RT structure and catalytic activity.";
RL J. Biol. Chem. 274:28301-28307(1999).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2).
RA Oka T., Ouchida M.;
RT "Gene silencing of SHP-1 gene in leukemias/lymphomas by aberrant
RT methylation.";
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Umbilical cord blood;
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [11]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Placenta;
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 [13]
RP PHOSPHORYLATION.
RX PubMed=7781604;
RA Li R.Y., Gaits F., Ragab A., Ragab-Thomas J.M.F., Chap H.;
RT "Tyrosine phosphorylation of an SH2-containing protein tyrosine
RT phosphatase is coupled to platelet thrombin receptor via a pertussis
RT toxin-sensitive heterotrimeric G-protein.";
RL EMBO J. 14:2519-2526(1995).
RN [14]
RP INTERACTION WITH LILRB1.
RX PubMed=9285411; DOI=10.1016/S1074-7613(00)80529-4;
RA Cosman D., Fanger N., Borges L., Kubin M., Chin W., Peterson L.,
RA Hsu M.-L.;
RT "A novel immunoglobulin superfamily receptor for cellular and viral
RT MHC class I molecules.";
RL Immunity 7:273-282(1997).
RN [15]
RP INTERACTION WITH LILRB2.
RX PubMed=9842885;
RX DOI=10.1002/(SICI)1521-4141(199811)28:11<3423::AID-IMMU3423>3.0.CO;2-2;
RA Fanger N.A., Cosman D., Peterson L., Braddy S.C., Maliszewski C.R.,
RA Borges L.;
RT "The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-
RT mediated signaling in monocytes.";
RL Eur. J. Immunol. 28:3423-3434(1998).
RN [16]
RP INTERACTION WITH PTPNS1.
RX PubMed=9712903; DOI=10.1074/jbc.273.35.22719;
RA Veillette A., Thibaudeau E., Latour S.;
RT "High expression of inhibitory receptor SHPS-1 and its association
RT with protein tyrosine phosphatase SHP-1 in macrophages.";
RL J. Biol. Chem. 273:22719-22728(1998).
RN [17]
RP INTERACTION WITH LYN, AND PHOSPHORYLATION AT TYR-564.
RX PubMed=10574931; DOI=10.1074/jbc.274.49.34663;
RA Yoshida K., Kharbanda S., Kufe D.;
RT "Functional interaction between SHPTP1 and the Lyn tyrosine kinase in
RT the apoptotic response to DNA damage.";
RL J. Biol. Chem. 274:34663-34668(1999).
RN [18]
RP INTERACTION WITH FCRL2 AND FCRL3.
RX PubMed=11162587; DOI=10.1006/bbrc.2000.4213;
RA Xu M.-J., Zhao R., Zhao Z.J.;
RT "Molecular cloning and characterization of SPAP1, an inhibitory
RT receptor.";
RL Biochem. Biophys. Res. Commun. 280:768-775(2001).
RN [19]
RP INTERACTION WITH CD84.
RX PubMed=11414741; DOI=10.1006/clim.2001.5035;
RA Lewis J., Eiben L.J., Nelson D.L., Cohen J.I., Nichols K.E.,
RA Ochs H.D., Notarangelo L.D., Duckett C.S.;
RT "Distinct interactions of the X-linked lymphoproliferative syndrome
RT gene product SAP with cytoplasmic domains of members of the CD2
RT receptor family.";
RL Clin. Immunol. 100:15-23(2001).
RN [20]
RP FUNCTION IN ROS1 DEPHOSPHORYLATION, AND INTERACTION WITH ROS1.
RX PubMed=11266449; DOI=10.1083/jcb.152.2.325;
RA Keilhack H., Mueller M., Boehmer S.A., Frank C., Weidner K.M.,
RA Birchmeier W., Ligensa T., Berndt A., Kosmehl H., Guenther B.,
RA Mueller T., Birchmeier C., Boehmer F.D.;
RT "Negative regulation of Ros receptor tyrosine kinase signaling. An
RT epithelial function of the SH2 domain protein tyrosine phosphatase
RT SHP-1.";
RL J. Cell Biol. 152:325-334(2001).
RN [21]
RP INTERACTION WITH FCRL4.
RX PubMed=14597715; DOI=10.1073/pnas.1935944100;
RA Ehrhardt G.R.A., Davis R.S., Hsu J.T., Leu C.-M., Ehrhardt A.,
RA Cooper M.D.;
RT "The inhibitory potential of Fc receptor homolog 4 on memory B
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:13489-13494(2003).
RN [22]
RP INTERACTION WITH CD300LF.
RX PubMed=15184070; DOI=10.1016/j.bbrc.2004.05.065;
RA Sui L., Li N., Liu Q., Zhang W., Wan T., Wang B., Luo K., Sun H.,
RA Cao X.;
RT "IgSF13, a novel human inhibitory receptor of the immunoglobulin
RT superfamily, is preferentially expressed in dendritic cells and
RT monocytes.";
RL Biochem. Biophys. Res. Commun. 319:920-928(2004).
RN [23]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [24]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=16129412; DOI=10.1016/j.bbrc.2005.08.055;
RA Roskoski R. Jr.;
RT "Signaling by Kit protein-tyrosine kinase--the stem cell factor
RT receptor.";
RL Biochem. Biophys. Res. Commun. 337:1-13(2005).
RN [25]
RP INTERACTION WITH KIR2DL1.
RX PubMed=18604210; DOI=10.1038/ni.1635;
RA Yu M.-C., Su L.-L., Zou L., Liu Y., Wu N., Kong L., Zhuang Z.-H.,
RA Sun L., Liu H.P., Hu J.-H., Li D., Strominger J.L., Zang J.-W.,
RA Pei G., Ge B.-X.;
RT "An essential function for beta-arrestin 2 in the inhibitory signaling
RT of natural killer cells.";
RL Nat. Immunol. 9:898-907(2008).
RN [26]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH PDPK1.
RX PubMed=19591923; DOI=10.1016/j.cellsig.2009.06.010;
RA Sephton C.F., Zhang D., Lehmann T.M., Pennington P.R., Scheid M.P.,
RA Mousseau D.D.;
RT "The nuclear localization of 3'-phosphoinositide-dependent kinase-1 is
RT dependent on its association with the protein tyrosine phosphatase
RT SHP-1.";
RL Cell. Signal. 21:1634-1644(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-64, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [28]
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 [29]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH CDK2.
RX PubMed=21262353; DOI=10.1016/j.cellsig.2011.01.019;
RA Fiset A., Xu E., Bergeron S., Marette A., Pelletier G.,
RA Siminovitch K.A., Olivier M., Beauchemin N., Faure R.L.;
RT "Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and
RT regulates insulin internalization.";
RL Cell. Signal. 23:911-919(2011).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 248-399.
RX PubMed=9774441; DOI=10.1074/jbc.273.43.28199;
RA Yang J., Liang X., Niu T., Meng W., Zhao Z., Zhou G.W.;
RT "Crystal structure of the catalytic domain of protein-tyrosine
RT phosphatase SHP-1.";
RL J. Biol. Chem. 273:28199-28207(1998).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-532, AND DOMAIN SH2.
RX PubMed=12482860; DOI=10.1074/jbc.M210430200;
RA Yang J., Liu L., He D., Song X., Liang X., Zhao Z.J., Zhou G.W.;
RT "Crystal structure of human protein-tyrosine phosphatase SHP-1.";
RL J. Biol. Chem. 278:6516-6520(2003).
RN [32]
RP STRUCTURE BY NMR OF 110-214.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structures of the SH2 domain of human protein-tyrosine
RT phosphatase SHP-1.";
RL Submitted (NOV-2005) to the PDB data bank.
RN [33]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS), AND DOMAIN SH2.
RX PubMed=21465528; DOI=10.1002/jcb.23125;
RA Wang W., Liu L., Song X., Mo Y., Komma C., Bellamy H.D., Zhao Z.J.,
RA Zhou G.W.;
RT "Crystal structure of human protein tyrosine phosphatase SHP-1 in the
RT open conformation.";
RL J. Cell. Biochem. 112:2062-2071(2011).
CC -!- FUNCTION: Modulates signaling by tyrosine phosphorylated cell
CC surface receptors such as KIT and the EGF receptor/EGFR. The SH2
CC regions may interact with other cellular components to modulate
CC its own phosphatase activity against interacting substrates.
CC Together with MTUS1, induces UBE2V2 expression upon angiotensin II
CC stimulation. Plays a key role in hematopoiesis.
CC -!- CATALYTIC ACTIVITY: Protein tyrosine phosphate + H(2)O = protein
CC tyrosine + phosphate.
CC -!- SUBUNIT: Monomer. Interacts with MTUS1 (By similarity). Interacts
CC with MILR1 (tyrosine-phosphorylated). Interacts with KIT (By
CC similarity). Binds PTPNS1, LILRB1 and LILRB2. Interacts with
CC FCRL2, FCRL3, FCRL4, CD300LF, CDK2 and CD84. Interacts with
CC KIR2DL1; the interaction is enhanced by ARRB2. Interacts (via SH2
CC 1 domain) with ROS1; the interaction is direct and promotes ROS1
CC dephosphorylation. Interacts with EGFR; inhibits EGFR-dependent
CC activation of MAPK/ERK. Interacts with LYN. Interacts with the
CC tyrosine phosphorylated form of PDPK1.
CC -!- INTERACTION:
CC Q14790:CASP8; NbExp=3; IntAct=EBI-78260, EBI-78060;
CC P20273:CD22; NbExp=4; IntAct=EBI-78260, EBI-78277;
CC P20138:CD33; NbExp=8; IntAct=EBI-78260, EBI-3906571;
CC P11049:CD37; NbExp=4; IntAct=EBI-78260, EBI-6139068;
CC P19235:EPOR; NbExp=11; IntAct=EBI-78260, EBI-617321;
CC P31994:FCGR2B; NbExp=3; IntAct=EBI-78260, EBI-724784;
CC P43626:KIR2DL1; NbExp=4; IntAct=EBI-78260, EBI-8684277;
CC P43628:KIR2DL3; NbExp=13; IntAct=EBI-78260, EBI-8632435;
CC Q6GTX8:LAIR1; NbExp=5; IntAct=EBI-78260, EBI-965864;
CC P06239:LCK; NbExp=5; IntAct=EBI-78260, EBI-1348;
CC P16284:PECAM1; NbExp=4; IntAct=EBI-78260, EBI-716404;
CC Q9UKJ1:PILRA; NbExp=5; IntAct=EBI-78260, EBI-965833;
CC P08922:ROS1; NbExp=2; IntAct=EBI-78260, EBI-7371065;
CC B7UM99:tir (xeno); NbExp=4; IntAct=EBI-78260, EBI-2504426;
CC Q7DB77:tir (xeno); NbExp=2; IntAct=EBI-78260, EBI-6480811;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=In neurons,
CC translocates into the nucleus after treatment with angiotensin II
CC (By similarity). Shuttles between the cytoplasm and nucleus via
CC its association with PDPK1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Long;
CC IsoId=P29350-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P29350-3; Sequence=VSP_007775;
CC Name=3; Synonyms=Short;
CC IsoId=P29350-2; Sequence=VSP_005129, VSP_005130;
CC Name=4; Synonyms=70-kDa, SHP-1L;
CC IsoId=P29350-4; Sequence=VSP_044447;
CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in hematopoietic cells.
CC Isoform 2 is expressed in non-hematopoietic cells.
CC -!- DOMAIN: The N-terminal SH2 domain functions as an auto-inhibitory
CC domain, blocking the catalytic domain in the ligand-free close
CC conformation.
CC -!- PTM: Phosphorylated on tyrosine residues. Binding of KITLG/SCF to
CC KIT increases tyrosine phosphorylation (By similarity).
CC Phosphorylation at Tyr-564 enhances phosphatase activity.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC Non-receptor class 2 subfamily.
CC -!- SIMILARITY: Contains 2 SH2 domains.
CC -!- SIMILARITY: Contains 1 tyrosine-protein phosphatase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PTPN6ID41920ch12p13.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M74903; AAA35963.1; -; mRNA.
DR EMBL; X62055; CAA43982.1; -; mRNA.
DR EMBL; M77273; AAA36610.1; -; mRNA.
DR EMBL; U15528; AAA82880.1; -; Genomic_DNA.
DR EMBL; U15536; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15535; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15534; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15533; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15532; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15531; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15530; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15529; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15528; AAA82879.1; -; Genomic_DNA.
DR EMBL; U15537; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15535; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15534; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15533; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15532; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15531; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15530; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15529; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U47924; AAB51322.1; -; Genomic_DNA.
DR EMBL; U47924; AAB51323.1; -; Genomic_DNA.
DR EMBL; AF178946; AAD53317.1; -; mRNA.
DR EMBL; AB079851; BAC81774.1; -; Genomic_DNA.
DR EMBL; AB079851; BAC81775.1; -; Genomic_DNA.
DR EMBL; AK290421; BAF83110.1; -; mRNA.
DR EMBL; CH471116; EAW88703.1; -; Genomic_DNA.
DR EMBL; CH471116; EAW88704.1; -; Genomic_DNA.
DR EMBL; BC002523; AAH02523.1; -; mRNA.
DR EMBL; BC007667; AAH07667.1; -; mRNA.
DR PIR; B42031; S20825.
DR RefSeq; NP_002822.2; NM_002831.5.
DR RefSeq; NP_536858.1; NM_080548.4.
DR RefSeq; NP_536859.1; NM_080549.3.
DR RefSeq; XP_005253776.1; XM_005253719.1.
DR RefSeq; XP_005277811.1; XM_005277754.1.
DR UniGene; Hs.63489; -.
DR PDB; 1FPR; X-ray; 2.50 A; A=243-526.
DR PDB; 1GWZ; X-ray; 2.50 A; A=243-541.
DR PDB; 1X6C; NMR; -; A=110-214.
DR PDB; 2B3O; X-ray; 2.80 A; A=1-532.
DR PDB; 2RMX; NMR; -; A=110-214.
DR PDB; 2YU7; NMR; -; A=110-214.
DR PDB; 3PS5; X-ray; 3.10 A; A=1-595.
DR PDB; 4GRY; X-ray; 1.70 A; A=243-528.
DR PDB; 4GRZ; X-ray; 1.37 A; A=243-528.
DR PDB; 4GS0; X-ray; 1.80 A; A/B=243-528.
DR PDB; 4HJP; X-ray; 1.40 A; A=243-528.
DR PDB; 4HJQ; X-ray; 1.80 A; A/B=243-528.
DR PDBsum; 1FPR; -.
DR PDBsum; 1GWZ; -.
DR PDBsum; 1X6C; -.
DR PDBsum; 2B3O; -.
DR PDBsum; 2RMX; -.
DR PDBsum; 2YU7; -.
DR PDBsum; 3PS5; -.
DR PDBsum; 4GRY; -.
DR PDBsum; 4GRZ; -.
DR PDBsum; 4GS0; -.
DR PDBsum; 4HJP; -.
DR PDBsum; 4HJQ; -.
DR ProteinModelPortal; P29350; -.
DR SMR; P29350; 1-529.
DR DIP; DIP-31002N; -.
DR IntAct; P29350; 43.
DR MINT; MINT-134053; -.
DR STRING; 9606.ENSP00000391592; -.
DR BindingDB; P29350; -.
DR ChEMBL; CHEMBL3166; -.
DR PhosphoSite; P29350; -.
DR DMDM; 131469; -.
DR OGP; P29350; -.
DR PaxDb; P29350; -.
DR PRIDE; P29350; -.
DR DNASU; 5777; -.
DR Ensembl; ENST00000318974; ENSP00000326010; ENSG00000111679.
DR Ensembl; ENST00000399448; ENSP00000382376; ENSG00000111679.
DR Ensembl; ENST00000447931; ENSP00000415979; ENSG00000111679.
DR Ensembl; ENST00000456013; ENSP00000391592; ENSG00000111679.
DR Ensembl; ENST00000594686; ENSP00000468853; ENSG00000268954.
DR Ensembl; ENST00000595623; ENSP00000472428; ENSG00000268954.
DR Ensembl; ENST00000595832; ENSP00000469169; ENSG00000268954.
DR Ensembl; ENST00000599028; ENSP00000470980; ENSG00000268954.
DR GeneID; 5777; -.
DR KEGG; hsa:5777; -.
DR UCSC; uc001qsb.2; human.
DR CTD; 5777; -.
DR GeneCards; GC12P007055; -.
DR HGNC; HGNC:9658; PTPN6.
DR HPA; CAB004572; -.
DR HPA; HPA001466; -.
DR MIM; 176883; gene.
DR neXtProt; NX_P29350; -.
DR PharmGKB; PA34002; -.
DR eggNOG; COG5599; -.
DR HOGENOM; HOG000273907; -.
DR HOVERGEN; HBG000223; -.
DR InParanoid; P29350; -.
DR KO; K05697; -.
DR OMA; QAKGEPW; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P29350; -.
DR ChiTaRS; PTPN6; human.
DR EvolutionaryTrace; P29350; -.
DR GeneWiki; PTPN6; -.
DR GenomeRNAi; 5777; -.
DR NextBio; 22466; -.
DR PMAP-CutDB; P29350; -.
DR PRO; PR:P29350; -.
DR ArrayExpress; P29350; -.
DR Bgee; P29350; -.
DR CleanEx; HS_PTPN6; -.
DR Genevestigator; P29350; -.
DR GO; GO:0042105; C:alpha-beta T cell receptor complex; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0005001; F:transmembrane receptor protein tyrosine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0050853; P:B cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0030154; P:cell differentiation; IDA:UniProtKB.
DR GO; GO:0008283; P:cell proliferation; IDA:UniProtKB.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0042267; P:natural killer cell mediated cytotoxicity; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; NAS:UniProtKB.
DR GO; GO:0002924; P:negative regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0050732; P:negative regulation of peptidyl-tyrosine phosphorylation; IMP:BHF-UCL.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IMP:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IMP:BHF-UCL.
DR GO; GO:0045577; P:regulation of B cell differentiation; IEA:Ensembl.
DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IMP:BHF-UCL.
DR GO; GO:0060334; P:regulation of interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0060338; P:regulation of type I interferon-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; TAS:Reactome.
DR Gene3D; 3.30.505.10; -; 2.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR000387; Tyr/Dual-sp_Pase.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR InterPro; IPR012152; Tyr_Pase_non-rcpt_typ-6/11.
DR InterPro; IPR000242; Tyr_Pase_rcpt/non-rcpt.
DR Pfam; PF00017; SH2; 2.
DR Pfam; PF00102; Y_phosphatase; 1.
DR PIRSF; PIRSF000929; Tyr-Ptase_nr_6; 1.
DR PRINTS; PR00700; PRTYPHPHTASE.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00194; PTPc; 1.
DR SMART; SM00252; SH2; 2.
DR PROSITE; PS50001; SH2; 2.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
DR PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Hydrolase; Nucleus; Phosphoprotein; Protein phosphatase;
KW Reference proteome; Repeat; SH2 domain.
FT CHAIN 1 595 Tyrosine-protein phosphatase non-receptor
FT type 6.
FT /FTId=PRO_0000094758.
FT DOMAIN 4 100 SH2 1.
FT DOMAIN 110 213 SH2 2.
FT DOMAIN 244 515 Tyrosine-protein phosphatase.
FT REGION 453 459 Substrate binding (By similarity).
FT ACT_SITE 453 453 Phosphocysteine intermediate.
FT BINDING 419 419 Substrate (By similarity).
FT BINDING 500 500 Substrate (By similarity).
FT MOD_RES 64 64 Phosphotyrosine.
FT MOD_RES 377 377 Phosphotyrosine (By similarity).
FT MOD_RES 536 536 Phosphotyrosine (By similarity).
FT MOD_RES 564 564 Phosphotyrosine; by LYN.
FT VAR_SEQ 1 39 Missing (in isoform 3).
FT /FTId=VSP_005129.
FT VAR_SEQ 1 3 MVR -> MLSRG (in isoform 2).
FT /FTId=VSP_007775.
FT VAR_SEQ 40 44 SLSVR -> MLSRG (in isoform 3).
FT /FTId=VSP_005130.
FT VAR_SEQ 559 595 HKEDVYENLHTKNKREEKVKKQRSADKEKSKGSLKRK ->
FT SLESSAGTVAASPVRRGGQRGLPVPGPPVLSPDLHQLPVLA
FT PLHPAADTRRMCMRTCTLRTRGRRK (in isoform 4).
FT /FTId=VSP_044447.
FT CONFLICT 6 6 H -> L (in Ref. 5; AAA82880).
FT CONFLICT 86 86 L -> V (in Ref. 4; AAA36610 and 7;
FT AAD53317).
FT CONFLICT 146 146 V -> E (in Ref. 5; AAA82880/AAA82879).
FT HELIX 11 21
FT STRAND 26 31
FT STRAND 33 45
FT STRAND 48 55
FT STRAND 57 59
FT STRAND 61 63
FT STRAND 68 70
FT HELIX 72 80
FT STRAND 89 91
FT HELIX 105 107
FT STRAND 111 114
FT HELIX 117 127
FT STRAND 132 137
FT STRAND 139 141
FT STRAND 145 154
FT STRAND 155 157
FT STRAND 162 170
FT HELIX 172 174
FT STRAND 175 181
FT STRAND 184 186
FT HELIX 187 197
FT STRAND 199 201
FT STRAND 202 204
FT STRAND 205 207
FT HELIX 221 223
FT STRAND 236 238
FT HELIX 244 256
FT TURN 257 259
FT HELIX 263 266
FT HELIX 268 273
FT STRAND 275 278
FT TURN 283 285
FT STRAND 286 288
FT STRAND 290 292
FT STRAND 294 296
FT TURN 297 300
FT STRAND 301 307
FT STRAND 309 312
FT HELIX 314 316
FT STRAND 321 324
FT HELIX 329 331
FT HELIX 332 341
FT STRAND 346 349
FT STRAND 353 355
FT STRAND 356 358
FT STRAND 371 374
FT STRAND 377 386
FT STRAND 388 399
FT HELIX 400 402
FT STRAND 403 405
FT STRAND 407 414
FT STRAND 419 421
FT STRAND 424 426
FT HELIX 427 442
FT STRAND 443 445
FT STRAND 449 452
FT STRAND 454 457
FT HELIX 458 476
FT HELIX 484 492
FT HELIX 502 523
SQ SEQUENCE 595 AA; 67561 MW; 4D7736C21D3542D2 CRC64;
MVRWFHRDLS GLDAETLLKG RGVHGSFLAR PSRKNQGDFS LSVRVGDQVT HIRIQNSGDF
YDLYGGEKFA TLTELVEYYT QQQGVLQDRD GTIIHLKYPL NCSDPTSERW YHGHMSGGQA
ETLLQAKGEP WTFLVRESLS QPGDFVLSVL SDQPKAGPGS PLRVTHIKVM CEGGRYTVGG
LETFDSLTDL VEHFKKTGIE EASGAFVYLR QPYYATRVNA ADIENRVLEL NKKQESEDTA
KAGFWEEFES LQKQEVKNLH QRLEGQRPEN KGKNRYKNIL PFDHSRVILQ GRDSNIPGSD
YINANYIKNQ LLGPDENAKT YIASQGCLEA TVNDFWQMAW QENSRVIVMT TREVEKGRNK
CVPYWPEVGM QRAYGPYSVT NCGEHDTTEY KLRTLQVSPL DNGDLIREIW HYQYLSWPDH
GVPSEPGGVL SFLDQINQRQ ESLPHAGPII VHCSAGIGRT GTIIVIDMLM ENISTKGLDC
DIDIQKTIQM VRAQRSGMVQ TEAQYKFIYV AIAQFIETTK KKLEVLQSQK GQESEYGNIT
YPPAMKNAHA KASRTSSKHK EDVYENLHTK NKREEKVKKQ RSADKEKSKG SLKRK
//
ID PTN6_HUMAN Reviewed; 595 AA.
AC P29350; A8K306; G3V0F8; Q969V8; Q9UK67;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-1992, sequence version 1.
DT 22-JAN-2014, entry version 168.
DE RecName: Full=Tyrosine-protein phosphatase non-receptor type 6;
DE EC=3.1.3.48;
DE AltName: Full=Hematopoietic cell protein-tyrosine phosphatase;
DE AltName: Full=Protein-tyrosine phosphatase 1C;
DE Short=PTP-1C;
DE AltName: Full=Protein-tyrosine phosphatase SHP-1;
DE AltName: Full=SH-PTP1;
GN Name=PTPN6; Synonyms=HCP, PTP1C;
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] (ISOFORM 1).
RX PubMed=1732748;
RA Yi T., Cleveland J.L., Ihle J.N.;
RT "Protein tyrosine phosphatase containing SH2 domains:
RT characterization, preferential expression in hematopoietic cells, and
RT localization to human chromosome 12p12-p13.";
RL Mol. Cell. Biol. 12:836-846(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Mammary gland;
RX PubMed=1652101; DOI=10.1038/352736a0;
RA Shen S.H., Bastien L., Posner B.I., Chretien P.;
RT "A protein-tyrosine phosphatase with sequence similarity to the SH2
RT domain of the protein-tyrosine kinases.";
RL Nature 352:736-739(1991).
RN [3]
RP ERRATUM, AND SEQUENCE REVISION.
RA Shen S.H., Bastien L., Posner B.I., Chretien P.;
RL Nature 353:868-868(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1736296; DOI=10.1073/pnas.89.3.1123;
RA Plutzky J., Neel B.G., Rosenberg R.D.;
RT "Isolation of a src homology 2-containing tyrosine phosphatase.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:1123-1127(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 2 AND 3).
RX PubMed=7665165; DOI=10.1006/geno.1995.1020;
RA Banville D., Stocco R., Shen S.H.;
RT "Human protein tyrosine phosphatase 1C (PTPN6) gene structure:
RT alternate promoter usage and exon skipping generate multiple
RT transcripts.";
RL Genomics 27:165-173(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9074930;
RA Ansari-Lari M.A., Shen Y., Muzny D.M., Lee W., Gibbs R.A.;
RT "Large-scale sequencing in human chromosome 12p13: experimental and
RT computational gene structure determination.";
RL Genome Res. 7:268-280(1997).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RX PubMed=10497187; DOI=10.1074/jbc.274.40.28301;
RA Jin Y.J., Yu C.L., Burakoff S.J.;
RT "Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-terminal
RT structure and catalytic activity.";
RL J. Biol. Chem. 274:28301-28307(1999).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2).
RA Oka T., Ouchida M.;
RT "Gene silencing of SHP-1 gene in leukemias/lymphomas by aberrant
RT methylation.";
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Umbilical cord blood;
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [11]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Placenta;
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 [13]
RP PHOSPHORYLATION.
RX PubMed=7781604;
RA Li R.Y., Gaits F., Ragab A., Ragab-Thomas J.M.F., Chap H.;
RT "Tyrosine phosphorylation of an SH2-containing protein tyrosine
RT phosphatase is coupled to platelet thrombin receptor via a pertussis
RT toxin-sensitive heterotrimeric G-protein.";
RL EMBO J. 14:2519-2526(1995).
RN [14]
RP INTERACTION WITH LILRB1.
RX PubMed=9285411; DOI=10.1016/S1074-7613(00)80529-4;
RA Cosman D., Fanger N., Borges L., Kubin M., Chin W., Peterson L.,
RA Hsu M.-L.;
RT "A novel immunoglobulin superfamily receptor for cellular and viral
RT MHC class I molecules.";
RL Immunity 7:273-282(1997).
RN [15]
RP INTERACTION WITH LILRB2.
RX PubMed=9842885;
RX DOI=10.1002/(SICI)1521-4141(199811)28:11<3423::AID-IMMU3423>3.0.CO;2-2;
RA Fanger N.A., Cosman D., Peterson L., Braddy S.C., Maliszewski C.R.,
RA Borges L.;
RT "The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-
RT mediated signaling in monocytes.";
RL Eur. J. Immunol. 28:3423-3434(1998).
RN [16]
RP INTERACTION WITH PTPNS1.
RX PubMed=9712903; DOI=10.1074/jbc.273.35.22719;
RA Veillette A., Thibaudeau E., Latour S.;
RT "High expression of inhibitory receptor SHPS-1 and its association
RT with protein tyrosine phosphatase SHP-1 in macrophages.";
RL J. Biol. Chem. 273:22719-22728(1998).
RN [17]
RP INTERACTION WITH LYN, AND PHOSPHORYLATION AT TYR-564.
RX PubMed=10574931; DOI=10.1074/jbc.274.49.34663;
RA Yoshida K., Kharbanda S., Kufe D.;
RT "Functional interaction between SHPTP1 and the Lyn tyrosine kinase in
RT the apoptotic response to DNA damage.";
RL J. Biol. Chem. 274:34663-34668(1999).
RN [18]
RP INTERACTION WITH FCRL2 AND FCRL3.
RX PubMed=11162587; DOI=10.1006/bbrc.2000.4213;
RA Xu M.-J., Zhao R., Zhao Z.J.;
RT "Molecular cloning and characterization of SPAP1, an inhibitory
RT receptor.";
RL Biochem. Biophys. Res. Commun. 280:768-775(2001).
RN [19]
RP INTERACTION WITH CD84.
RX PubMed=11414741; DOI=10.1006/clim.2001.5035;
RA Lewis J., Eiben L.J., Nelson D.L., Cohen J.I., Nichols K.E.,
RA Ochs H.D., Notarangelo L.D., Duckett C.S.;
RT "Distinct interactions of the X-linked lymphoproliferative syndrome
RT gene product SAP with cytoplasmic domains of members of the CD2
RT receptor family.";
RL Clin. Immunol. 100:15-23(2001).
RN [20]
RP FUNCTION IN ROS1 DEPHOSPHORYLATION, AND INTERACTION WITH ROS1.
RX PubMed=11266449; DOI=10.1083/jcb.152.2.325;
RA Keilhack H., Mueller M., Boehmer S.A., Frank C., Weidner K.M.,
RA Birchmeier W., Ligensa T., Berndt A., Kosmehl H., Guenther B.,
RA Mueller T., Birchmeier C., Boehmer F.D.;
RT "Negative regulation of Ros receptor tyrosine kinase signaling. An
RT epithelial function of the SH2 domain protein tyrosine phosphatase
RT SHP-1.";
RL J. Cell Biol. 152:325-334(2001).
RN [21]
RP INTERACTION WITH FCRL4.
RX PubMed=14597715; DOI=10.1073/pnas.1935944100;
RA Ehrhardt G.R.A., Davis R.S., Hsu J.T., Leu C.-M., Ehrhardt A.,
RA Cooper M.D.;
RT "The inhibitory potential of Fc receptor homolog 4 on memory B
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:13489-13494(2003).
RN [22]
RP INTERACTION WITH CD300LF.
RX PubMed=15184070; DOI=10.1016/j.bbrc.2004.05.065;
RA Sui L., Li N., Liu Q., Zhang W., Wan T., Wang B., Luo K., Sun H.,
RA Cao X.;
RT "IgSF13, a novel human inhibitory receptor of the immunoglobulin
RT superfamily, is preferentially expressed in dendritic cells and
RT monocytes.";
RL Biochem. Biophys. Res. Commun. 319:920-928(2004).
RN [23]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [24]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=16129412; DOI=10.1016/j.bbrc.2005.08.055;
RA Roskoski R. Jr.;
RT "Signaling by Kit protein-tyrosine kinase--the stem cell factor
RT receptor.";
RL Biochem. Biophys. Res. Commun. 337:1-13(2005).
RN [25]
RP INTERACTION WITH KIR2DL1.
RX PubMed=18604210; DOI=10.1038/ni.1635;
RA Yu M.-C., Su L.-L., Zou L., Liu Y., Wu N., Kong L., Zhuang Z.-H.,
RA Sun L., Liu H.P., Hu J.-H., Li D., Strominger J.L., Zang J.-W.,
RA Pei G., Ge B.-X.;
RT "An essential function for beta-arrestin 2 in the inhibitory signaling
RT of natural killer cells.";
RL Nat. Immunol. 9:898-907(2008).
RN [26]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH PDPK1.
RX PubMed=19591923; DOI=10.1016/j.cellsig.2009.06.010;
RA Sephton C.F., Zhang D., Lehmann T.M., Pennington P.R., Scheid M.P.,
RA Mousseau D.D.;
RT "The nuclear localization of 3'-phosphoinositide-dependent kinase-1 is
RT dependent on its association with the protein tyrosine phosphatase
RT SHP-1.";
RL Cell. Signal. 21:1634-1644(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-64, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [28]
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 [29]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH CDK2.
RX PubMed=21262353; DOI=10.1016/j.cellsig.2011.01.019;
RA Fiset A., Xu E., Bergeron S., Marette A., Pelletier G.,
RA Siminovitch K.A., Olivier M., Beauchemin N., Faure R.L.;
RT "Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and
RT regulates insulin internalization.";
RL Cell. Signal. 23:911-919(2011).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 248-399.
RX PubMed=9774441; DOI=10.1074/jbc.273.43.28199;
RA Yang J., Liang X., Niu T., Meng W., Zhao Z., Zhou G.W.;
RT "Crystal structure of the catalytic domain of protein-tyrosine
RT phosphatase SHP-1.";
RL J. Biol. Chem. 273:28199-28207(1998).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-532, AND DOMAIN SH2.
RX PubMed=12482860; DOI=10.1074/jbc.M210430200;
RA Yang J., Liu L., He D., Song X., Liang X., Zhao Z.J., Zhou G.W.;
RT "Crystal structure of human protein-tyrosine phosphatase SHP-1.";
RL J. Biol. Chem. 278:6516-6520(2003).
RN [32]
RP STRUCTURE BY NMR OF 110-214.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structures of the SH2 domain of human protein-tyrosine
RT phosphatase SHP-1.";
RL Submitted (NOV-2005) to the PDB data bank.
RN [33]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS), AND DOMAIN SH2.
RX PubMed=21465528; DOI=10.1002/jcb.23125;
RA Wang W., Liu L., Song X., Mo Y., Komma C., Bellamy H.D., Zhao Z.J.,
RA Zhou G.W.;
RT "Crystal structure of human protein tyrosine phosphatase SHP-1 in the
RT open conformation.";
RL J. Cell. Biochem. 112:2062-2071(2011).
CC -!- FUNCTION: Modulates signaling by tyrosine phosphorylated cell
CC surface receptors such as KIT and the EGF receptor/EGFR. The SH2
CC regions may interact with other cellular components to modulate
CC its own phosphatase activity against interacting substrates.
CC Together with MTUS1, induces UBE2V2 expression upon angiotensin II
CC stimulation. Plays a key role in hematopoiesis.
CC -!- CATALYTIC ACTIVITY: Protein tyrosine phosphate + H(2)O = protein
CC tyrosine + phosphate.
CC -!- SUBUNIT: Monomer. Interacts with MTUS1 (By similarity). Interacts
CC with MILR1 (tyrosine-phosphorylated). Interacts with KIT (By
CC similarity). Binds PTPNS1, LILRB1 and LILRB2. Interacts with
CC FCRL2, FCRL3, FCRL4, CD300LF, CDK2 and CD84. Interacts with
CC KIR2DL1; the interaction is enhanced by ARRB2. Interacts (via SH2
CC 1 domain) with ROS1; the interaction is direct and promotes ROS1
CC dephosphorylation. Interacts with EGFR; inhibits EGFR-dependent
CC activation of MAPK/ERK. Interacts with LYN. Interacts with the
CC tyrosine phosphorylated form of PDPK1.
CC -!- INTERACTION:
CC Q14790:CASP8; NbExp=3; IntAct=EBI-78260, EBI-78060;
CC P20273:CD22; NbExp=4; IntAct=EBI-78260, EBI-78277;
CC P20138:CD33; NbExp=8; IntAct=EBI-78260, EBI-3906571;
CC P11049:CD37; NbExp=4; IntAct=EBI-78260, EBI-6139068;
CC P19235:EPOR; NbExp=11; IntAct=EBI-78260, EBI-617321;
CC P31994:FCGR2B; NbExp=3; IntAct=EBI-78260, EBI-724784;
CC P43626:KIR2DL1; NbExp=4; IntAct=EBI-78260, EBI-8684277;
CC P43628:KIR2DL3; NbExp=13; IntAct=EBI-78260, EBI-8632435;
CC Q6GTX8:LAIR1; NbExp=5; IntAct=EBI-78260, EBI-965864;
CC P06239:LCK; NbExp=5; IntAct=EBI-78260, EBI-1348;
CC P16284:PECAM1; NbExp=4; IntAct=EBI-78260, EBI-716404;
CC Q9UKJ1:PILRA; NbExp=5; IntAct=EBI-78260, EBI-965833;
CC P08922:ROS1; NbExp=2; IntAct=EBI-78260, EBI-7371065;
CC B7UM99:tir (xeno); NbExp=4; IntAct=EBI-78260, EBI-2504426;
CC Q7DB77:tir (xeno); NbExp=2; IntAct=EBI-78260, EBI-6480811;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=In neurons,
CC translocates into the nucleus after treatment with angiotensin II
CC (By similarity). Shuttles between the cytoplasm and nucleus via
CC its association with PDPK1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Long;
CC IsoId=P29350-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P29350-3; Sequence=VSP_007775;
CC Name=3; Synonyms=Short;
CC IsoId=P29350-2; Sequence=VSP_005129, VSP_005130;
CC Name=4; Synonyms=70-kDa, SHP-1L;
CC IsoId=P29350-4; Sequence=VSP_044447;
CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in hematopoietic cells.
CC Isoform 2 is expressed in non-hematopoietic cells.
CC -!- DOMAIN: The N-terminal SH2 domain functions as an auto-inhibitory
CC domain, blocking the catalytic domain in the ligand-free close
CC conformation.
CC -!- PTM: Phosphorylated on tyrosine residues. Binding of KITLG/SCF to
CC KIT increases tyrosine phosphorylation (By similarity).
CC Phosphorylation at Tyr-564 enhances phosphatase activity.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC Non-receptor class 2 subfamily.
CC -!- SIMILARITY: Contains 2 SH2 domains.
CC -!- SIMILARITY: Contains 1 tyrosine-protein phosphatase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PTPN6ID41920ch12p13.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M74903; AAA35963.1; -; mRNA.
DR EMBL; X62055; CAA43982.1; -; mRNA.
DR EMBL; M77273; AAA36610.1; -; mRNA.
DR EMBL; U15528; AAA82880.1; -; Genomic_DNA.
DR EMBL; U15536; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15535; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15534; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15533; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15532; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15531; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15530; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15529; AAA82880.1; JOINED; Genomic_DNA.
DR EMBL; U15528; AAA82879.1; -; Genomic_DNA.
DR EMBL; U15537; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15535; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15534; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15533; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15532; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15531; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15530; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U15529; AAA82879.1; JOINED; Genomic_DNA.
DR EMBL; U47924; AAB51322.1; -; Genomic_DNA.
DR EMBL; U47924; AAB51323.1; -; Genomic_DNA.
DR EMBL; AF178946; AAD53317.1; -; mRNA.
DR EMBL; AB079851; BAC81774.1; -; Genomic_DNA.
DR EMBL; AB079851; BAC81775.1; -; Genomic_DNA.
DR EMBL; AK290421; BAF83110.1; -; mRNA.
DR EMBL; CH471116; EAW88703.1; -; Genomic_DNA.
DR EMBL; CH471116; EAW88704.1; -; Genomic_DNA.
DR EMBL; BC002523; AAH02523.1; -; mRNA.
DR EMBL; BC007667; AAH07667.1; -; mRNA.
DR PIR; B42031; S20825.
DR RefSeq; NP_002822.2; NM_002831.5.
DR RefSeq; NP_536858.1; NM_080548.4.
DR RefSeq; NP_536859.1; NM_080549.3.
DR RefSeq; XP_005253776.1; XM_005253719.1.
DR RefSeq; XP_005277811.1; XM_005277754.1.
DR UniGene; Hs.63489; -.
DR PDB; 1FPR; X-ray; 2.50 A; A=243-526.
DR PDB; 1GWZ; X-ray; 2.50 A; A=243-541.
DR PDB; 1X6C; NMR; -; A=110-214.
DR PDB; 2B3O; X-ray; 2.80 A; A=1-532.
DR PDB; 2RMX; NMR; -; A=110-214.
DR PDB; 2YU7; NMR; -; A=110-214.
DR PDB; 3PS5; X-ray; 3.10 A; A=1-595.
DR PDB; 4GRY; X-ray; 1.70 A; A=243-528.
DR PDB; 4GRZ; X-ray; 1.37 A; A=243-528.
DR PDB; 4GS0; X-ray; 1.80 A; A/B=243-528.
DR PDB; 4HJP; X-ray; 1.40 A; A=243-528.
DR PDB; 4HJQ; X-ray; 1.80 A; A/B=243-528.
DR PDBsum; 1FPR; -.
DR PDBsum; 1GWZ; -.
DR PDBsum; 1X6C; -.
DR PDBsum; 2B3O; -.
DR PDBsum; 2RMX; -.
DR PDBsum; 2YU7; -.
DR PDBsum; 3PS5; -.
DR PDBsum; 4GRY; -.
DR PDBsum; 4GRZ; -.
DR PDBsum; 4GS0; -.
DR PDBsum; 4HJP; -.
DR PDBsum; 4HJQ; -.
DR ProteinModelPortal; P29350; -.
DR SMR; P29350; 1-529.
DR DIP; DIP-31002N; -.
DR IntAct; P29350; 43.
DR MINT; MINT-134053; -.
DR STRING; 9606.ENSP00000391592; -.
DR BindingDB; P29350; -.
DR ChEMBL; CHEMBL3166; -.
DR PhosphoSite; P29350; -.
DR DMDM; 131469; -.
DR OGP; P29350; -.
DR PaxDb; P29350; -.
DR PRIDE; P29350; -.
DR DNASU; 5777; -.
DR Ensembl; ENST00000318974; ENSP00000326010; ENSG00000111679.
DR Ensembl; ENST00000399448; ENSP00000382376; ENSG00000111679.
DR Ensembl; ENST00000447931; ENSP00000415979; ENSG00000111679.
DR Ensembl; ENST00000456013; ENSP00000391592; ENSG00000111679.
DR Ensembl; ENST00000594686; ENSP00000468853; ENSG00000268954.
DR Ensembl; ENST00000595623; ENSP00000472428; ENSG00000268954.
DR Ensembl; ENST00000595832; ENSP00000469169; ENSG00000268954.
DR Ensembl; ENST00000599028; ENSP00000470980; ENSG00000268954.
DR GeneID; 5777; -.
DR KEGG; hsa:5777; -.
DR UCSC; uc001qsb.2; human.
DR CTD; 5777; -.
DR GeneCards; GC12P007055; -.
DR HGNC; HGNC:9658; PTPN6.
DR HPA; CAB004572; -.
DR HPA; HPA001466; -.
DR MIM; 176883; gene.
DR neXtProt; NX_P29350; -.
DR PharmGKB; PA34002; -.
DR eggNOG; COG5599; -.
DR HOGENOM; HOG000273907; -.
DR HOVERGEN; HBG000223; -.
DR InParanoid; P29350; -.
DR KO; K05697; -.
DR OMA; QAKGEPW; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P29350; -.
DR ChiTaRS; PTPN6; human.
DR EvolutionaryTrace; P29350; -.
DR GeneWiki; PTPN6; -.
DR GenomeRNAi; 5777; -.
DR NextBio; 22466; -.
DR PMAP-CutDB; P29350; -.
DR PRO; PR:P29350; -.
DR ArrayExpress; P29350; -.
DR Bgee; P29350; -.
DR CleanEx; HS_PTPN6; -.
DR Genevestigator; P29350; -.
DR GO; GO:0042105; C:alpha-beta T cell receptor complex; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0005001; F:transmembrane receptor protein tyrosine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0050853; P:B cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0030154; P:cell differentiation; IDA:UniProtKB.
DR GO; GO:0008283; P:cell proliferation; IDA:UniProtKB.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0042267; P:natural killer cell mediated cytotoxicity; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; NAS:UniProtKB.
DR GO; GO:0002924; P:negative regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0050732; P:negative regulation of peptidyl-tyrosine phosphorylation; IMP:BHF-UCL.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IMP:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IMP:BHF-UCL.
DR GO; GO:0045577; P:regulation of B cell differentiation; IEA:Ensembl.
DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IMP:BHF-UCL.
DR GO; GO:0060334; P:regulation of interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0060338; P:regulation of type I interferon-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; TAS:Reactome.
DR Gene3D; 3.30.505.10; -; 2.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR000387; Tyr/Dual-sp_Pase.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR InterPro; IPR012152; Tyr_Pase_non-rcpt_typ-6/11.
DR InterPro; IPR000242; Tyr_Pase_rcpt/non-rcpt.
DR Pfam; PF00017; SH2; 2.
DR Pfam; PF00102; Y_phosphatase; 1.
DR PIRSF; PIRSF000929; Tyr-Ptase_nr_6; 1.
DR PRINTS; PR00700; PRTYPHPHTASE.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00194; PTPc; 1.
DR SMART; SM00252; SH2; 2.
DR PROSITE; PS50001; SH2; 2.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
DR PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Hydrolase; Nucleus; Phosphoprotein; Protein phosphatase;
KW Reference proteome; Repeat; SH2 domain.
FT CHAIN 1 595 Tyrosine-protein phosphatase non-receptor
FT type 6.
FT /FTId=PRO_0000094758.
FT DOMAIN 4 100 SH2 1.
FT DOMAIN 110 213 SH2 2.
FT DOMAIN 244 515 Tyrosine-protein phosphatase.
FT REGION 453 459 Substrate binding (By similarity).
FT ACT_SITE 453 453 Phosphocysteine intermediate.
FT BINDING 419 419 Substrate (By similarity).
FT BINDING 500 500 Substrate (By similarity).
FT MOD_RES 64 64 Phosphotyrosine.
FT MOD_RES 377 377 Phosphotyrosine (By similarity).
FT MOD_RES 536 536 Phosphotyrosine (By similarity).
FT MOD_RES 564 564 Phosphotyrosine; by LYN.
FT VAR_SEQ 1 39 Missing (in isoform 3).
FT /FTId=VSP_005129.
FT VAR_SEQ 1 3 MVR -> MLSRG (in isoform 2).
FT /FTId=VSP_007775.
FT VAR_SEQ 40 44 SLSVR -> MLSRG (in isoform 3).
FT /FTId=VSP_005130.
FT VAR_SEQ 559 595 HKEDVYENLHTKNKREEKVKKQRSADKEKSKGSLKRK ->
FT SLESSAGTVAASPVRRGGQRGLPVPGPPVLSPDLHQLPVLA
FT PLHPAADTRRMCMRTCTLRTRGRRK (in isoform 4).
FT /FTId=VSP_044447.
FT CONFLICT 6 6 H -> L (in Ref. 5; AAA82880).
FT CONFLICT 86 86 L -> V (in Ref. 4; AAA36610 and 7;
FT AAD53317).
FT CONFLICT 146 146 V -> E (in Ref. 5; AAA82880/AAA82879).
FT HELIX 11 21
FT STRAND 26 31
FT STRAND 33 45
FT STRAND 48 55
FT STRAND 57 59
FT STRAND 61 63
FT STRAND 68 70
FT HELIX 72 80
FT STRAND 89 91
FT HELIX 105 107
FT STRAND 111 114
FT HELIX 117 127
FT STRAND 132 137
FT STRAND 139 141
FT STRAND 145 154
FT STRAND 155 157
FT STRAND 162 170
FT HELIX 172 174
FT STRAND 175 181
FT STRAND 184 186
FT HELIX 187 197
FT STRAND 199 201
FT STRAND 202 204
FT STRAND 205 207
FT HELIX 221 223
FT STRAND 236 238
FT HELIX 244 256
FT TURN 257 259
FT HELIX 263 266
FT HELIX 268 273
FT STRAND 275 278
FT TURN 283 285
FT STRAND 286 288
FT STRAND 290 292
FT STRAND 294 296
FT TURN 297 300
FT STRAND 301 307
FT STRAND 309 312
FT HELIX 314 316
FT STRAND 321 324
FT HELIX 329 331
FT HELIX 332 341
FT STRAND 346 349
FT STRAND 353 355
FT STRAND 356 358
FT STRAND 371 374
FT STRAND 377 386
FT STRAND 388 399
FT HELIX 400 402
FT STRAND 403 405
FT STRAND 407 414
FT STRAND 419 421
FT STRAND 424 426
FT HELIX 427 442
FT STRAND 443 445
FT STRAND 449 452
FT STRAND 454 457
FT HELIX 458 476
FT HELIX 484 492
FT HELIX 502 523
SQ SEQUENCE 595 AA; 67561 MW; 4D7736C21D3542D2 CRC64;
MVRWFHRDLS GLDAETLLKG RGVHGSFLAR PSRKNQGDFS LSVRVGDQVT HIRIQNSGDF
YDLYGGEKFA TLTELVEYYT QQQGVLQDRD GTIIHLKYPL NCSDPTSERW YHGHMSGGQA
ETLLQAKGEP WTFLVRESLS QPGDFVLSVL SDQPKAGPGS PLRVTHIKVM CEGGRYTVGG
LETFDSLTDL VEHFKKTGIE EASGAFVYLR QPYYATRVNA ADIENRVLEL NKKQESEDTA
KAGFWEEFES LQKQEVKNLH QRLEGQRPEN KGKNRYKNIL PFDHSRVILQ GRDSNIPGSD
YINANYIKNQ LLGPDENAKT YIASQGCLEA TVNDFWQMAW QENSRVIVMT TREVEKGRNK
CVPYWPEVGM QRAYGPYSVT NCGEHDTTEY KLRTLQVSPL DNGDLIREIW HYQYLSWPDH
GVPSEPGGVL SFLDQINQRQ ESLPHAGPII VHCSAGIGRT GTIIVIDMLM ENISTKGLDC
DIDIQKTIQM VRAQRSGMVQ TEAQYKFIYV AIAQFIETTK KKLEVLQSQK GQESEYGNIT
YPPAMKNAHA KASRTSSKHK EDVYENLHTK NKREEKVKKQ RSADKEKSKG SLKRK
//
MIM
176883
*RECORD*
*FIELD* NO
176883
*FIELD* TI
*176883 PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 6; PTPN6
;;PROTEIN-TYROSINE PHOSPHATASE 1C; PTP1C;;
read moreTYROSINE PHOSPHATASE SHP1; SHP1;;
HEMATOPOIETIC CELL PHOSPHATASE; HCPH
*FIELD* TX
CLONING
The growth and functional responses of hematopoietic cells are regulated
through tyrosine phosphorylation of proteins. Using a PCR approach, Yi
et al. (1991) identified 3 novel tyrosine protein phosphatases in
hematopoietic cells. One of these, expressed predominantly in
hematopoietic cells, was termed hematopoietic cell phosphatase (HCPH).
From a pre-B-cell-derived library, Matthews et al. (1992) cloned the
mouse PTPN6 cDNA, which they designated SHP (Src homology region
2-domain phosphatase). Yi et al. (1992) obtained complete cDNAs for both
the human and murine HCPH genes. The human gene was also cloned from a
breast cancer cell line and termed PTP1C by Shen et al. (1991). PTP1C
encodes a cytoplasmic protein that contains a phosphatase-catalytic
domain in the C-terminal region and 2 tandemly repeated, src-homology 2
(SH2) domains in the N-terminal region. SH2 domains were first
identified in the SRC gene family and found in a variety of proteins
involved in signal transduction. The SH2 domains may recognize
phosphorylated tyrosine residues and direct protein-protein
associations.
GENE STRUCTURE
Banville et al. (1995) demonstrated that the PTPN6 gene consists of 17
exons spanning 17 kb of DNA. Three nonhematopoietic PTPN6 transcripts
were identified in a variety of cell lines and were shown to be
transcribed from a common promoter. The hematopoietic form of the PTPN6
transcript is initiated at a downstream promoter separated by 7 kb from
the upstream promoter. This downstream promoter is active exclusively in
cells of the hematopoietic lineage.
MAPPING
Yi et al. (1992) mapped the human HCPH gene to chromosome 12p13-p12 by
fluorescence in situ hybridization. By study of panels of somatic cell
hybrids and fluorescence in situ hybridization, Plutzky et al. (1992)
determined that the gene encoding the nontransmembrane protein-tyrosine
phosphatase of the nonreceptor type 6 is located in region 12p13.
Using a genomic probe in interspecific backcross analysis, Yi et al.
(1992) mapped the murine Hcph gene to chromosome 6 where it was found to
be tightly linked to the Tnfr2 and Ly4 genes.
GENE FUNCTION
Plutzky et al. (1992) suggested that since PTPN6 is expressed at high
levels in hematopoietic cells of all lineages and its expression is
induced early in hematopoietic differentiation, and since 12p13 is a
region commonly involved in leukemia-associated chromosomal
abnormalities, altered expression and/or structure of PTPN6 may play a
role in leukemogenesis.
T-cell lymphomas lose expression of SHP1 due to DNA methylation of its
promoter. Zhang et al. (2005) demonstrated that malignant T cells
expressed DNMT1 (126375) and that STAT3 (102582) could bind sites in the
SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 (601241) formed
complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1 and
STAT3 small interfering RNA induced DNA demethylation in malignant T
cells and expression of SHP1. Zhang et al. (2005) concluded that STAT3
may transform cells by inducing epigenetic silencing of SHP1 in
cooperation with DNMT1 and HDAC1.
Combining computer modeling and single-cell measurements, Feinerman et
al. (2008) examined how endogenous variation in the expression levels of
signaling proteins might affect antigen responsiveness during T-cell
activation. They found that the CD8 (186910) coreceptor fine-tuned
activation thresholds, whereas SHP1 digitally regulated cell
responsiveness. Stochastic variation in expression of these proteins
generated substantial diversity of activation within a clonal population
of T cells, but coregulation of CD8 and SHP1 levels ultimately limited
this very diversity. Feinerman et al. (2008) concluded that these
findings revealed how eukaryotic cells can draw on regulated variation
in gene expression to achieve phenotypic variability in a controlled
manner.
In a cultured bovine retinal pericyte model, Geraldes et al. (2009)
demonstrated that hyperglycemia persistently activates PRKCD (176977)
and p38-alpha MAPK (MAPK14; 600289), thus increasing expression of SHP1,
and that this occurs independently of NFKB (see 164011) activation. This
signaling cascade leads to PDGF receptor-beta (PDGFRB; 173410)
dephosphorylation and a reduction in downstream signaling from this
receptor, resulting in pericyte apoptosis, the most specific vascular
histopathology associated with diabetic complications. The authors
observed increased PRKCD activity and an increase in the number of
acellular capillaries in diabetic mouse retinas, which were not
reversible with insulin treatment that achieved normoglycemia. Unlike
diabetic age-matched wildtype mice, diabetic Prkcd -/- mice did not show
activation of MAPK14 or SHP1, inhibition of PDGFB (190040) signaling in
vascular cells, or the presence of acellular capillaries. The authors
also observed PRKCD, MAPK14, and SHP1 activation in brain pericytes and
in the renal cortex of diabetic mice. Geraldes et al. (2009) concluded
that this represents a new signaling pathway by which hyperglycemia can
induce PDGFB resistance and increased vascular cell apoptosis to cause
diabetic vascular complications.
Khalil et al. (2012) showed that most proliferating germinal center B
cells do not demonstrate active B cell receptor signaling. Rather,
spontaneous and induced signaling was limited by increased phosphatase
activity. Accordingly, both SHP1 and SH2 domain-containing inositol
5-phosphatase (SHIP1; 601582) were hyperphosphorylated in germinal
center cells and remained colocalized with B cell receptors after
ligation. Furthermore, SHP1 was required for germinal cell maintenance.
Intriguingly, germinal center B cells in the cell cycle G2 period
regained responsiveness to B cell receptor stimulation.
MOLECULAR GENETICS
Beghini et al. (2000) examined the expression of PTPN6 in CD34+/CD117+
blasts from acute myeloid leukemia patients. They identified and cloned
novel PTPN6 mRNA species, derived from aberrant splicing within the
N-SH2 domain leading to retention of intron 3. Sequence analysis
revealed an A-to-G conversion of A7866, which represents the putative
branch site in IVS3 of PTPN6 mRNA. The level of the aberrant
intron-retaining splice variant, evaluated by semiquantitative RT-PCR,
was lower in CD117 +/- AML bone marrow mononuclear cells at remission
than at diagnosis, suggesting an involvement of posttranscriptional
PTPN6 processing in leukemogenesis.
ANIMAL MODEL
Mice with the recessive 'moth eaten' (me) or the allelic 'viable moth
eaten' mutations express a severe autoimmune and immunodeficiency
syndrome. Tsui et al. (1993) showed that the basic defect involves
lesions in the gene that encodes hematopoietic cell phosphatase. Shultz
et al. (1993) showed that 2 allelic 'motheaten' mutations result in
aberrant splicing of the Hcph transcript. Thus, 'motheaten' was the
first animal model for a specific protein-tyrosine phosphatase
deficiency, useful in determining the precise role of HCPH in
hematopoiesis.
Kamata et al. (2003) found that CD4 T cells in mice heterozygous for the
motheaten mutation express about half the normal amount of SHP1. Th2
cell differentiation and Th2 cytokine production in CD4 T cells and
specific cytokine production in mast cells were enhanced in these mice.
Eosinophilic infiltration and enhanced airway hyperresponsiveness were
also noted in OVA-sensitized heterozygous mice, but only after OVA
inhalation. Kamata et al. (2003) suggested that SHP1 may be a negative
regulator in the development of allergic responses such as allergic
asthma.
Dubois et al. (2006) demonstrated that 'viable motheaten' mice bearing a
functionally deficient SHP1 protein are markedly glucose tolerant and
insulin sensitive compared to wildtype littermates, due to enhanced
insulin receptor signaling to IRS (see 147545)-PI3K (see PIK3CA;
171834)-Akt (164730) in liver and muscle and increased phosphorylation
of CEACAM1 (109770). This metabolic phenotype was recapitulated in
normal mice through adenoviral expression of a dominant-negative
inactive form of SHP1 in the liver or hepatic knockdown of SHP1 by small
hairpin RNA-mediated gene silencing. Dubois et al. (2006) concluded that
SHP1 plays a crucial role in negatively modulating insulin action and
clearance in the liver, thereby regulating whole-body glucose
homeostasis.
Using chemical mutagenesis, Croker et al. (2008) obtained mice with a
recessive phenotype they termed 'spin,' for spontaneous inflammation.
Homozygous spin mice had chronic lesions in feet, salivary glands, and
lungs and antichromatin antibodies. Spin mice had enhanced resistance to
Listeria monocytogenes infection. Testing the suppressive effects of
mutations at other loci showed that the autoinflammatory phenotype of
spin mice required Myd88 (602170), Irak4 (606883), and Il1r1 (147810),
but not Ticam1 (607601), Stat1 (600555), or Tnf (191160). Spin mice
derived into a germ-free environment did not show either autoimmune or
autoinflammatory phenotypes. Positional cloning mapped spin to the
distal region of chromosome 6, and Croker et al. (2008) identified a
T-to-A transversion in exon 5 of the Ptpn6 gene, resulting in a
tyr208-to-asn (Y208N) substitution in the N-terminal SH2 domain of the
protein. Croker et al. (2008) concluded that the spin phenotype is due
to a viable hypomorphic allele of Ptpn6 and that spin autoimmunity is
driven by commensal microbes acting through the Tlr (e.g., TLR4; 603030)
pathway requiring Myd88, Irak4, and Il1r1.
PTPN6(spin) mice spontaneously develop a severe inflammatory syndrome
that resembles neutrophilic dermatosis in humans and is characterized by
persistent footpad swelling and suppurative inflammation. Lukens et al.
(2013) reported that receptor-interacting protein-1 (RIP1;
603453)-regulated interleukin 1-alpha (IL1A; 147760) production by
hematopoietic cells critically mediates chronic inflammatory disease in
Ptpn6(spin) mice, whereas inflammasome signaling and IL1-beta
(147720)-mediated events are dispensable. IL1A was also crucial for
exacerbated inflammatory responses and unremitting tissue damage upon
footpad microabrasion of Ptpn6(spin) mice. Notably, pharmacologic and
genetic blockade of the kinase RIP1 protected against wound-induced
inflammation and tissue damage in Ptpn6(spin) mice, whereas RIP3
(605817) deletion failed to do so. Moreover, RIP1-mediated inflammatory
cytokine production was attenuated by NF-kappa-B (see 164011) and ERK
(see 601795) inhibition. Lukens et al. (2013) concluded that
wound-induced tissue damage and chronic inflammation in Ptpn6(spin) mice
are critically dependent on RIP1-mediated IL1-alpha production, whereas
inflammasome signaling and RIP3-mediated necroptosis are dispensable.
*FIELD* RF
1. Banville, D.; Stocco, R.; Shen, S.-H.: Human protein tyrosine
phosphatase 1C (PTPN6) gene structure: alternate promoter usage and
exon skipping generate multiple transcripts. Genomics 27: 165-173,
1995.
2. Beghini, A.; Ripamonti, C. B.; Peterlongo, P.; Roversi, G.; Cairoli,
R.; Morra, E.; Larizza, L.: RNA hyperediting and alternative splicing
of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. Hum.
Molec. Genet. 9: 2297-2304, 2000.
3. Croker, B. A.; Lawson, B. R.; Rutschmann, S.; Berger, M.; Eidenschenk,
C.; Blasius, A. L.; Moresco, E. M. Y.; Sovath, S.; Cengia, L.; Shultz,
L. D.; Theofilopoulos, A. N.; Pettersson, S.; Beutler, B. A.: Inflammation
and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88,
and microbial trigger. Proc. Nat. Acad. Sci. 105: 15028-15033, 2008.
Note: Erratum: Proc. Nat. Acad. Sci. 105: 19561 only, 2008.
4. Dubois, M.-J.; Bergeron, S.; Kim, H.-J.; Dombrowski, L.; Perreault,
M.; Fournes, B.; Faure, R.; Olivier, M.; Beauchemin, N.; Shulman,
G. I.; Siminovitch, K. A.; Kim, J. K.; Marette, A.: The SHP-1 protein
tyrosine phosphatase negatively modulates glucose homeostasis. Nature
Med. 12: 549-556, 2006.
5. Feinerman, O.; Veiga, J.; Dorfman, J. R.; Germain, R. N.; Altan-Bonnet,
G.: Variability and robustness in T cell activation from regulated
heterogeneity in protein levels. Science 321: 1081-1084, 2008.
6. Geraldes, P.; Hiraoka-Yamamoto, J.; Matsumoto, M.; Clermont, A.;
Leitges, M.; Marette, A.; Aiello, L. P.; Kern, T. S.; King, G. L.
: Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular
cell apoptosis and diabetic retinopathy. Nature Med. 15: 1298-1306,
2009.
7. Kamata, T.; Yamashita, M.; Kimura, M.; Murata, K.; Inami, M.; Shimizu,
C.; Sugaya, K.; Wang, C.-R.; Taniguchi, M.; Nakayama, T.: Src homology
2 domain-containing tyrosine phosphatase SHP-1 controls the development
of allergic airway inflammation. J. Clin. Invest. 111: 109-119,
2003.
8. Khalil, A. M.; Cambier, J. C.; Shlomchik, M. J.: B cell receptor
signal transduction in the GC is short-circuited by high phosphatase
activity. Science 336: 1178-1181, 2012.
9. Lukens, J. R.; Vogel, P.; Johnson, G. R.; Kelliher, M. A.; Iwakura,
Y.; Lamkanfi, M.; Kanneganti, T. D.: RIP1-driven autoinflammation
targets IL-1-alpha independently of inflammasomes and RIP3. Nature 498:
224-227, 2013.
10. Matthews, R. J.; Bowne, D. B.; Flores, E.; Thomas, M. L.: Characterization
of hematopoietic intracellular protein tyrosine phosphatases: description
of a phosphatase containing an SH2 domain and another enriched in
proline-, glutamic acid-, serine-, and threonine-rich sequences. Molec.
Cell. Biol. 12: 2396-2405, 1992.
11. Plutzky, J.; Neel, B. G.; Rosenberg, R. D.; Eddy, R. L.; Byers,
M. G.; Jani-Sait, S.; Shows, T. B.: Chromosomal localization of an
SH2-containing tyrosine phosphatase (PTPN6). Genomics 13: 869-872,
1992.
12. Shen, S.-H.; Bastien, L.; Posner, B. I.; Chretien, P.: A protein-tyrosine
phosphatase with sequence similarity to the SH2 domain of the protein-tyrosine
kinases. Nature 352: 736-739, 1991. Note: Erratum: Nature: 353:
868 only, 1991.
13. Shultz, L. D.; Schweitzer, P. A.; Rajan, T. V.; Yi, T.; Ihle,
J. N.; Matthews, R. J.; Thomas, M. L.; Beier, D. R.: Mutations at
the murine motheaten locus are within the hematopoietic cell protein-tyrosine
phosphatase (Hcph) gene. Cell 73: 1445-1454, 1993.
14. Tsui, H. W.; Siminovitch, K. A.; de Souza, L.; Tsui, F. W. L.
: Motheaten and viable motheaten mice have mutations in the haematopoietic
cell phosphatase gene. Nature Genet. 4: 124-129, 1993.
15. Yi, T.; Cleveland, J. L.; Ihle, J. N.: Protein tyrosine phosphatase
containing SH2 domains: characterization, preferential expression
in hematopoietic cells, and localization to human chromosome 12p12-p13. Molec.
Cell. Biol. 12: 836-846, 1992.
16. Yi, T.; Cleveland, J. L.; Ihle, J. N.: Identification of novel
protein tyrosine phosphatases of hematopoietic cells by PCR amplification. Blood 78:
2222-2228, 1991.
17. Yi, T.; Gilbert, D. J.; Jenkins, N. A.; Copeland, N. G.; Ihle,
J. N.: Assignment of a novel protein tyrosine phosphatase gene (Hcph)
to mouse chromosome 6. Genomics 14: 793-795, 1992.
18. Zhang, Q.; Wang, H. Y.; Marzec, M.; Raghunath, P. N.; Nagasawa,
T.; Wasik, M. A.: STAT3- and DNA methyltransferase 1-mediated epigenetic
silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant
T lymphocytes. Proc. Nat. Acad. Sci. 102: 6948-6953, 2005.
*FIELD* CN
Ada Hamosh - updated: 7/24/2013
Ada Hamosh - updated: 7/19/2012
Marla J. F. O'Neill - updated: 12/2/2009
Paul J. Converse - updated: 3/24/2009
Paul J. Converse - updated: 2/4/2009
Ada Hamosh - updated: 9/4/2008
Marla J. F. O'Neill - updated: 9/14/2006
Denise L. M. Goh - updated: 4/17/2003
George E. Tiller - updated: 12/14/2000
*FIELD* CD
Victor A. McKusick: 7/22/1991
*FIELD* ED
carol: 10/22/2013
alopez: 7/24/2013
carol: 4/22/2013
alopez: 7/24/2012
terry: 7/19/2012
wwang: 12/7/2009
terry: 12/2/2009
mgross: 3/24/2009
terry: 3/24/2009
mgross: 2/4/2009
terry: 2/4/2009
alopez: 9/12/2008
terry: 9/4/2008
wwang: 9/18/2006
terry: 9/14/2006
carol: 4/17/2003
cwells: 1/16/2001
terry: 12/14/2000
dkim: 7/23/1998
carol: 6/22/1998
terry: 8/4/1995
mark: 6/1/1995
carol: 11/18/1994
carol: 6/21/1993
carol: 4/6/1993
carol: 12/14/1992
*RECORD*
*FIELD* NO
176883
*FIELD* TI
*176883 PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 6; PTPN6
;;PROTEIN-TYROSINE PHOSPHATASE 1C; PTP1C;;
read moreTYROSINE PHOSPHATASE SHP1; SHP1;;
HEMATOPOIETIC CELL PHOSPHATASE; HCPH
*FIELD* TX
CLONING
The growth and functional responses of hematopoietic cells are regulated
through tyrosine phosphorylation of proteins. Using a PCR approach, Yi
et al. (1991) identified 3 novel tyrosine protein phosphatases in
hematopoietic cells. One of these, expressed predominantly in
hematopoietic cells, was termed hematopoietic cell phosphatase (HCPH).
From a pre-B-cell-derived library, Matthews et al. (1992) cloned the
mouse PTPN6 cDNA, which they designated SHP (Src homology region
2-domain phosphatase). Yi et al. (1992) obtained complete cDNAs for both
the human and murine HCPH genes. The human gene was also cloned from a
breast cancer cell line and termed PTP1C by Shen et al. (1991). PTP1C
encodes a cytoplasmic protein that contains a phosphatase-catalytic
domain in the C-terminal region and 2 tandemly repeated, src-homology 2
(SH2) domains in the N-terminal region. SH2 domains were first
identified in the SRC gene family and found in a variety of proteins
involved in signal transduction. The SH2 domains may recognize
phosphorylated tyrosine residues and direct protein-protein
associations.
GENE STRUCTURE
Banville et al. (1995) demonstrated that the PTPN6 gene consists of 17
exons spanning 17 kb of DNA. Three nonhematopoietic PTPN6 transcripts
were identified in a variety of cell lines and were shown to be
transcribed from a common promoter. The hematopoietic form of the PTPN6
transcript is initiated at a downstream promoter separated by 7 kb from
the upstream promoter. This downstream promoter is active exclusively in
cells of the hematopoietic lineage.
MAPPING
Yi et al. (1992) mapped the human HCPH gene to chromosome 12p13-p12 by
fluorescence in situ hybridization. By study of panels of somatic cell
hybrids and fluorescence in situ hybridization, Plutzky et al. (1992)
determined that the gene encoding the nontransmembrane protein-tyrosine
phosphatase of the nonreceptor type 6 is located in region 12p13.
Using a genomic probe in interspecific backcross analysis, Yi et al.
(1992) mapped the murine Hcph gene to chromosome 6 where it was found to
be tightly linked to the Tnfr2 and Ly4 genes.
GENE FUNCTION
Plutzky et al. (1992) suggested that since PTPN6 is expressed at high
levels in hematopoietic cells of all lineages and its expression is
induced early in hematopoietic differentiation, and since 12p13 is a
region commonly involved in leukemia-associated chromosomal
abnormalities, altered expression and/or structure of PTPN6 may play a
role in leukemogenesis.
T-cell lymphomas lose expression of SHP1 due to DNA methylation of its
promoter. Zhang et al. (2005) demonstrated that malignant T cells
expressed DNMT1 (126375) and that STAT3 (102582) could bind sites in the
SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 (601241) formed
complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1 and
STAT3 small interfering RNA induced DNA demethylation in malignant T
cells and expression of SHP1. Zhang et al. (2005) concluded that STAT3
may transform cells by inducing epigenetic silencing of SHP1 in
cooperation with DNMT1 and HDAC1.
Combining computer modeling and single-cell measurements, Feinerman et
al. (2008) examined how endogenous variation in the expression levels of
signaling proteins might affect antigen responsiveness during T-cell
activation. They found that the CD8 (186910) coreceptor fine-tuned
activation thresholds, whereas SHP1 digitally regulated cell
responsiveness. Stochastic variation in expression of these proteins
generated substantial diversity of activation within a clonal population
of T cells, but coregulation of CD8 and SHP1 levels ultimately limited
this very diversity. Feinerman et al. (2008) concluded that these
findings revealed how eukaryotic cells can draw on regulated variation
in gene expression to achieve phenotypic variability in a controlled
manner.
In a cultured bovine retinal pericyte model, Geraldes et al. (2009)
demonstrated that hyperglycemia persistently activates PRKCD (176977)
and p38-alpha MAPK (MAPK14; 600289), thus increasing expression of SHP1,
and that this occurs independently of NFKB (see 164011) activation. This
signaling cascade leads to PDGF receptor-beta (PDGFRB; 173410)
dephosphorylation and a reduction in downstream signaling from this
receptor, resulting in pericyte apoptosis, the most specific vascular
histopathology associated with diabetic complications. The authors
observed increased PRKCD activity and an increase in the number of
acellular capillaries in diabetic mouse retinas, which were not
reversible with insulin treatment that achieved normoglycemia. Unlike
diabetic age-matched wildtype mice, diabetic Prkcd -/- mice did not show
activation of MAPK14 or SHP1, inhibition of PDGFB (190040) signaling in
vascular cells, or the presence of acellular capillaries. The authors
also observed PRKCD, MAPK14, and SHP1 activation in brain pericytes and
in the renal cortex of diabetic mice. Geraldes et al. (2009) concluded
that this represents a new signaling pathway by which hyperglycemia can
induce PDGFB resistance and increased vascular cell apoptosis to cause
diabetic vascular complications.
Khalil et al. (2012) showed that most proliferating germinal center B
cells do not demonstrate active B cell receptor signaling. Rather,
spontaneous and induced signaling was limited by increased phosphatase
activity. Accordingly, both SHP1 and SH2 domain-containing inositol
5-phosphatase (SHIP1; 601582) were hyperphosphorylated in germinal
center cells and remained colocalized with B cell receptors after
ligation. Furthermore, SHP1 was required for germinal cell maintenance.
Intriguingly, germinal center B cells in the cell cycle G2 period
regained responsiveness to B cell receptor stimulation.
MOLECULAR GENETICS
Beghini et al. (2000) examined the expression of PTPN6 in CD34+/CD117+
blasts from acute myeloid leukemia patients. They identified and cloned
novel PTPN6 mRNA species, derived from aberrant splicing within the
N-SH2 domain leading to retention of intron 3. Sequence analysis
revealed an A-to-G conversion of A7866, which represents the putative
branch site in IVS3 of PTPN6 mRNA. The level of the aberrant
intron-retaining splice variant, evaluated by semiquantitative RT-PCR,
was lower in CD117 +/- AML bone marrow mononuclear cells at remission
than at diagnosis, suggesting an involvement of posttranscriptional
PTPN6 processing in leukemogenesis.
ANIMAL MODEL
Mice with the recessive 'moth eaten' (me) or the allelic 'viable moth
eaten' mutations express a severe autoimmune and immunodeficiency
syndrome. Tsui et al. (1993) showed that the basic defect involves
lesions in the gene that encodes hematopoietic cell phosphatase. Shultz
et al. (1993) showed that 2 allelic 'motheaten' mutations result in
aberrant splicing of the Hcph transcript. Thus, 'motheaten' was the
first animal model for a specific protein-tyrosine phosphatase
deficiency, useful in determining the precise role of HCPH in
hematopoiesis.
Kamata et al. (2003) found that CD4 T cells in mice heterozygous for the
motheaten mutation express about half the normal amount of SHP1. Th2
cell differentiation and Th2 cytokine production in CD4 T cells and
specific cytokine production in mast cells were enhanced in these mice.
Eosinophilic infiltration and enhanced airway hyperresponsiveness were
also noted in OVA-sensitized heterozygous mice, but only after OVA
inhalation. Kamata et al. (2003) suggested that SHP1 may be a negative
regulator in the development of allergic responses such as allergic
asthma.
Dubois et al. (2006) demonstrated that 'viable motheaten' mice bearing a
functionally deficient SHP1 protein are markedly glucose tolerant and
insulin sensitive compared to wildtype littermates, due to enhanced
insulin receptor signaling to IRS (see 147545)-PI3K (see PIK3CA;
171834)-Akt (164730) in liver and muscle and increased phosphorylation
of CEACAM1 (109770). This metabolic phenotype was recapitulated in
normal mice through adenoviral expression of a dominant-negative
inactive form of SHP1 in the liver or hepatic knockdown of SHP1 by small
hairpin RNA-mediated gene silencing. Dubois et al. (2006) concluded that
SHP1 plays a crucial role in negatively modulating insulin action and
clearance in the liver, thereby regulating whole-body glucose
homeostasis.
Using chemical mutagenesis, Croker et al. (2008) obtained mice with a
recessive phenotype they termed 'spin,' for spontaneous inflammation.
Homozygous spin mice had chronic lesions in feet, salivary glands, and
lungs and antichromatin antibodies. Spin mice had enhanced resistance to
Listeria monocytogenes infection. Testing the suppressive effects of
mutations at other loci showed that the autoinflammatory phenotype of
spin mice required Myd88 (602170), Irak4 (606883), and Il1r1 (147810),
but not Ticam1 (607601), Stat1 (600555), or Tnf (191160). Spin mice
derived into a germ-free environment did not show either autoimmune or
autoinflammatory phenotypes. Positional cloning mapped spin to the
distal region of chromosome 6, and Croker et al. (2008) identified a
T-to-A transversion in exon 5 of the Ptpn6 gene, resulting in a
tyr208-to-asn (Y208N) substitution in the N-terminal SH2 domain of the
protein. Croker et al. (2008) concluded that the spin phenotype is due
to a viable hypomorphic allele of Ptpn6 and that spin autoimmunity is
driven by commensal microbes acting through the Tlr (e.g., TLR4; 603030)
pathway requiring Myd88, Irak4, and Il1r1.
PTPN6(spin) mice spontaneously develop a severe inflammatory syndrome
that resembles neutrophilic dermatosis in humans and is characterized by
persistent footpad swelling and suppurative inflammation. Lukens et al.
(2013) reported that receptor-interacting protein-1 (RIP1;
603453)-regulated interleukin 1-alpha (IL1A; 147760) production by
hematopoietic cells critically mediates chronic inflammatory disease in
Ptpn6(spin) mice, whereas inflammasome signaling and IL1-beta
(147720)-mediated events are dispensable. IL1A was also crucial for
exacerbated inflammatory responses and unremitting tissue damage upon
footpad microabrasion of Ptpn6(spin) mice. Notably, pharmacologic and
genetic blockade of the kinase RIP1 protected against wound-induced
inflammation and tissue damage in Ptpn6(spin) mice, whereas RIP3
(605817) deletion failed to do so. Moreover, RIP1-mediated inflammatory
cytokine production was attenuated by NF-kappa-B (see 164011) and ERK
(see 601795) inhibition. Lukens et al. (2013) concluded that
wound-induced tissue damage and chronic inflammation in Ptpn6(spin) mice
are critically dependent on RIP1-mediated IL1-alpha production, whereas
inflammasome signaling and RIP3-mediated necroptosis are dispensable.
*FIELD* RF
1. Banville, D.; Stocco, R.; Shen, S.-H.: Human protein tyrosine
phosphatase 1C (PTPN6) gene structure: alternate promoter usage and
exon skipping generate multiple transcripts. Genomics 27: 165-173,
1995.
2. Beghini, A.; Ripamonti, C. B.; Peterlongo, P.; Roversi, G.; Cairoli,
R.; Morra, E.; Larizza, L.: RNA hyperediting and alternative splicing
of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. Hum.
Molec. Genet. 9: 2297-2304, 2000.
3. Croker, B. A.; Lawson, B. R.; Rutschmann, S.; Berger, M.; Eidenschenk,
C.; Blasius, A. L.; Moresco, E. M. Y.; Sovath, S.; Cengia, L.; Shultz,
L. D.; Theofilopoulos, A. N.; Pettersson, S.; Beutler, B. A.: Inflammation
and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88,
and microbial trigger. Proc. Nat. Acad. Sci. 105: 15028-15033, 2008.
Note: Erratum: Proc. Nat. Acad. Sci. 105: 19561 only, 2008.
4. Dubois, M.-J.; Bergeron, S.; Kim, H.-J.; Dombrowski, L.; Perreault,
M.; Fournes, B.; Faure, R.; Olivier, M.; Beauchemin, N.; Shulman,
G. I.; Siminovitch, K. A.; Kim, J. K.; Marette, A.: The SHP-1 protein
tyrosine phosphatase negatively modulates glucose homeostasis. Nature
Med. 12: 549-556, 2006.
5. Feinerman, O.; Veiga, J.; Dorfman, J. R.; Germain, R. N.; Altan-Bonnet,
G.: Variability and robustness in T cell activation from regulated
heterogeneity in protein levels. Science 321: 1081-1084, 2008.
6. Geraldes, P.; Hiraoka-Yamamoto, J.; Matsumoto, M.; Clermont, A.;
Leitges, M.; Marette, A.; Aiello, L. P.; Kern, T. S.; King, G. L.
: Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular
cell apoptosis and diabetic retinopathy. Nature Med. 15: 1298-1306,
2009.
7. Kamata, T.; Yamashita, M.; Kimura, M.; Murata, K.; Inami, M.; Shimizu,
C.; Sugaya, K.; Wang, C.-R.; Taniguchi, M.; Nakayama, T.: Src homology
2 domain-containing tyrosine phosphatase SHP-1 controls the development
of allergic airway inflammation. J. Clin. Invest. 111: 109-119,
2003.
8. Khalil, A. M.; Cambier, J. C.; Shlomchik, M. J.: B cell receptor
signal transduction in the GC is short-circuited by high phosphatase
activity. Science 336: 1178-1181, 2012.
9. Lukens, J. R.; Vogel, P.; Johnson, G. R.; Kelliher, M. A.; Iwakura,
Y.; Lamkanfi, M.; Kanneganti, T. D.: RIP1-driven autoinflammation
targets IL-1-alpha independently of inflammasomes and RIP3. Nature 498:
224-227, 2013.
10. Matthews, R. J.; Bowne, D. B.; Flores, E.; Thomas, M. L.: Characterization
of hematopoietic intracellular protein tyrosine phosphatases: description
of a phosphatase containing an SH2 domain and another enriched in
proline-, glutamic acid-, serine-, and threonine-rich sequences. Molec.
Cell. Biol. 12: 2396-2405, 1992.
11. Plutzky, J.; Neel, B. G.; Rosenberg, R. D.; Eddy, R. L.; Byers,
M. G.; Jani-Sait, S.; Shows, T. B.: Chromosomal localization of an
SH2-containing tyrosine phosphatase (PTPN6). Genomics 13: 869-872,
1992.
12. Shen, S.-H.; Bastien, L.; Posner, B. I.; Chretien, P.: A protein-tyrosine
phosphatase with sequence similarity to the SH2 domain of the protein-tyrosine
kinases. Nature 352: 736-739, 1991. Note: Erratum: Nature: 353:
868 only, 1991.
13. Shultz, L. D.; Schweitzer, P. A.; Rajan, T. V.; Yi, T.; Ihle,
J. N.; Matthews, R. J.; Thomas, M. L.; Beier, D. R.: Mutations at
the murine motheaten locus are within the hematopoietic cell protein-tyrosine
phosphatase (Hcph) gene. Cell 73: 1445-1454, 1993.
14. Tsui, H. W.; Siminovitch, K. A.; de Souza, L.; Tsui, F. W. L.
: Motheaten and viable motheaten mice have mutations in the haematopoietic
cell phosphatase gene. Nature Genet. 4: 124-129, 1993.
15. Yi, T.; Cleveland, J. L.; Ihle, J. N.: Protein tyrosine phosphatase
containing SH2 domains: characterization, preferential expression
in hematopoietic cells, and localization to human chromosome 12p12-p13. Molec.
Cell. Biol. 12: 836-846, 1992.
16. Yi, T.; Cleveland, J. L.; Ihle, J. N.: Identification of novel
protein tyrosine phosphatases of hematopoietic cells by PCR amplification. Blood 78:
2222-2228, 1991.
17. Yi, T.; Gilbert, D. J.; Jenkins, N. A.; Copeland, N. G.; Ihle,
J. N.: Assignment of a novel protein tyrosine phosphatase gene (Hcph)
to mouse chromosome 6. Genomics 14: 793-795, 1992.
18. Zhang, Q.; Wang, H. Y.; Marzec, M.; Raghunath, P. N.; Nagasawa,
T.; Wasik, M. A.: STAT3- and DNA methyltransferase 1-mediated epigenetic
silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant
T lymphocytes. Proc. Nat. Acad. Sci. 102: 6948-6953, 2005.
*FIELD* CN
Ada Hamosh - updated: 7/24/2013
Ada Hamosh - updated: 7/19/2012
Marla J. F. O'Neill - updated: 12/2/2009
Paul J. Converse - updated: 3/24/2009
Paul J. Converse - updated: 2/4/2009
Ada Hamosh - updated: 9/4/2008
Marla J. F. O'Neill - updated: 9/14/2006
Denise L. M. Goh - updated: 4/17/2003
George E. Tiller - updated: 12/14/2000
*FIELD* CD
Victor A. McKusick: 7/22/1991
*FIELD* ED
carol: 10/22/2013
alopez: 7/24/2013
carol: 4/22/2013
alopez: 7/24/2012
terry: 7/19/2012
wwang: 12/7/2009
terry: 12/2/2009
mgross: 3/24/2009
terry: 3/24/2009
mgross: 2/4/2009
terry: 2/4/2009
alopez: 9/12/2008
terry: 9/4/2008
wwang: 9/18/2006
terry: 9/14/2006
carol: 4/17/2003
cwells: 1/16/2001
terry: 12/14/2000
dkim: 7/23/1998
carol: 6/22/1998
terry: 8/4/1995
mark: 6/1/1995
carol: 11/18/1994
carol: 6/21/1993
carol: 4/6/1993
carol: 12/14/1992