Full text data of RTN4
RTN4
(KIAA0886, NOGO)
[Confidence: high (present in two of the MS resources)]
Reticulon-4 (Foocen; Neurite outgrowth inhibitor; Nogo protein; Neuroendocrine-specific protein; NSP; Neuroendocrine-specific protein C homolog; RTN-x; Reticulon-5)
Reticulon-4 (Foocen; Neurite outgrowth inhibitor; Nogo protein; Neuroendocrine-specific protein; NSP; Neuroendocrine-specific protein C homolog; RTN-x; Reticulon-5)
UniProt
Q9NQC3
ID RTN4_HUMAN Reviewed; 1192 AA.
AC Q9NQC3; O94962; Q7L7Q5; Q7L7Q6; Q7L7Q8; Q8IUA4; Q96B16; Q9BXG5;
read moreAC Q9H212; Q9H3I3; Q9UQ42; Q9Y293; Q9Y2Y7; Q9Y5U6;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2001, sequence version 2.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Reticulon-4;
DE AltName: Full=Foocen;
DE AltName: Full=Neurite outgrowth inhibitor;
DE Short=Nogo protein;
DE AltName: Full=Neuroendocrine-specific protein;
DE Short=NSP;
DE AltName: Full=Neuroendocrine-specific protein C homolog;
DE AltName: Full=RTN-x;
DE AltName: Full=Reticulon-5;
GN Name=RTN4; Synonyms=KIAA0886, NOGO; ORFNames=My043, SP1507;
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] (ISOFORMS 1; 2 AND 3).
RX PubMed=10773680;
RA Yang J., Yu L., Bi A.D., Zhao S.-Y.;
RT "Assignment of the human reticulon 4 gene (RTN4) to chromosome
RT 2p14-->2p13 by radiation hybrid mapping.";
RL Cytogenet. Cell Genet. 88:101-102(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
RX PubMed=10667780; DOI=10.1038/35000287;
RA Prinjha R., Moore S.E., Vinson M., Blake S., Morrow R., Christie G.,
RA Michalovich D., Simmons D.L., Walsh F.S.;
RT "Inhibitor of neurite outgrowth in humans.";
RL Nature 403:383-384(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain;
RX PubMed=11126360; DOI=10.1038/sj.onc.1203948;
RA Tagami S., Eguchi Y., Kinoshita M., Takeda M., Tsujimoto Y.;
RT "A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on
RT endoplasmic reticulum and reduces their anti-apoptotic activity.";
RL Oncogene 19:5736-5746(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6).
RC TISSUE=Testis;
RX PubMed=11866689;
RA Zhou Z.M., Sha J.H., Li J.M., Lin M., Zhu H., Zhou Y.D., Wang L.R.,
RA Zhu H., Wang Y.Q., Zhou K.Y.;
RT "Expression of a novel reticulon-like gene in human testis.";
RL Reproduction 123:227-234(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2; 3; 5 AND 6).
RX PubMed=12488097; DOI=10.1016/S0022-2836(02)01179-8;
RA Oertle T., Huber C., van der Putten H., Schwab M.E.;
RT "Genomic structure and functional characterisation of the promoters of
RT human and mouse nogo/rtn4.";
RL J. Mol. Biol. 325:299-323(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Fibroblast;
RA Yutsudo M.;
RT "Isolation of a cell death-inducing gene.";
RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Pituitary;
RA Song H., Peng Y., Zhou J., Huang Q., Dai M., Mao Y.M., Yu Y., Xu X.,
RA Luo B., Hu R., Chen J.;
RT "Human neuroendocrine-specific protein C (NSP) homolog gene.";
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Placenta, and Skeletal muscle;
RA Ito T., Schwartz S.M.;
RT "Cloning of a member of the reticulon gene family in human.";
RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Jin W.-L., Ju G.;
RT "Developmentally-regulated alternative splicing in a novel Nogo-A.";
RL Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M.,
RA Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XII.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 5:355-364(1998).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for
RT 300 previously undefined genes expressed in CD34+ hematopoietic
RT stem/progenitor cells.";
RL Genome Res. 10:1546-1560(2000).
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [14]
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 [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 5).
RC TISSUE=Brain, Eye, Kidney, Ovary, Pancreas, Placenta, and
RC Skeletal muscle;
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 [16]
RP PROTEIN SEQUENCE OF 1-24; 92-104; 1075-1090 AND 1158-1171, ACETYLATION
RP AT MET-1, PHOSPHORYLATION AT SER-15, AND MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V.;
RL Submitted (JAN-2010) to UniProtKB.
RN [17]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 482-1192 (ISOFORMS 1/4).
RC TISSUE=Fetal brain;
RA Mao Y.M., Xie Y., Zheng Z.H.;
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [18]
RP TOPOLOGY, AND FUNCTION.
RC TISSUE=Brain;
RX PubMed=10667797; DOI=10.1038/35000226;
RA GrandPre T., Nakamura F., Vartanian T., Strittmatter S.M.;
RT "Identification of the Nogo inhibitor of axon regeneration as a
RT Reticulon protein.";
RL Nature 403:439-444(2000).
RN [19]
RP FUNCTION.
RC TISSUE=Brain;
RX PubMed=11201742; DOI=10.1038/35053072;
RA Fournier A.E., GrandPre T., Strittmatter S.M.;
RT "Identification of a receptor mediating Nogo-66 inhibition of axonal
RT regeneration.";
RL Nature 409:341-346(2001).
RN [20]
RP REVIEW.
RX PubMed=11891768; DOI=10.1002/jnr.10134;
RA Ng C.E.L., Tang B.L.;
RT "Nogos and the Nogo-66 receptor: factors inhibiting CNS neuron
RT regeneration.";
RL J. Neurosci. Res. 67:559-565(2002).
RN [21]
RP INTERACTION WITH RTN3.
RX PubMed=12811824; DOI=10.1002/jcp.10297;
RA Qi B., Qi Y., Watari A., Yoshioka N., Inoue H., Minemoto Y.,
RA Yamashita K., Sasagawa T., Yutsudo M.;
RT "Pro-apoptotic ASY/Nogo-B protein associates with ASYIP.";
RL J. Cell. Physiol. 196:312-318(2003).
RN [22]
RP INTERACTION WITH BACE1.
RX PubMed=15286784; DOI=10.1038/nm1088;
RA He W., Lu Y., Qahwash I., Hu X.-Y., Chang A., Yan R.;
RT "Reticulon family members modulate BACE1 activity and amyloid-beta
RT peptide generation.";
RL Nat. Med. 10:959-965(2004).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7 AND SER-107, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [24]
RP INTERACTION WITH BACE1 AND BACE2, IDENTIFICATION BY MASS SPECTROMETRY,
RP AND FUNCTION.
RX PubMed=16965550; DOI=10.1111/j.1460-9568.2006.05005.x;
RA Murayama K.S., Kametani F., Saito S., Kume H., Akiyama H., Araki W.;
RT "Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its
RT ability to produce amyloid beta-protein.";
RL Eur. J. Neurosci. 24:1237-1244(2006).
RN [25]
RP INTERACTION WITH RTN3.
RX PubMed=16979658; DOI=10.1016/j.jmb.2006.07.094;
RA He W., Hu X., Shi Q., Zhou X., Lu Y., Fisher C., Yan R.;
RT "Mapping of interaction domains mediating binding between BACE1 and
RT RTN/Nogo proteins.";
RL J. Mol. Biol. 363:625-634(2006).
RN [26]
RP INTERACTION WITH NGBR.
RX PubMed=16835300; DOI=10.1073/pnas.0602427103;
RA Miao R.Q., Gao Y., Harrison K.D., Prendergast J., Acevedo L.M., Yu J.,
RA Hu F., Strittmatter S.M., Sessa W.C.;
RT "Identification of a receptor necessary for Nogo-B stimulated
RT chemotaxis and morphogenesis of endothelial cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10997-11002(2006).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-181 AND SER-182, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [29]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [30]
RP INTERACTION WITH ATL1.
RX PubMed=19665976; DOI=10.1016/j.cell.2009.05.025;
RA Hu J., Shibata Y., Zhu P.-P., Voss C., Rismanchi N., Prinz W.A.,
RA Rapoport T.A., Blackstone C.;
RT "A class of dynamin-like GTPases involved in the generation of the
RT tubular ER network.";
RL Cell 138:549-561(2009).
RN [31]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [33]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1104, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [34]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-7 AND SER-15, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [35]
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 [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-15 AND SER-107, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [37]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [38]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-429.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Developmental neurite growth regulatory factor with a
CC role as a negative regulator of axon-axon adhesion and growth, and
CC as a facilitator of neurite branching. Regulates neurite
CC fasciculation, branching and extension in the developing nervous
CC system. Involved in down-regulation of growth, stabilization of
CC wiring and restriction of plasticity in the adult CNS. Regulates
CC the radial migration of cortical neurons via an RTN4R-LINGO1
CC containing receptor complex (By similarity). Isoform 2 reduces the
CC anti-apoptotic activity of Bcl-xl and Bcl-2. This is likely
CC consecutive to their change in subcellular location, from the
CC mitochondria to the endoplasmic reticulum, after binding and
CC sequestration. Isoform 2 and isoform 3 inhibit BACE1 activity and
CC amyloid precursor protein processing.
CC -!- SUBUNIT: Binds to RTN4R. Interacts with Bcl-xl and Bcl-2. Isoform
CC 2 binds to NGBR and RTN3. Isoform 2 and isoform 3 interact with
CC BACE1 and BACE2. Interacts with RTN4IP1. Interacts with ATL1.
CC -!- INTERACTION:
CC Q8WXF7:ATL1; NbExp=2; IntAct=EBI-715972, EBI-2410266;
CC O43639:NCK2; NbExp=2; IntAct=EBI-715945, EBI-713635;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein. Note=Anchored to the membrane of the endoplasmic
CC reticulum through 2 putative transmembrane domains.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=RTN 4A, Nogo-A, RTN-xL;
CC IsoId=Q9NQC3-1; Sequence=Displayed;
CC Name=2; Synonyms=RTN 4B, ASY, Nogo-B, RTN-xS, Foocen-M;
CC IsoId=Q9NQC3-2; Sequence=VSP_005655;
CC Name=3; Synonyms=RTN 4C, Nogo-C, Foocen-S;
CC IsoId=Q9NQC3-3; Sequence=VSP_005652, VSP_005653;
CC Name=4;
CC IsoId=Q9NQC3-4; Sequence=VSP_005654;
CC Name=5; Synonyms=RTN4-B2;
CC IsoId=Q9NQC3-5; Sequence=VSP_037113;
CC Name=6; Synonyms=Rtn-T;
CC IsoId=Q9NQC3-6; Sequence=VSP_037112;
CC -!- TISSUE SPECIFICITY: Isoform 1 is specifically expressed in brain
CC and testis and weakly in heart and skeletal muscle. Isoform 2 is
CC widely expressed except for the liver. Isoform 3 is expressed in
CC brain, skeletal muscle and adipocytes. Isoform 4 is testis-
CC specific.
CC -!- DOMAIN: Three regions, residues 59-172, 544-725 and the loop 66
CC amino acids, between the two transmembrane domains, known as Nogo-
CC 66 loop, appear to be responsible for the inhibitory effect on
CC neurite outgrowth and the spreading of neurons. This Nogo-66 loop,
CC mediates also the binding of RTN4 to its receptor (By similarity).
CC -!- SIMILARITY: Contains 1 reticulon domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD39920.1; Type=Frameshift; Positions=1149, 1156;
CC Sequence=AAG43160.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAG43160.1; Type=Frameshift; Positions=684, 700;
CC Sequence=BAA74909.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=R&genename;=RTN4+%40+NOGO";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Nerve regrowth: nipped
CC by a no-go - Issue 69 of April 2006;
CC URL="http://web.expasy.org/spotlight/back_issues/sptlt069.shtml";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/RTN4ID42182ch2p16.html";
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DR EMBL; AF087901; AAG12205.1; -; mRNA.
DR EMBL; AF148537; AAG12176.1; -; mRNA.
DR EMBL; AF148538; AAG12177.1; -; mRNA.
DR EMBL; AJ251383; CAB99248.1; -; mRNA.
DR EMBL; AJ251384; CAB99249.1; -; mRNA.
DR EMBL; AJ251385; CAB99250.1; -; mRNA.
DR EMBL; AB040462; BAB18927.1; -; mRNA.
DR EMBL; AB040463; BAB18928.1; -; mRNA.
DR EMBL; AF333336; AAK20831.1; -; mRNA.
DR EMBL; AY102285; AAM64240.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64241.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64242.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64243.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64244.1; -; Genomic_DNA.
DR EMBL; AY102276; AAM64245.1; -; mRNA.
DR EMBL; AY102277; AAM64246.1; -; mRNA.
DR EMBL; AY102278; AAM64247.1; -; mRNA.
DR EMBL; AY102279; AAM64248.1; -; mRNA.
DR EMBL; AY123245; AAM64249.1; -; mRNA.
DR EMBL; AY123246; AAM64250.1; -; mRNA.
DR EMBL; AY123247; AAM64251.1; -; mRNA.
DR EMBL; AY123248; AAM64252.1; -; mRNA.
DR EMBL; AY123249; AAM64253.1; -; mRNA.
DR EMBL; AY123250; AAM64254.1; -; mRNA.
DR EMBL; AB015639; BAA83712.1; -; mRNA.
DR EMBL; AF077050; AAD27783.1; -; mRNA.
DR EMBL; AF132047; AAD31021.1; -; mRNA.
DR EMBL; AF132048; AAD31022.1; -; mRNA.
DR EMBL; AF320999; AAG40878.1; -; mRNA.
DR EMBL; AB020693; BAA74909.2; ALT_INIT; mRNA.
DR EMBL; AF125103; AAD39920.1; ALT_FRAME; mRNA.
DR EMBL; AF177332; AAG17976.1; -; mRNA.
DR EMBL; AC013414; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC092461; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093165; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471053; EAX00115.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00116.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00117.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00118.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00119.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00121.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00122.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00123.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00124.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00125.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00127.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00130.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00132.1; -; Genomic_DNA.
DR EMBL; BC001035; AAH01035.1; -; mRNA.
DR EMBL; BC007109; AAH07109.1; -; mRNA.
DR EMBL; BC010737; AAH10737.1; -; mRNA.
DR EMBL; BC012619; AAH12619.1; -; mRNA.
DR EMBL; BC014366; AAH14366.1; -; mRNA.
DR EMBL; BC016165; AAH16165.1; -; mRNA.
DR EMBL; BC026788; AAH26788.1; -; mRNA.
DR EMBL; BC068991; AAH68991.1; -; mRNA.
DR EMBL; BC150182; AAI50183.1; -; mRNA.
DR EMBL; BC152425; AAI52426.1; -; mRNA.
DR EMBL; BC152555; AAI52556.1; -; mRNA.
DR EMBL; AF063601; AAG43160.1; ALT_SEQ; mRNA.
DR RefSeq; NP_008939.1; NM_007008.2.
DR RefSeq; NP_065393.1; NM_020532.4.
DR RefSeq; NP_722550.1; NM_153828.2.
DR RefSeq; NP_997403.1; NM_207520.1.
DR RefSeq; NP_997404.1; NM_207521.1.
DR RefSeq; XP_005264491.1; XM_005264434.1.
DR UniGene; Hs.637850; -.
DR PDB; 2G31; NMR; -; A=1055-1114.
DR PDB; 2JV5; NMR; -; A=1055-1108.
DR PDBsum; 2G31; -.
DR PDBsum; 2JV5; -.
DR DisProt; DP00524; -.
DR ProteinModelPortal; Q9NQC3; -.
DR SMR; Q9NQC3; 1055-1114.
DR IntAct; Q9NQC3; 26.
DR MINT; MINT-154434; -.
DR PhosphoSite; Q9NQC3; -.
DR DMDM; 17369290; -.
DR PaxDb; Q9NQC3; -.
DR PRIDE; Q9NQC3; -.
DR DNASU; 57142; -.
DR Ensembl; ENST00000317610; ENSP00000322147; ENSG00000115310.
DR Ensembl; ENST00000337526; ENSP00000337838; ENSG00000115310.
DR Ensembl; ENST00000357376; ENSP00000349944; ENSG00000115310.
DR Ensembl; ENST00000357732; ENSP00000350365; ENSG00000115310.
DR Ensembl; ENST00000394609; ENSP00000378107; ENSG00000115310.
DR Ensembl; ENST00000394611; ENSP00000378109; ENSG00000115310.
DR Ensembl; ENST00000404909; ENSP00000385650; ENSG00000115310.
DR Ensembl; ENST00000405240; ENSP00000384471; ENSG00000115310.
DR GeneID; 57142; -.
DR KEGG; hsa:57142; -.
DR UCSC; uc002ryd.3; human.
DR CTD; 57142; -.
DR GeneCards; GC02M055199; -.
DR H-InvDB; HIX0002059; -.
DR HGNC; HGNC:14085; RTN4.
DR HPA; CAB005388; -.
DR HPA; HPA023977; -.
DR MIM; 604475; gene.
DR neXtProt; NX_Q9NQC3; -.
DR PharmGKB; PA34883; -.
DR eggNOG; NOG306139; -.
DR HOVERGEN; HBG023134; -.
DR InParanoid; Q9NQC3; -.
DR OMA; HTSENKT; -.
DR OrthoDB; EOG7CZK7J; -.
DR Reactome; REACT_111102; Signal Transduction.
DR ChiTaRS; RTN4; human.
DR EvolutionaryTrace; Q9NQC3; -.
DR GeneWiki; Reticulon_4; -.
DR GenomeRNAi; 57142; -.
DR NextBio; 63075; -.
DR PMAP-CutDB; Q9NQC3; -.
DR PRO; PR:Q9NQC3; -.
DR ArrayExpress; Q9NQC3; -.
DR Bgee; Q9NQC3; -.
DR Genevestigator; Q9NQC3; -.
DR GO; GO:0042995; C:cell projection; IEA:Ensembl.
DR GO; GO:0030176; C:integral to endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; NAS:UniProtKB.
DR GO; GO:0007413; P:axonal fasciculation; ISS:UniProtKB.
DR GO; GO:0060317; P:cardiac epithelial to mesenchymal transition; IEA:Ensembl.
DR GO; GO:0021801; P:cerebral cortex radial glia guided migration; ISS:UniProtKB.
DR GO; GO:0071786; P:endoplasmic reticulum tubular network organization; IMP:UniProtKB.
DR GO; GO:0030517; P:negative regulation of axon extension; IDA:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB.
DR GO; GO:2000172; P:regulation of branching morphogenesis of a nerve; ISS:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; IDA:MGI.
DR InterPro; IPR003388; Reticulon.
DR PANTHER; PTHR10994; PTHR10994; 1.
DR Pfam; PF02453; Reticulon; 1.
DR PROSITE; PS50845; RETICULON; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Endoplasmic reticulum; Membrane;
KW Neurogenesis; Phosphoprotein; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 1192 Reticulon-4.
FT /FTId=PRO_0000168165.
FT TOPO_DOM 1 1018 Cytoplasmic (Potential).
FT TRANSMEM 1019 1039 Helical; (Potential).
FT TOPO_DOM 1040 1133 Lumenal (Potential).
FT TRANSMEM 1134 1154 Helical; (Potential).
FT TOPO_DOM 1155 1192 Cytoplasmic (Potential).
FT DOMAIN 1005 1192 Reticulon.
FT COMPBIAS 30 47 Poly-Glu.
FT COMPBIAS 143 148 Poly-Pro.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 7 7 Phosphoserine.
FT MOD_RES 15 15 Phosphoserine.
FT MOD_RES 107 107 Phosphoserine.
FT MOD_RES 152 152 Phosphoserine (By similarity).
FT MOD_RES 181 181 Phosphoserine.
FT MOD_RES 182 182 Phosphoserine.
FT MOD_RES 361 361 Phosphoserine (By similarity).
FT MOD_RES 511 511 Phosphoserine (By similarity).
FT MOD_RES 1104 1104 N6-acetyllysine.
FT VAR_SEQ 1 993 Missing (in isoform 3).
FT /FTId=VSP_005652.
FT VAR_SEQ 1 206 Missing (in isoform 6).
FT /FTId=VSP_037112.
FT VAR_SEQ 58 289 Missing (in isoform 4).
FT /FTId=VSP_005654.
FT VAR_SEQ 186 1004 Missing (in isoform 2).
FT /FTId=VSP_005655.
FT VAR_SEQ 205 1004 Missing (in isoform 5).
FT /FTId=VSP_037113.
FT VAR_SEQ 994 1004 AIFSAELSKTS -> MDGQKKNWKDK (in isoform
FT 3).
FT /FTId=VSP_005653.
FT VARIANT 357 357 D -> V (in dbSNP:rs11677099).
FT /FTId=VAR_053633.
FT VARIANT 429 429 L -> V (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035904.
FT VARIANT 899 899 E -> Q (in dbSNP:rs6757519).
FT /FTId=VAR_053634.
FT VARIANT 920 920 S -> C (in dbSNP:rs6757705).
FT /FTId=VAR_053635.
FT CONFLICT 107 107 S -> C (in Ref. 6; BAA83712).
FT CONFLICT 135 135 E -> Q (in Ref. 6; BAA83712).
FT CONFLICT 458 458 S -> P (in Ref. 2; CAB99248).
FT CONFLICT 564 564 N -> S (in Ref. 4; AAK20831).
FT TURN 1059 1062
FT HELIX 1063 1070
FT HELIX 1074 1094
FT HELIX 1095 1097
FT HELIX 1100 1107
SQ SEQUENCE 1192 AA; 129931 MW; CDE239BBF31589CA CRC64;
MEDLDQSPLV SSSDSPPRPQ PAFKYQFVRE PEDEEEEEEE EEEDEDEDLE ELEVLERKPA
AGLSAAPVPT APAAGAPLMD FGNDFVPPAP RGPLPAAPPV APERQPSWDP SPVSSTVPAP
SPLSAAAVSP SKLPEDDEPP ARPPPPPPAS VSPQAEPVWT PPAPAPAAPP STPAAPKRRG
SSGSVDETLF ALPAASEPVI RSSAENMDLK EQPGNTISAG QEDFPSVLLE TAASLPSLSP
LSAASFKEHE YLGNLSTVLP TEGTLQENVS EASKEVSEKA KTLLIDRDLT EFSELEYSEM
GSSFSVSPKA ESAVIVANPR EEIIVKNKDE EEKLVSNNIL HNQQELPTAL TKLVKEDEVV
SSEKAKDSFN EKRVAVEAPM REEYADFKPF ERVWEVKDSK EDSDMLAAGG KIESNLESKV
DKKCFADSLE QTNHEKDSES SNDDTSFPST PEGIKDRSGA YITCAPFNPA ATESIATNIF
PLLGDPTSEN KTDEKKIEEK KAQIVTEKNT STKTSNPFLV AAQDSETDYV TTDNLTKVTE
EVVANMPEGL TPDLVQEACE SELNEVTGTK IAYETKMDLV QTSEVMQESL YPAAQLCPSF
EESEATPSPV LPDIVMEAPL NSAVPSAGAS VIQPSSSPLE ASSVNYESIK HEPENPPPYE
EAMSVSLKKV SGIKEEIKEP ENINAALQET EAPYISIACD LIKETKLSAE PAPDFSDYSE
MAKVEQPVPD HSELVEDSSP DSEPVDLFSD DSIPDVPQKQ DETVMLVKES LTETSFESMI
EYENKEKLSA LPPEGGKPYL ESFKLSLDNT KDTLLPDEVS TLSKKEKIPL QMEELSTAVY
SNDDLFISKE AQIRETETFS DSSPIEIIDE FPTLISSKTD SFSKLAREYT DLEVSHKSEI
ANAPDGAGSL PCTELPHDLS LKNIQPKVEE KISFSDDFSK NGSATSKVLL LPPDVSALAT
QAEIESIVKP KVLVKEAEKK LPSDTEKEDR SPSAIFSAEL SKTSVVDLLY WRDIKKTGVV
FGASLFLLLS LTVFSIVSVT AYIALALLSV TISFRIYKGV IQAIQKSDEG HPFRAYLESE
VAISEELVQK YSNSALGHVN CTIKELRRLF LVDDLVDSLK FAVLMWVFTY VGALFNGLTL
LILALISLFS VPVIYERHQA QIDHYLGLAN KNVKDAMAKI QAKIPGLKRK AE
//
ID RTN4_HUMAN Reviewed; 1192 AA.
AC Q9NQC3; O94962; Q7L7Q5; Q7L7Q6; Q7L7Q8; Q8IUA4; Q96B16; Q9BXG5;
read moreAC Q9H212; Q9H3I3; Q9UQ42; Q9Y293; Q9Y2Y7; Q9Y5U6;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2001, sequence version 2.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Reticulon-4;
DE AltName: Full=Foocen;
DE AltName: Full=Neurite outgrowth inhibitor;
DE Short=Nogo protein;
DE AltName: Full=Neuroendocrine-specific protein;
DE Short=NSP;
DE AltName: Full=Neuroendocrine-specific protein C homolog;
DE AltName: Full=RTN-x;
DE AltName: Full=Reticulon-5;
GN Name=RTN4; Synonyms=KIAA0886, NOGO; ORFNames=My043, SP1507;
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] (ISOFORMS 1; 2 AND 3).
RX PubMed=10773680;
RA Yang J., Yu L., Bi A.D., Zhao S.-Y.;
RT "Assignment of the human reticulon 4 gene (RTN4) to chromosome
RT 2p14-->2p13 by radiation hybrid mapping.";
RL Cytogenet. Cell Genet. 88:101-102(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
RX PubMed=10667780; DOI=10.1038/35000287;
RA Prinjha R., Moore S.E., Vinson M., Blake S., Morrow R., Christie G.,
RA Michalovich D., Simmons D.L., Walsh F.S.;
RT "Inhibitor of neurite outgrowth in humans.";
RL Nature 403:383-384(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain;
RX PubMed=11126360; DOI=10.1038/sj.onc.1203948;
RA Tagami S., Eguchi Y., Kinoshita M., Takeda M., Tsujimoto Y.;
RT "A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on
RT endoplasmic reticulum and reduces their anti-apoptotic activity.";
RL Oncogene 19:5736-5746(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6).
RC TISSUE=Testis;
RX PubMed=11866689;
RA Zhou Z.M., Sha J.H., Li J.M., Lin M., Zhu H., Zhou Y.D., Wang L.R.,
RA Zhu H., Wang Y.Q., Zhou K.Y.;
RT "Expression of a novel reticulon-like gene in human testis.";
RL Reproduction 123:227-234(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2; 3; 5 AND 6).
RX PubMed=12488097; DOI=10.1016/S0022-2836(02)01179-8;
RA Oertle T., Huber C., van der Putten H., Schwab M.E.;
RT "Genomic structure and functional characterisation of the promoters of
RT human and mouse nogo/rtn4.";
RL J. Mol. Biol. 325:299-323(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Fibroblast;
RA Yutsudo M.;
RT "Isolation of a cell death-inducing gene.";
RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Pituitary;
RA Song H., Peng Y., Zhou J., Huang Q., Dai M., Mao Y.M., Yu Y., Xu X.,
RA Luo B., Hu R., Chen J.;
RT "Human neuroendocrine-specific protein C (NSP) homolog gene.";
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Placenta, and Skeletal muscle;
RA Ito T., Schwartz S.M.;
RT "Cloning of a member of the reticulon gene family in human.";
RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Jin W.-L., Ju G.;
RT "Developmentally-regulated alternative splicing in a novel Nogo-A.";
RL Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M.,
RA Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XII.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 5:355-364(1998).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for
RT 300 previously undefined genes expressed in CD34+ hematopoietic
RT stem/progenitor cells.";
RL Genome Res. 10:1546-1560(2000).
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [14]
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 [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 5).
RC TISSUE=Brain, Eye, Kidney, Ovary, Pancreas, Placenta, and
RC Skeletal muscle;
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 [16]
RP PROTEIN SEQUENCE OF 1-24; 92-104; 1075-1090 AND 1158-1171, ACETYLATION
RP AT MET-1, PHOSPHORYLATION AT SER-15, AND MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V.;
RL Submitted (JAN-2010) to UniProtKB.
RN [17]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 482-1192 (ISOFORMS 1/4).
RC TISSUE=Fetal brain;
RA Mao Y.M., Xie Y., Zheng Z.H.;
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [18]
RP TOPOLOGY, AND FUNCTION.
RC TISSUE=Brain;
RX PubMed=10667797; DOI=10.1038/35000226;
RA GrandPre T., Nakamura F., Vartanian T., Strittmatter S.M.;
RT "Identification of the Nogo inhibitor of axon regeneration as a
RT Reticulon protein.";
RL Nature 403:439-444(2000).
RN [19]
RP FUNCTION.
RC TISSUE=Brain;
RX PubMed=11201742; DOI=10.1038/35053072;
RA Fournier A.E., GrandPre T., Strittmatter S.M.;
RT "Identification of a receptor mediating Nogo-66 inhibition of axonal
RT regeneration.";
RL Nature 409:341-346(2001).
RN [20]
RP REVIEW.
RX PubMed=11891768; DOI=10.1002/jnr.10134;
RA Ng C.E.L., Tang B.L.;
RT "Nogos and the Nogo-66 receptor: factors inhibiting CNS neuron
RT regeneration.";
RL J. Neurosci. Res. 67:559-565(2002).
RN [21]
RP INTERACTION WITH RTN3.
RX PubMed=12811824; DOI=10.1002/jcp.10297;
RA Qi B., Qi Y., Watari A., Yoshioka N., Inoue H., Minemoto Y.,
RA Yamashita K., Sasagawa T., Yutsudo M.;
RT "Pro-apoptotic ASY/Nogo-B protein associates with ASYIP.";
RL J. Cell. Physiol. 196:312-318(2003).
RN [22]
RP INTERACTION WITH BACE1.
RX PubMed=15286784; DOI=10.1038/nm1088;
RA He W., Lu Y., Qahwash I., Hu X.-Y., Chang A., Yan R.;
RT "Reticulon family members modulate BACE1 activity and amyloid-beta
RT peptide generation.";
RL Nat. Med. 10:959-965(2004).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7 AND SER-107, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [24]
RP INTERACTION WITH BACE1 AND BACE2, IDENTIFICATION BY MASS SPECTROMETRY,
RP AND FUNCTION.
RX PubMed=16965550; DOI=10.1111/j.1460-9568.2006.05005.x;
RA Murayama K.S., Kametani F., Saito S., Kume H., Akiyama H., Araki W.;
RT "Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its
RT ability to produce amyloid beta-protein.";
RL Eur. J. Neurosci. 24:1237-1244(2006).
RN [25]
RP INTERACTION WITH RTN3.
RX PubMed=16979658; DOI=10.1016/j.jmb.2006.07.094;
RA He W., Hu X., Shi Q., Zhou X., Lu Y., Fisher C., Yan R.;
RT "Mapping of interaction domains mediating binding between BACE1 and
RT RTN/Nogo proteins.";
RL J. Mol. Biol. 363:625-634(2006).
RN [26]
RP INTERACTION WITH NGBR.
RX PubMed=16835300; DOI=10.1073/pnas.0602427103;
RA Miao R.Q., Gao Y., Harrison K.D., Prendergast J., Acevedo L.M., Yu J.,
RA Hu F., Strittmatter S.M., Sessa W.C.;
RT "Identification of a receptor necessary for Nogo-B stimulated
RT chemotaxis and morphogenesis of endothelial cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10997-11002(2006).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-181 AND SER-182, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [29]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [30]
RP INTERACTION WITH ATL1.
RX PubMed=19665976; DOI=10.1016/j.cell.2009.05.025;
RA Hu J., Shibata Y., Zhu P.-P., Voss C., Rismanchi N., Prinz W.A.,
RA Rapoport T.A., Blackstone C.;
RT "A class of dynamin-like GTPases involved in the generation of the
RT tubular ER network.";
RL Cell 138:549-561(2009).
RN [31]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [33]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1104, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [34]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-7 AND SER-15, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [35]
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 [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-15 AND SER-107, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [37]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [38]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-429.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Developmental neurite growth regulatory factor with a
CC role as a negative regulator of axon-axon adhesion and growth, and
CC as a facilitator of neurite branching. Regulates neurite
CC fasciculation, branching and extension in the developing nervous
CC system. Involved in down-regulation of growth, stabilization of
CC wiring and restriction of plasticity in the adult CNS. Regulates
CC the radial migration of cortical neurons via an RTN4R-LINGO1
CC containing receptor complex (By similarity). Isoform 2 reduces the
CC anti-apoptotic activity of Bcl-xl and Bcl-2. This is likely
CC consecutive to their change in subcellular location, from the
CC mitochondria to the endoplasmic reticulum, after binding and
CC sequestration. Isoform 2 and isoform 3 inhibit BACE1 activity and
CC amyloid precursor protein processing.
CC -!- SUBUNIT: Binds to RTN4R. Interacts with Bcl-xl and Bcl-2. Isoform
CC 2 binds to NGBR and RTN3. Isoform 2 and isoform 3 interact with
CC BACE1 and BACE2. Interacts with RTN4IP1. Interacts with ATL1.
CC -!- INTERACTION:
CC Q8WXF7:ATL1; NbExp=2; IntAct=EBI-715972, EBI-2410266;
CC O43639:NCK2; NbExp=2; IntAct=EBI-715945, EBI-713635;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein. Note=Anchored to the membrane of the endoplasmic
CC reticulum through 2 putative transmembrane domains.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=RTN 4A, Nogo-A, RTN-xL;
CC IsoId=Q9NQC3-1; Sequence=Displayed;
CC Name=2; Synonyms=RTN 4B, ASY, Nogo-B, RTN-xS, Foocen-M;
CC IsoId=Q9NQC3-2; Sequence=VSP_005655;
CC Name=3; Synonyms=RTN 4C, Nogo-C, Foocen-S;
CC IsoId=Q9NQC3-3; Sequence=VSP_005652, VSP_005653;
CC Name=4;
CC IsoId=Q9NQC3-4; Sequence=VSP_005654;
CC Name=5; Synonyms=RTN4-B2;
CC IsoId=Q9NQC3-5; Sequence=VSP_037113;
CC Name=6; Synonyms=Rtn-T;
CC IsoId=Q9NQC3-6; Sequence=VSP_037112;
CC -!- TISSUE SPECIFICITY: Isoform 1 is specifically expressed in brain
CC and testis and weakly in heart and skeletal muscle. Isoform 2 is
CC widely expressed except for the liver. Isoform 3 is expressed in
CC brain, skeletal muscle and adipocytes. Isoform 4 is testis-
CC specific.
CC -!- DOMAIN: Three regions, residues 59-172, 544-725 and the loop 66
CC amino acids, between the two transmembrane domains, known as Nogo-
CC 66 loop, appear to be responsible for the inhibitory effect on
CC neurite outgrowth and the spreading of neurons. This Nogo-66 loop,
CC mediates also the binding of RTN4 to its receptor (By similarity).
CC -!- SIMILARITY: Contains 1 reticulon domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD39920.1; Type=Frameshift; Positions=1149, 1156;
CC Sequence=AAG43160.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAG43160.1; Type=Frameshift; Positions=684, 700;
CC Sequence=BAA74909.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=R&genename;=RTN4+%40+NOGO";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Nerve regrowth: nipped
CC by a no-go - Issue 69 of April 2006;
CC URL="http://web.expasy.org/spotlight/back_issues/sptlt069.shtml";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/RTN4ID42182ch2p16.html";
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DR EMBL; AF087901; AAG12205.1; -; mRNA.
DR EMBL; AF148537; AAG12176.1; -; mRNA.
DR EMBL; AF148538; AAG12177.1; -; mRNA.
DR EMBL; AJ251383; CAB99248.1; -; mRNA.
DR EMBL; AJ251384; CAB99249.1; -; mRNA.
DR EMBL; AJ251385; CAB99250.1; -; mRNA.
DR EMBL; AB040462; BAB18927.1; -; mRNA.
DR EMBL; AB040463; BAB18928.1; -; mRNA.
DR EMBL; AF333336; AAK20831.1; -; mRNA.
DR EMBL; AY102285; AAM64240.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64241.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64242.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64243.1; -; Genomic_DNA.
DR EMBL; AY102285; AAM64244.1; -; Genomic_DNA.
DR EMBL; AY102276; AAM64245.1; -; mRNA.
DR EMBL; AY102277; AAM64246.1; -; mRNA.
DR EMBL; AY102278; AAM64247.1; -; mRNA.
DR EMBL; AY102279; AAM64248.1; -; mRNA.
DR EMBL; AY123245; AAM64249.1; -; mRNA.
DR EMBL; AY123246; AAM64250.1; -; mRNA.
DR EMBL; AY123247; AAM64251.1; -; mRNA.
DR EMBL; AY123248; AAM64252.1; -; mRNA.
DR EMBL; AY123249; AAM64253.1; -; mRNA.
DR EMBL; AY123250; AAM64254.1; -; mRNA.
DR EMBL; AB015639; BAA83712.1; -; mRNA.
DR EMBL; AF077050; AAD27783.1; -; mRNA.
DR EMBL; AF132047; AAD31021.1; -; mRNA.
DR EMBL; AF132048; AAD31022.1; -; mRNA.
DR EMBL; AF320999; AAG40878.1; -; mRNA.
DR EMBL; AB020693; BAA74909.2; ALT_INIT; mRNA.
DR EMBL; AF125103; AAD39920.1; ALT_FRAME; mRNA.
DR EMBL; AF177332; AAG17976.1; -; mRNA.
DR EMBL; AC013414; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC092461; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093165; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471053; EAX00115.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00116.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00117.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00118.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00119.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00121.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00122.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00123.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00124.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00125.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00127.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00130.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00132.1; -; Genomic_DNA.
DR EMBL; BC001035; AAH01035.1; -; mRNA.
DR EMBL; BC007109; AAH07109.1; -; mRNA.
DR EMBL; BC010737; AAH10737.1; -; mRNA.
DR EMBL; BC012619; AAH12619.1; -; mRNA.
DR EMBL; BC014366; AAH14366.1; -; mRNA.
DR EMBL; BC016165; AAH16165.1; -; mRNA.
DR EMBL; BC026788; AAH26788.1; -; mRNA.
DR EMBL; BC068991; AAH68991.1; -; mRNA.
DR EMBL; BC150182; AAI50183.1; -; mRNA.
DR EMBL; BC152425; AAI52426.1; -; mRNA.
DR EMBL; BC152555; AAI52556.1; -; mRNA.
DR EMBL; AF063601; AAG43160.1; ALT_SEQ; mRNA.
DR RefSeq; NP_008939.1; NM_007008.2.
DR RefSeq; NP_065393.1; NM_020532.4.
DR RefSeq; NP_722550.1; NM_153828.2.
DR RefSeq; NP_997403.1; NM_207520.1.
DR RefSeq; NP_997404.1; NM_207521.1.
DR RefSeq; XP_005264491.1; XM_005264434.1.
DR UniGene; Hs.637850; -.
DR PDB; 2G31; NMR; -; A=1055-1114.
DR PDB; 2JV5; NMR; -; A=1055-1108.
DR PDBsum; 2G31; -.
DR PDBsum; 2JV5; -.
DR DisProt; DP00524; -.
DR ProteinModelPortal; Q9NQC3; -.
DR SMR; Q9NQC3; 1055-1114.
DR IntAct; Q9NQC3; 26.
DR MINT; MINT-154434; -.
DR PhosphoSite; Q9NQC3; -.
DR DMDM; 17369290; -.
DR PaxDb; Q9NQC3; -.
DR PRIDE; Q9NQC3; -.
DR DNASU; 57142; -.
DR Ensembl; ENST00000317610; ENSP00000322147; ENSG00000115310.
DR Ensembl; ENST00000337526; ENSP00000337838; ENSG00000115310.
DR Ensembl; ENST00000357376; ENSP00000349944; ENSG00000115310.
DR Ensembl; ENST00000357732; ENSP00000350365; ENSG00000115310.
DR Ensembl; ENST00000394609; ENSP00000378107; ENSG00000115310.
DR Ensembl; ENST00000394611; ENSP00000378109; ENSG00000115310.
DR Ensembl; ENST00000404909; ENSP00000385650; ENSG00000115310.
DR Ensembl; ENST00000405240; ENSP00000384471; ENSG00000115310.
DR GeneID; 57142; -.
DR KEGG; hsa:57142; -.
DR UCSC; uc002ryd.3; human.
DR CTD; 57142; -.
DR GeneCards; GC02M055199; -.
DR H-InvDB; HIX0002059; -.
DR HGNC; HGNC:14085; RTN4.
DR HPA; CAB005388; -.
DR HPA; HPA023977; -.
DR MIM; 604475; gene.
DR neXtProt; NX_Q9NQC3; -.
DR PharmGKB; PA34883; -.
DR eggNOG; NOG306139; -.
DR HOVERGEN; HBG023134; -.
DR InParanoid; Q9NQC3; -.
DR OMA; HTSENKT; -.
DR OrthoDB; EOG7CZK7J; -.
DR Reactome; REACT_111102; Signal Transduction.
DR ChiTaRS; RTN4; human.
DR EvolutionaryTrace; Q9NQC3; -.
DR GeneWiki; Reticulon_4; -.
DR GenomeRNAi; 57142; -.
DR NextBio; 63075; -.
DR PMAP-CutDB; Q9NQC3; -.
DR PRO; PR:Q9NQC3; -.
DR ArrayExpress; Q9NQC3; -.
DR Bgee; Q9NQC3; -.
DR Genevestigator; Q9NQC3; -.
DR GO; GO:0042995; C:cell projection; IEA:Ensembl.
DR GO; GO:0030176; C:integral to endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; NAS:UniProtKB.
DR GO; GO:0007413; P:axonal fasciculation; ISS:UniProtKB.
DR GO; GO:0060317; P:cardiac epithelial to mesenchymal transition; IEA:Ensembl.
DR GO; GO:0021801; P:cerebral cortex radial glia guided migration; ISS:UniProtKB.
DR GO; GO:0071786; P:endoplasmic reticulum tubular network organization; IMP:UniProtKB.
DR GO; GO:0030517; P:negative regulation of axon extension; IDA:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB.
DR GO; GO:2000172; P:regulation of branching morphogenesis of a nerve; ISS:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; IDA:MGI.
DR InterPro; IPR003388; Reticulon.
DR PANTHER; PTHR10994; PTHR10994; 1.
DR Pfam; PF02453; Reticulon; 1.
DR PROSITE; PS50845; RETICULON; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Endoplasmic reticulum; Membrane;
KW Neurogenesis; Phosphoprotein; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 1192 Reticulon-4.
FT /FTId=PRO_0000168165.
FT TOPO_DOM 1 1018 Cytoplasmic (Potential).
FT TRANSMEM 1019 1039 Helical; (Potential).
FT TOPO_DOM 1040 1133 Lumenal (Potential).
FT TRANSMEM 1134 1154 Helical; (Potential).
FT TOPO_DOM 1155 1192 Cytoplasmic (Potential).
FT DOMAIN 1005 1192 Reticulon.
FT COMPBIAS 30 47 Poly-Glu.
FT COMPBIAS 143 148 Poly-Pro.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 7 7 Phosphoserine.
FT MOD_RES 15 15 Phosphoserine.
FT MOD_RES 107 107 Phosphoserine.
FT MOD_RES 152 152 Phosphoserine (By similarity).
FT MOD_RES 181 181 Phosphoserine.
FT MOD_RES 182 182 Phosphoserine.
FT MOD_RES 361 361 Phosphoserine (By similarity).
FT MOD_RES 511 511 Phosphoserine (By similarity).
FT MOD_RES 1104 1104 N6-acetyllysine.
FT VAR_SEQ 1 993 Missing (in isoform 3).
FT /FTId=VSP_005652.
FT VAR_SEQ 1 206 Missing (in isoform 6).
FT /FTId=VSP_037112.
FT VAR_SEQ 58 289 Missing (in isoform 4).
FT /FTId=VSP_005654.
FT VAR_SEQ 186 1004 Missing (in isoform 2).
FT /FTId=VSP_005655.
FT VAR_SEQ 205 1004 Missing (in isoform 5).
FT /FTId=VSP_037113.
FT VAR_SEQ 994 1004 AIFSAELSKTS -> MDGQKKNWKDK (in isoform
FT 3).
FT /FTId=VSP_005653.
FT VARIANT 357 357 D -> V (in dbSNP:rs11677099).
FT /FTId=VAR_053633.
FT VARIANT 429 429 L -> V (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035904.
FT VARIANT 899 899 E -> Q (in dbSNP:rs6757519).
FT /FTId=VAR_053634.
FT VARIANT 920 920 S -> C (in dbSNP:rs6757705).
FT /FTId=VAR_053635.
FT CONFLICT 107 107 S -> C (in Ref. 6; BAA83712).
FT CONFLICT 135 135 E -> Q (in Ref. 6; BAA83712).
FT CONFLICT 458 458 S -> P (in Ref. 2; CAB99248).
FT CONFLICT 564 564 N -> S (in Ref. 4; AAK20831).
FT TURN 1059 1062
FT HELIX 1063 1070
FT HELIX 1074 1094
FT HELIX 1095 1097
FT HELIX 1100 1107
SQ SEQUENCE 1192 AA; 129931 MW; CDE239BBF31589CA CRC64;
MEDLDQSPLV SSSDSPPRPQ PAFKYQFVRE PEDEEEEEEE EEEDEDEDLE ELEVLERKPA
AGLSAAPVPT APAAGAPLMD FGNDFVPPAP RGPLPAAPPV APERQPSWDP SPVSSTVPAP
SPLSAAAVSP SKLPEDDEPP ARPPPPPPAS VSPQAEPVWT PPAPAPAAPP STPAAPKRRG
SSGSVDETLF ALPAASEPVI RSSAENMDLK EQPGNTISAG QEDFPSVLLE TAASLPSLSP
LSAASFKEHE YLGNLSTVLP TEGTLQENVS EASKEVSEKA KTLLIDRDLT EFSELEYSEM
GSSFSVSPKA ESAVIVANPR EEIIVKNKDE EEKLVSNNIL HNQQELPTAL TKLVKEDEVV
SSEKAKDSFN EKRVAVEAPM REEYADFKPF ERVWEVKDSK EDSDMLAAGG KIESNLESKV
DKKCFADSLE QTNHEKDSES SNDDTSFPST PEGIKDRSGA YITCAPFNPA ATESIATNIF
PLLGDPTSEN KTDEKKIEEK KAQIVTEKNT STKTSNPFLV AAQDSETDYV TTDNLTKVTE
EVVANMPEGL TPDLVQEACE SELNEVTGTK IAYETKMDLV QTSEVMQESL YPAAQLCPSF
EESEATPSPV LPDIVMEAPL NSAVPSAGAS VIQPSSSPLE ASSVNYESIK HEPENPPPYE
EAMSVSLKKV SGIKEEIKEP ENINAALQET EAPYISIACD LIKETKLSAE PAPDFSDYSE
MAKVEQPVPD HSELVEDSSP DSEPVDLFSD DSIPDVPQKQ DETVMLVKES LTETSFESMI
EYENKEKLSA LPPEGGKPYL ESFKLSLDNT KDTLLPDEVS TLSKKEKIPL QMEELSTAVY
SNDDLFISKE AQIRETETFS DSSPIEIIDE FPTLISSKTD SFSKLAREYT DLEVSHKSEI
ANAPDGAGSL PCTELPHDLS LKNIQPKVEE KISFSDDFSK NGSATSKVLL LPPDVSALAT
QAEIESIVKP KVLVKEAEKK LPSDTEKEDR SPSAIFSAEL SKTSVVDLLY WRDIKKTGVV
FGASLFLLLS LTVFSIVSVT AYIALALLSV TISFRIYKGV IQAIQKSDEG HPFRAYLESE
VAISEELVQK YSNSALGHVN CTIKELRRLF LVDDLVDSLK FAVLMWVFTY VGALFNGLTL
LILALISLFS VPVIYERHQA QIDHYLGLAN KNVKDAMAKI QAKIPGLKRK AE
//
MIM
604475
*RECORD*
*FIELD* NO
604475
*FIELD* TI
*604475 RETICULON 4; RTN4
;;NEURITE OUTGROWTH INHIBITOR; NOGO
NOGOA, INCLUDED;;
NOGOB, INCLUDED;;
read moreNOGOC, INCLUDED;;
NEURITE GROWTH INHIBITOR 220, INCLUDED; NI220, INCLUDED;;
NI220/250, INCLUDED
*FIELD* TX
DESCRIPTION
Adult mammalian axon regeneration is generally successful in the
peripheral nervous system but poor in the central nervous system.
Inhibition results from physical barriers imposed by glial scars, a lack
of neurotrophic factors, and growth-inhibitory molecules associated with
myelin, the insulating axon sheath. These molecules include NI35,
myelin-associated glycoprotein (159460), and Nogo.
CLONING
Spillmann et al. (1998) identified and purified Nogo, a novel
myelin-associated neurite growth inhibitory protein, from bovine spinal
cord. They referred to Nogo as NI220 in reference to its neurite growth
inhibitory activity and molecular weight.
As part of the Kazusa DNA Research Institute effort to sequence random
high molecular weight human brain-derived cDNAs, Nagase et al. (1998)
isolated a 4.1-kb cDNA clone (KIAA0886) encoding a protein of molecular
mass 135,000 that matched all 6 of the peptide sequences derived from
bovine Nogo.
Prinjha et al. (2000) cloned human NOGO cDNAs encoding 3 splice
variants. The longest cDNA, designated NOGOA, has an open reading frame
of 1,192 amino acids. An intermediate-length splice variant, designated
NOGOB, lacks residues 186 to 1004, in the putative extracellular domain.
The shortest splice variant, NOGOC, had been described as rat vp20 and
foocen-s. NOGOC also lacks residues 186 to 1004 and has a smaller,
alternative N-terminal domain. The N-terminal region of NOGO showed no
significant homology to any known protein, whereas the C-terminal region
was found to share significant homology with neuroendocrine-specific
proteins and other members of the reticulon gene family. Prinjha et al.
(2000) suggested that NOGO may be a membrane-associated protein
consisting of a putative large extracellular domain of 1,024 residues
with 7 predicted N-linked glycosylation sites, 2 or 3 transmembrane
domains, and a short C-terminal region of 43 residues. Prinjha et al.
(2000) developed a soluble version of NOGOA with a relative molecular
mass of 220 kD and found it to be a dose-dependent inhibitor of nerve
growth.
GrandPre et al. (2000) independently identified NOGO as a member of the
reticulon family and designated it reticulon-4A. NOGO is expressed by
oligodendrocytes but not by Schwann cells, and associates primarily with
the endoplasmic reticulum (ER). A 66-residue luminal/extracellular
domain inhibits axonal extension and collapses dorsal root ganglion
growth cones. In contrast to NOGO, neither reticulon-1 (600865) nor
reticulon-3 (604249) are expressed by oligodendrocytes, and the
luminal/extracellular domains from reticulon-1, -2 (603183), and -3 do
not inhibit axonal regeneration. GrandPre et al. (2000) suggested that
their data provided a molecular basis to assess the contribution of NOGO
to the failure of axonal regeneration in the adult central nervous
system.
Chen et al. (2000) cloned the rat Nogo cDNA and found 3 isoforms within
that species. Antibodies against rat NOGOA were found to stain central
nervous system myelin and oligodendrocytes and allow dorsal root
ganglion neurites to grow on central nervous system myelin and into
optic nerve explants. Chen et al. (2000) concluded that NOGOA is a
potent inhibitor of neurite growth and an IN-1 antigen produced by
oligodendrocytes, and suggested that their data may allow the generation
of new reagents to enhance central nervous system regeneration and
plasticity.
GENE FUNCTION
The IN-1 antibody recognizes NI35 and NI250-NOGO and allows moderate
degrees of axonal regeneration and functional recovery after spinal cord
injury. NOGOB, with a relative mass of 37 kD, may correspond to NI35 and
explain the antigenic relatedness of the NI35 and NI250 axon
outgrowth-inhibiting activity. GrandPre et al. (2000) generated an
antiserum directed against the C-terminal luminal/extracellular domain
of NOGO. The antibody detected a low level of surface expression, and a
Myc epitope at the N or C terminus of expressed NOGO was not detected
unless the cells were permeabilized. These data supported a topographic
model wherein the N and C termini of the NOGO protein reside in the
cytoplasm and 66 residues of the protein protrude on the luminal or
extracellular side of the ER or plasma membrane, respectively. Northern
blot analysis of NOGO expression using a probe derived from the 5-prime
NOGOA/B-specific region detected a single band of 4.1 kb in rat optic
nerve but not in sciatic nerve samples, consistent with NOGO functioning
as a central nervous system myelin-specific axon outgrowth inhibitor.
Northern blot analysis with a probe derived from the 3-prime common
region showed that the optic nerve expresses high levels of NOGOA mRNA
and much lower levels of NOGOB and NOGOC. Within the reticulon family,
optic nerve expression appears to be selective for NOGO with no
detectable expression of reticulon-1 or reticulon-3. Reticulon-2 was not
examined.
NOGO has been identified as a component of the central nervous system
myelin that prevents axonal regeneration in the adult vertebrate central
nervous system. Analysis of NOGOA has shown that an axon-inhibiting
domain of 66 amino acids is expressed at the extracellular surface and
at the ER lumen of transfected cells and oligodendrocytes. The acidic
amino terminus of NOGOA is detected at the cytosolic face of cellular
membranes and may contribute to inhibition of axon regeneration at sites
of oligodendrocyte injury. Fournier et al. (2001) showed that the
extracellular domain of NOGO (NOGO-66) inhibits axonal extension but
does not alter nonneuronal cell morphology. In contrast, a multivalent
form of the N terminus of NOGOA affects the morphology of both neurons
and other cell types. Fournier et al. (2001) identified a
brain-specific, leucine-rich-repeat protein with high affinity for
soluble NOGO-66. Cleavage of the NOGO-66 receptor (NGR; 605566) and
other glycosylphosphatidylinositol-linked proteins from axonal surfaces
renders neurons insensitive to NOGO-66. NOGO-66 receptor expression is
sufficient to impart NOGO-66 axonal inhibition to unresponsive neurons.
Disruption of the interaction between NOGO-66 and its receptor provides
the potential for enhanced recovery after human central nervous system
injury.
GrandPre et al. (2002) identified competitive antagonists of the NOGO
receptor derived from amino-terminal peptide fragments of NOGO-66. The
NOGO-66(1-40) antagonist peptide blocks NOGO-66 or central nervous
system myelin inhibition of axonal outgrowth in vitro, demonstrating
that the NOGO receptor mediates a significant portion of axonal
outgrowth inhibition by myelin. Intrathecal administration of the
amino-terminal antagonist peptide to rats with midthoracic spinal cord
hemisection resulted in significant axon outgrowth of the corticospinal
tract, and improved functional recovery. Thus, GrandPre et al. (2002)
concluded that NOGO-66 and the NOGO receptor have central roles in
limiting axonal regeneration after central nervous system injury.
Axonal regeneration in the adult central nervous system (CNS) is limited
by 2 proteins in myelin, NOGO and myelin-associated glycoprotein (MAG;
159460). The receptor for Nogo (NgR) had been identified as an axonal
glycosylphosphatidylinositol (GPI)-anchored protein, whereas the MAG
receptor had remained elusive. Liu et al. (2002) demonstrated that MAG
binds directly, with high affinity, to NgR. Cleavage of GPI-linked
proteins from axons protects growth cones from MAG-induced collapse, and
dominant-negative NgR eliminates MAG inhibition of neurite outgrowth.
MAG-resistant embryonic neurons were rendered MAG-sensitive by
expression of NgR. MAG and NOGO-66 activate NgR independently and serve
as redundant NgR ligands that may limit axonal regeneration after CNS
injury.
Using a proteomic screen for proteins enriched in caveolin-1
(601047)-containing, cholesterol-rich, buoyant membrane microdomains
(CEM/LR), Acevedo et al. (2004) found that NOGOB is enriched in intact
blood vessels, smooth muscle cells, and endothelial cells, with its N
terminus oriented extracellularly. In vitro, NOGOB promoted vascular
cell adhesion and endothelial cell migration, but inhibited the
migration of vascular smooth muscle cells, all of which are processes
necessary for vascular remodeling. Vascular injury in Nogoa/b-deficient
mice resulted in exaggerated neointimal proliferation and, in some
cases, vascular occlusion; adenoviral-mediated Nogob gene transfer
rescued the abnormal vascular expansion in the knockout mice. Acevedo et
al. (2004) concluded that NOGOB is a regulator of vascular homeostasis
and remodeling.
Jokic et al. (2005) found that increased levels of NOGOA and NOGOB in
muscle biopsies from 15 patients with amyotrophic lateral sclerosis
(ALS; 105400) correlated with clinical disability and with the degree of
muscle fiber atrophy. NOGOA was detected selectively in atrophic
slow-twitch type I fibers. Jokic et al. (2005) suggested that muscle
NOGO expression could be a marker for ALS disease severity.
Miao et al. (2006) found that the N-terminal domain of NOGOB induced
chemotaxis in human umbilical vein endothelial cells (HUVECs). By
screening a heart cDNAs expression library for genes that supported
chemotaxis following transfection in COS or CHO cells, they identified
NOGOB receptor (NGBR; 610463). NOGOB and NGBR colocalized during
angiogenesis induced by VEGF (192240) and wound healing in vivo. NOGOB
and NGBR mediated chemotaxis in HUVECs and induced tube formation in
3-dimensional cultures.
Using an in vitro system to identify Xenopus membrane proteins involved
in ER network formation, followed by localization, overexpression, and
deletion experiments in mammalian and yeast cells, Voeltz et al. (2006)
identified the reticulons, particularly Rtn4a/NogoA, and the
reticulon-interacting protein DP1/Yop1 (REEP5; 125265) as the major
components shaping the tubular ER.
Pradat et al. (2007) found muscle NOGOA expression in 17 of 33 patients
with spinal lower motor neuron syndrome observed for 12 months. NOGOA
expression correctly identified patients who further progressed to ALS
with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was
detected as early as 3 months after symptom onset in patients who later
developed typical ALS. Tagerud et al. (2007) and Askanas et al. (2007)
both commented that studies have demonstrated that NOGOA expression is
increased in denervated muscles in mouse models and in other human
neuropathies and myopathies. Both groups suggested that it may be
premature to consider NOGOA muscle expression as a specific biomarker
for ALS, as suggested by Pradat et al. (2007).
Using expression cloning, Atwal et al. (2008) found that paired
immunoglobulin-like receptor B (PIRB; 604820), which had been implicated
in nervous system plasticity, is a high-affinity receptor for NOGO, MAG
(159460), and OMGP (164345). Interfering with PIRB activity, either with
antibodies or genetically, partially rescued neurite inhibition by
NOGO66, MAG, OMGP, and myelin in cultured neurons. Blocking both PIRB
and NGR activities led to near-complete release from myelin inhibition.
Atwal et al. (2008) concluded that their results implicated PIRB in
mediating regeneration block, identified PIRB as a potential target for
axon regeneration therapies, and provided an explanation for the similar
enhancements of visual system plasticity in PIRB and NGR knockout mice.
GENE STRUCTURE
Zheng et al. (2003) determined that the mouse Rtn4 gene contains 10
exons and spans more than 50 kb. The first 4 exons are alternatively
spliced to generate Nogo transcripts A, B, and C, whereas the last 6
exons are common to all 3 variants.
MAPPING
By radiation hybrid analysis, Nagase et al. (1998) mapped the NOGO gene
to chromosome 2. By the same method, Yang et al. (2000) localized the
gene to 2p14-p13.
ANIMAL MODEL
Kim et al. (2003) disrupted expression of Nogoa and Nogob, but not
Nogoc, in mice. Brain size and gross anatomy were normal in adult
homozygous mutants. Nogoa/Nogob-null mice showed no developmental
abnormalities, and neurologic exam and locomotor analysis found no
deficits. Unlike wildtype myelin, myelin lacking Nogoa and Nogob did not
inhibit axonal outgrowth of dorsal root ganglion cells in culture.
Axonal regeneration following hemisection of the descending
corticospinal tract (CST) was prominent in a majority of
Nogoa/Nogob-null mice, and their locomotor recovery was enhanced over
control animals. Simonen et al. (2003) found similar results following
disruption of Nogoa expression in mice.
Zheng et al. (2003) reported that myelin from Nogoa/Nogob-null mice
showed reduced inhibition of neurite outgrowth, but Nogoa/Nogob deletion
had no effect on CST axon regeneration following hemisection. There was
no difference between mutant and wildtype animals in functional recovery
following injury. Zheng et al. (2003) found that disruption of 3-prime
exons common to Nogoa, Nogob, and Nogoc resulted in a high degree of
embryonic lethality. Nogoa/Nogob/Nogoc-null mice derived from a
surviving male also lacked enhanced axonal regeneration.
Using an experimental autoimmune encephalomyelitis (EAE) mouse model for
multiple sclerosis (MS; 126200), Karnezis et al. (2004) showed that both
active and passive immunization against Nogoa suppressed clinical signs,
demyelination, and axonal damage associated with the disease. The mice
that were vaccinated or infused with a Nogoa antibody had delayed
disease onset, a decrease in pathologic inflammatory lesions, and a
shift in cytokine balance. Karnezis et al. (2004) concluded that
specific blockade of NOGOA may aid in maintaining neuronal integrity in
the CNS in certain neurodegenerative diseases.
Liebscher et al. (2005) found that intrathecal administration of
anti-Nogaa monoclonal IgG antibodies to rats with spinal cord injuries
resulted in improvement in motor behavior and enhanced regeneration of
corticospinal axons compared to control animals. In addition, functional
MRI studies indicated enhanced somatosensory cortical responses to
stimulation of the hind paw in animals that received antibodies.
Liebscher et al. (2005) hypothesized that Nogoa antibodies enhanced the
lesion-induced growth response of axotomized neurons in the injured CNS
and induced growth in noninjured neurons.
In mice with EAE, Yang et al. (2010) found that inhibition of Nogoa
using small interfering RNA (siRNA) resulted in suppression of Nogoa
expression and functional neurologic recovery. Myelin-specific T-cell
proliferation and cytokine production were unchanged, and the response
was determined to result from increased axonal repair, as demonstrated
by enhanced GAP43 (162060)-positive axons in the lesions. Of note, mice
given the treatment at the time of disease onset showed a better
response than those given treatment at the time of disease induction,
indicating that a compromised blood-brain barrier was necessary for the
siRNA to gain access to the central nervous system. The findings
indicated that inhibition of NogoA can promote neuronal repair and
functional recovery in a mouse model of MS.
*FIELD* RF
1. Acevedo, L.; Yu, J.; Erdjument-Bromage, H.; Miao, R. Q.; Kim, J.-E.;
Fulton, D.; Tempst, P.; Strittmatter, S. M.; Sessa, W. C.: A new
role for Nogo as a regulator of vascular remodeling. Nature Med. 10:
382-388, 2004.
2. Askanas, V.; Wojcik, S.; Engel, W. K.: Expression of Nogo-A in
human muscle fibers is not specific for amyotrophic lateral sclerosis.
(Letter) Ann. Neurol. 62: 676-677, 2007.
3. Atwal, J. K.; Pinkston-Gosse, J.; Syken, J.; Stawicki, S.; Wu,
J.; Shatz, C.; Tessier-Lavigne, M.: PirB is a functional receptor
for myelin inhibitors of axonal regeneration. Science 322: 967-970,
2008.
4. Chen, M. S.; Huber, A. B.; van der Haar, M. E.; Frank, M.; Schnell,
L.; Spillmann, A. A.; Christ, F.; Schwab, M. E.: Nogo-A is a myelin-associated
neurite outgrowth inhibitor and an antigen for monoclonal antibody
IN-1. Nature 403: 434-439, 2000.
5. Fournier, A. E.; GrandPre, T.; Strittmatter, S. M.: Identification
of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409:
341-346, 2001.
6. GrandPre, T.; Li, S.; Strittmatter, S. M.: Nogo-66 receptor antagonist
peptide promotes axonal regeneration. Nature 417: 547-551, 2002.
7. GrandPre, T.; Nakamura, F.; Vartanian, T.; Strittmatter, S. M.
: Identification of the Nogo inhibitor of axon regeneration as a reticulon
protein. Nature 403: 439-444, 2000.
8. Jokic, N.; Gonzalez de Aguilar, J.-L.; Pradat, P.-F.; Dupuis, L.;
Echaniz-Laguna, A.; Muller, A.; Dubourg, O.; Seilhean, D.; Hauw, J.-J.;
Loeffler, J.-P.; Meininger, V.: Nogo expression in muscle correlates
with amyotrophic lateral sclerosis severity. Ann. Neurol. 57: 553-556,
2005.
9. Karnezis, T.; Mandemakers, W.; McQualter, J. L.; Zheng, B.; Ho,
P. P.; Jordan, K. A.; Murray, B. M.; Barres, B.; Tessier-Lavigne,
M.; Bernard, C. C. A.: The neurite outgrowth inhibitor Nogo A is
involved in autoimmune-mediated demyelination. Nature Neurosci. 7:
736-744, 2004.
10. Kim, J.-E.; Li, S.; GrandPre, T.; Qiu, D.; Strittmatter, S. M.
: Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38:
187-199, 2003.
11. Liebscher, T.; Schnell, L.; Schnell, D.; Scholl, J.; Schneider,
R.; Gullo, M.; Fouad, K.; Mir, A.; Rausch, M.; Kindler, D.; Hamers,
F. P. T.; Schwab, M. E.: Nogo-A antibody improves regeneration and
locomotion of spinal cord-injured rats. Ann. Neurol. 58: 706-719,
2005.
12. Liu, B. P.; Fournier, A.; GrandPre, T.; Strittmatter, S. M.:
Myelin-associated glycoprotein as a functional ligand for the Nogo-66
receptor. Science 297: 1190-1193, 2002.
13. Miao, R. Q.; Gao, Y.; Harrison, K. D.; Prendergast, J.; Acevedo,
L. M.; Yu, J.; Hu, F.; Strittmatter, S. M.; Sessa, W. C.: Identification
of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis
of endothelial cells. Proc. Nat. Acad. Sci. 103: 10997-11002, 2006.
14. Nagase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;
Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Oharo, O.: Prediction
of the coding sequences of unidentified human genes. XII. The complete
sequences of 100 new cDNA clones from brain which code for large proteins
in vitro. DNA Res. 5: 355-364, 1998.
15. Pradat, P.-F.; Bruneteau, G.; Gonzalez de Aguilar, J.-L.; Dupuis,
L.; Jokic, N.; Salachas, F.; Le Forestier, N.; Echaniz-Laguna, A.;
Dubourg, O.; Hauw, J.-J.; Tranchant, C.; Loeffler, J.-P.; Meininger,
V.: Muscle Nogo-A expression is a prognostic marker in lower motor
neuron syndromes. Ann. Neurol. 62: 15-20, 2007.
16. Prinjha, R.; Moore, S. E.; Vinson, M.; Blake, S.; Morrow, R.;
Christie, G.; Michalovich, D.; Simmons, D. L.; Walsh, F. S.: Inhibitor
of neurite outgrowth in humans. (Letter) Nature 403: 383-384, 2000.
17. Simonen, M.; Pedersen, V.; Weinmann, O.; Schnell, L.; Buss, A.;
Ledermann, B.; Christ, F.; Sansig, G.; van der Putten, H.; Schwab,
M. E.: Systemic deletion of the myelin-associated outgrowth inhibitor
Nogo-A improves regenerative and plastic responses after spinal cord
injury. Neuron 38: 201-211, 2003.
18. Spillmann, A. A.; Bandtlow, C. E.; Lottspeich, F.; Keller, F.;
Schwab, M. E.: Identification and characterization of a bovine neurite
growth inhibitor (bNI-220). J. Biol. Chem. 273: 19283-19293, 1998.
19. Tagerud, S.; Libelius, R.; Magnusson, C.: Muscle Nogo-A: a marker
for amyotrophic lateral sclerosis or for denervation? (Letter) Ann.
Neurol. 62: 676 only, 2007.
20. Voeltz, G. K.; Prinz, W. A.; Shibata, Y.; Rist, J. M.; Rapoport,
T. A.: A class of membrane proteins shaping the tubular endoplasmic
reticulum. Cell 573-586, 2006.
21. Yang, J.; Yu, L.; Bi, A. D.; Zhao, S.-Y.: Assignment of the human
reticulon 4 gene (RTN4) to chromosome 2p14-2p13 by radiation hybrid
mapping. Cytogenet. Cell Genet. 88: 101-102, 2000.
22. Yang, Y.; Liu, Y.; Wei, P.; Peng, H.; Winger, R.; Hussain, R.
Z.; Ben, L.-H.; Cravens, P. D.; Gocke, A. R.; Puttaparthi, K.; Racke,
M. K.; McTigue, D. M.; Lovett-Racke, A. E.: Silencing Nogo-A promotes
functional recovery in demyelinating disease. Ann. Neurol. 67: 498-507,
2010.
23. Zheng, B.; Ho, C.; Li, S.; Keirstead, H.; Steward, O.; Tessier-Lavigne,
M.: Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38:
213-224, 2003.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/25/2010
Matthew B. Gross - updated: 5/21/2009
Ada Hamosh - updated: 12/30/2008
Cassandra L. Kniffin - updated: 3/14/2008
Cassandra L. Kniffin - updated: 1/7/2008
Patricia A. Hartz - updated: 10/5/2006
Cassandra L. Kniffin - updated: 3/6/2006
Patricia A. Hartz - updated: 8/4/2005
Cassandra L. Kniffin -updated: 5/12/2005
Cassandra L. Kniffin - updated: 7/23/2004
Cassandra L. Kniffin - updated: 3/24/2004
Ada Hamosh - updated: 9/18/2002
Ada Hamosh - updated: 5/28/2002
Ada Hamosh - updated: 1/19/2001
Carol A. Bocchini - updated: 11/29/2000
Ada Hamosh - updated: 2/1/2000
*FIELD* CD
Ada Hamosh: 1/28/2000
*FIELD* ED
terry: 09/09/2010
wwang: 7/6/2010
ckniffin: 6/25/2010
wwang: 5/28/2009
mgross: 5/21/2009
alopez: 1/5/2009
terry: 12/30/2008
wwang: 4/1/2008
ckniffin: 3/14/2008
wwang: 1/18/2008
ckniffin: 1/7/2008
mgross: 1/18/2007
mgross: 10/5/2006
terry: 7/26/2006
wwang: 3/13/2006
ckniffin: 3/6/2006
mgross: 8/4/2005
wwang: 5/27/2005
ckniffin: 5/12/2005
tkritzer: 7/29/2004
ckniffin: 7/23/2004
alopez: 4/2/2004
tkritzer: 3/25/2004
ckniffin: 3/24/2004
alopez: 9/20/2002
tkritzer: 9/18/2002
alopez: 5/29/2002
terry: 5/28/2002
terry: 3/21/2001
carol: 1/19/2001
terry: 1/19/2001
carol: 11/29/2000
alopez: 2/1/2000
alopez: 1/28/2000
*RECORD*
*FIELD* NO
604475
*FIELD* TI
*604475 RETICULON 4; RTN4
;;NEURITE OUTGROWTH INHIBITOR; NOGO
NOGOA, INCLUDED;;
NOGOB, INCLUDED;;
read moreNOGOC, INCLUDED;;
NEURITE GROWTH INHIBITOR 220, INCLUDED; NI220, INCLUDED;;
NI220/250, INCLUDED
*FIELD* TX
DESCRIPTION
Adult mammalian axon regeneration is generally successful in the
peripheral nervous system but poor in the central nervous system.
Inhibition results from physical barriers imposed by glial scars, a lack
of neurotrophic factors, and growth-inhibitory molecules associated with
myelin, the insulating axon sheath. These molecules include NI35,
myelin-associated glycoprotein (159460), and Nogo.
CLONING
Spillmann et al. (1998) identified and purified Nogo, a novel
myelin-associated neurite growth inhibitory protein, from bovine spinal
cord. They referred to Nogo as NI220 in reference to its neurite growth
inhibitory activity and molecular weight.
As part of the Kazusa DNA Research Institute effort to sequence random
high molecular weight human brain-derived cDNAs, Nagase et al. (1998)
isolated a 4.1-kb cDNA clone (KIAA0886) encoding a protein of molecular
mass 135,000 that matched all 6 of the peptide sequences derived from
bovine Nogo.
Prinjha et al. (2000) cloned human NOGO cDNAs encoding 3 splice
variants. The longest cDNA, designated NOGOA, has an open reading frame
of 1,192 amino acids. An intermediate-length splice variant, designated
NOGOB, lacks residues 186 to 1004, in the putative extracellular domain.
The shortest splice variant, NOGOC, had been described as rat vp20 and
foocen-s. NOGOC also lacks residues 186 to 1004 and has a smaller,
alternative N-terminal domain. The N-terminal region of NOGO showed no
significant homology to any known protein, whereas the C-terminal region
was found to share significant homology with neuroendocrine-specific
proteins and other members of the reticulon gene family. Prinjha et al.
(2000) suggested that NOGO may be a membrane-associated protein
consisting of a putative large extracellular domain of 1,024 residues
with 7 predicted N-linked glycosylation sites, 2 or 3 transmembrane
domains, and a short C-terminal region of 43 residues. Prinjha et al.
(2000) developed a soluble version of NOGOA with a relative molecular
mass of 220 kD and found it to be a dose-dependent inhibitor of nerve
growth.
GrandPre et al. (2000) independently identified NOGO as a member of the
reticulon family and designated it reticulon-4A. NOGO is expressed by
oligodendrocytes but not by Schwann cells, and associates primarily with
the endoplasmic reticulum (ER). A 66-residue luminal/extracellular
domain inhibits axonal extension and collapses dorsal root ganglion
growth cones. In contrast to NOGO, neither reticulon-1 (600865) nor
reticulon-3 (604249) are expressed by oligodendrocytes, and the
luminal/extracellular domains from reticulon-1, -2 (603183), and -3 do
not inhibit axonal regeneration. GrandPre et al. (2000) suggested that
their data provided a molecular basis to assess the contribution of NOGO
to the failure of axonal regeneration in the adult central nervous
system.
Chen et al. (2000) cloned the rat Nogo cDNA and found 3 isoforms within
that species. Antibodies against rat NOGOA were found to stain central
nervous system myelin and oligodendrocytes and allow dorsal root
ganglion neurites to grow on central nervous system myelin and into
optic nerve explants. Chen et al. (2000) concluded that NOGOA is a
potent inhibitor of neurite growth and an IN-1 antigen produced by
oligodendrocytes, and suggested that their data may allow the generation
of new reagents to enhance central nervous system regeneration and
plasticity.
GENE FUNCTION
The IN-1 antibody recognizes NI35 and NI250-NOGO and allows moderate
degrees of axonal regeneration and functional recovery after spinal cord
injury. NOGOB, with a relative mass of 37 kD, may correspond to NI35 and
explain the antigenic relatedness of the NI35 and NI250 axon
outgrowth-inhibiting activity. GrandPre et al. (2000) generated an
antiserum directed against the C-terminal luminal/extracellular domain
of NOGO. The antibody detected a low level of surface expression, and a
Myc epitope at the N or C terminus of expressed NOGO was not detected
unless the cells were permeabilized. These data supported a topographic
model wherein the N and C termini of the NOGO protein reside in the
cytoplasm and 66 residues of the protein protrude on the luminal or
extracellular side of the ER or plasma membrane, respectively. Northern
blot analysis of NOGO expression using a probe derived from the 5-prime
NOGOA/B-specific region detected a single band of 4.1 kb in rat optic
nerve but not in sciatic nerve samples, consistent with NOGO functioning
as a central nervous system myelin-specific axon outgrowth inhibitor.
Northern blot analysis with a probe derived from the 3-prime common
region showed that the optic nerve expresses high levels of NOGOA mRNA
and much lower levels of NOGOB and NOGOC. Within the reticulon family,
optic nerve expression appears to be selective for NOGO with no
detectable expression of reticulon-1 or reticulon-3. Reticulon-2 was not
examined.
NOGO has been identified as a component of the central nervous system
myelin that prevents axonal regeneration in the adult vertebrate central
nervous system. Analysis of NOGOA has shown that an axon-inhibiting
domain of 66 amino acids is expressed at the extracellular surface and
at the ER lumen of transfected cells and oligodendrocytes. The acidic
amino terminus of NOGOA is detected at the cytosolic face of cellular
membranes and may contribute to inhibition of axon regeneration at sites
of oligodendrocyte injury. Fournier et al. (2001) showed that the
extracellular domain of NOGO (NOGO-66) inhibits axonal extension but
does not alter nonneuronal cell morphology. In contrast, a multivalent
form of the N terminus of NOGOA affects the morphology of both neurons
and other cell types. Fournier et al. (2001) identified a
brain-specific, leucine-rich-repeat protein with high affinity for
soluble NOGO-66. Cleavage of the NOGO-66 receptor (NGR; 605566) and
other glycosylphosphatidylinositol-linked proteins from axonal surfaces
renders neurons insensitive to NOGO-66. NOGO-66 receptor expression is
sufficient to impart NOGO-66 axonal inhibition to unresponsive neurons.
Disruption of the interaction between NOGO-66 and its receptor provides
the potential for enhanced recovery after human central nervous system
injury.
GrandPre et al. (2002) identified competitive antagonists of the NOGO
receptor derived from amino-terminal peptide fragments of NOGO-66. The
NOGO-66(1-40) antagonist peptide blocks NOGO-66 or central nervous
system myelin inhibition of axonal outgrowth in vitro, demonstrating
that the NOGO receptor mediates a significant portion of axonal
outgrowth inhibition by myelin. Intrathecal administration of the
amino-terminal antagonist peptide to rats with midthoracic spinal cord
hemisection resulted in significant axon outgrowth of the corticospinal
tract, and improved functional recovery. Thus, GrandPre et al. (2002)
concluded that NOGO-66 and the NOGO receptor have central roles in
limiting axonal regeneration after central nervous system injury.
Axonal regeneration in the adult central nervous system (CNS) is limited
by 2 proteins in myelin, NOGO and myelin-associated glycoprotein (MAG;
159460). The receptor for Nogo (NgR) had been identified as an axonal
glycosylphosphatidylinositol (GPI)-anchored protein, whereas the MAG
receptor had remained elusive. Liu et al. (2002) demonstrated that MAG
binds directly, with high affinity, to NgR. Cleavage of GPI-linked
proteins from axons protects growth cones from MAG-induced collapse, and
dominant-negative NgR eliminates MAG inhibition of neurite outgrowth.
MAG-resistant embryonic neurons were rendered MAG-sensitive by
expression of NgR. MAG and NOGO-66 activate NgR independently and serve
as redundant NgR ligands that may limit axonal regeneration after CNS
injury.
Using a proteomic screen for proteins enriched in caveolin-1
(601047)-containing, cholesterol-rich, buoyant membrane microdomains
(CEM/LR), Acevedo et al. (2004) found that NOGOB is enriched in intact
blood vessels, smooth muscle cells, and endothelial cells, with its N
terminus oriented extracellularly. In vitro, NOGOB promoted vascular
cell adhesion and endothelial cell migration, but inhibited the
migration of vascular smooth muscle cells, all of which are processes
necessary for vascular remodeling. Vascular injury in Nogoa/b-deficient
mice resulted in exaggerated neointimal proliferation and, in some
cases, vascular occlusion; adenoviral-mediated Nogob gene transfer
rescued the abnormal vascular expansion in the knockout mice. Acevedo et
al. (2004) concluded that NOGOB is a regulator of vascular homeostasis
and remodeling.
Jokic et al. (2005) found that increased levels of NOGOA and NOGOB in
muscle biopsies from 15 patients with amyotrophic lateral sclerosis
(ALS; 105400) correlated with clinical disability and with the degree of
muscle fiber atrophy. NOGOA was detected selectively in atrophic
slow-twitch type I fibers. Jokic et al. (2005) suggested that muscle
NOGO expression could be a marker for ALS disease severity.
Miao et al. (2006) found that the N-terminal domain of NOGOB induced
chemotaxis in human umbilical vein endothelial cells (HUVECs). By
screening a heart cDNAs expression library for genes that supported
chemotaxis following transfection in COS or CHO cells, they identified
NOGOB receptor (NGBR; 610463). NOGOB and NGBR colocalized during
angiogenesis induced by VEGF (192240) and wound healing in vivo. NOGOB
and NGBR mediated chemotaxis in HUVECs and induced tube formation in
3-dimensional cultures.
Using an in vitro system to identify Xenopus membrane proteins involved
in ER network formation, followed by localization, overexpression, and
deletion experiments in mammalian and yeast cells, Voeltz et al. (2006)
identified the reticulons, particularly Rtn4a/NogoA, and the
reticulon-interacting protein DP1/Yop1 (REEP5; 125265) as the major
components shaping the tubular ER.
Pradat et al. (2007) found muscle NOGOA expression in 17 of 33 patients
with spinal lower motor neuron syndrome observed for 12 months. NOGOA
expression correctly identified patients who further progressed to ALS
with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was
detected as early as 3 months after symptom onset in patients who later
developed typical ALS. Tagerud et al. (2007) and Askanas et al. (2007)
both commented that studies have demonstrated that NOGOA expression is
increased in denervated muscles in mouse models and in other human
neuropathies and myopathies. Both groups suggested that it may be
premature to consider NOGOA muscle expression as a specific biomarker
for ALS, as suggested by Pradat et al. (2007).
Using expression cloning, Atwal et al. (2008) found that paired
immunoglobulin-like receptor B (PIRB; 604820), which had been implicated
in nervous system plasticity, is a high-affinity receptor for NOGO, MAG
(159460), and OMGP (164345). Interfering with PIRB activity, either with
antibodies or genetically, partially rescued neurite inhibition by
NOGO66, MAG, OMGP, and myelin in cultured neurons. Blocking both PIRB
and NGR activities led to near-complete release from myelin inhibition.
Atwal et al. (2008) concluded that their results implicated PIRB in
mediating regeneration block, identified PIRB as a potential target for
axon regeneration therapies, and provided an explanation for the similar
enhancements of visual system plasticity in PIRB and NGR knockout mice.
GENE STRUCTURE
Zheng et al. (2003) determined that the mouse Rtn4 gene contains 10
exons and spans more than 50 kb. The first 4 exons are alternatively
spliced to generate Nogo transcripts A, B, and C, whereas the last 6
exons are common to all 3 variants.
MAPPING
By radiation hybrid analysis, Nagase et al. (1998) mapped the NOGO gene
to chromosome 2. By the same method, Yang et al. (2000) localized the
gene to 2p14-p13.
ANIMAL MODEL
Kim et al. (2003) disrupted expression of Nogoa and Nogob, but not
Nogoc, in mice. Brain size and gross anatomy were normal in adult
homozygous mutants. Nogoa/Nogob-null mice showed no developmental
abnormalities, and neurologic exam and locomotor analysis found no
deficits. Unlike wildtype myelin, myelin lacking Nogoa and Nogob did not
inhibit axonal outgrowth of dorsal root ganglion cells in culture.
Axonal regeneration following hemisection of the descending
corticospinal tract (CST) was prominent in a majority of
Nogoa/Nogob-null mice, and their locomotor recovery was enhanced over
control animals. Simonen et al. (2003) found similar results following
disruption of Nogoa expression in mice.
Zheng et al. (2003) reported that myelin from Nogoa/Nogob-null mice
showed reduced inhibition of neurite outgrowth, but Nogoa/Nogob deletion
had no effect on CST axon regeneration following hemisection. There was
no difference between mutant and wildtype animals in functional recovery
following injury. Zheng et al. (2003) found that disruption of 3-prime
exons common to Nogoa, Nogob, and Nogoc resulted in a high degree of
embryonic lethality. Nogoa/Nogob/Nogoc-null mice derived from a
surviving male also lacked enhanced axonal regeneration.
Using an experimental autoimmune encephalomyelitis (EAE) mouse model for
multiple sclerosis (MS; 126200), Karnezis et al. (2004) showed that both
active and passive immunization against Nogoa suppressed clinical signs,
demyelination, and axonal damage associated with the disease. The mice
that were vaccinated or infused with a Nogoa antibody had delayed
disease onset, a decrease in pathologic inflammatory lesions, and a
shift in cytokine balance. Karnezis et al. (2004) concluded that
specific blockade of NOGOA may aid in maintaining neuronal integrity in
the CNS in certain neurodegenerative diseases.
Liebscher et al. (2005) found that intrathecal administration of
anti-Nogaa monoclonal IgG antibodies to rats with spinal cord injuries
resulted in improvement in motor behavior and enhanced regeneration of
corticospinal axons compared to control animals. In addition, functional
MRI studies indicated enhanced somatosensory cortical responses to
stimulation of the hind paw in animals that received antibodies.
Liebscher et al. (2005) hypothesized that Nogoa antibodies enhanced the
lesion-induced growth response of axotomized neurons in the injured CNS
and induced growth in noninjured neurons.
In mice with EAE, Yang et al. (2010) found that inhibition of Nogoa
using small interfering RNA (siRNA) resulted in suppression of Nogoa
expression and functional neurologic recovery. Myelin-specific T-cell
proliferation and cytokine production were unchanged, and the response
was determined to result from increased axonal repair, as demonstrated
by enhanced GAP43 (162060)-positive axons in the lesions. Of note, mice
given the treatment at the time of disease onset showed a better
response than those given treatment at the time of disease induction,
indicating that a compromised blood-brain barrier was necessary for the
siRNA to gain access to the central nervous system. The findings
indicated that inhibition of NogoA can promote neuronal repair and
functional recovery in a mouse model of MS.
*FIELD* RF
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*FIELD* CN
Cassandra L. Kniffin - updated: 6/25/2010
Matthew B. Gross - updated: 5/21/2009
Ada Hamosh - updated: 12/30/2008
Cassandra L. Kniffin - updated: 3/14/2008
Cassandra L. Kniffin - updated: 1/7/2008
Patricia A. Hartz - updated: 10/5/2006
Cassandra L. Kniffin - updated: 3/6/2006
Patricia A. Hartz - updated: 8/4/2005
Cassandra L. Kniffin -updated: 5/12/2005
Cassandra L. Kniffin - updated: 7/23/2004
Cassandra L. Kniffin - updated: 3/24/2004
Ada Hamosh - updated: 9/18/2002
Ada Hamosh - updated: 5/28/2002
Ada Hamosh - updated: 1/19/2001
Carol A. Bocchini - updated: 11/29/2000
Ada Hamosh - updated: 2/1/2000
*FIELD* CD
Ada Hamosh: 1/28/2000
*FIELD* ED
terry: 09/09/2010
wwang: 7/6/2010
ckniffin: 6/25/2010
wwang: 5/28/2009
mgross: 5/21/2009
alopez: 1/5/2009
terry: 12/30/2008
wwang: 4/1/2008
ckniffin: 3/14/2008
wwang: 1/18/2008
ckniffin: 1/7/2008
mgross: 1/18/2007
mgross: 10/5/2006
terry: 7/26/2006
wwang: 3/13/2006
ckniffin: 3/6/2006
mgross: 8/4/2005
wwang: 5/27/2005
ckniffin: 5/12/2005
tkritzer: 7/29/2004
ckniffin: 7/23/2004
alopez: 4/2/2004
tkritzer: 3/25/2004
ckniffin: 3/24/2004
alopez: 9/20/2002
tkritzer: 9/18/2002
alopez: 5/29/2002
terry: 5/28/2002
terry: 3/21/2001
carol: 1/19/2001
terry: 1/19/2001
carol: 11/29/2000
alopez: 2/1/2000
alopez: 1/28/2000