Full text data of LCN2
LCN2
(HNL, NGAL)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Neutrophil gelatinase-associated lipocalin; NGAL (25 kDa alpha-2-microglobulin-related subunit of MMP-9; Lipocalin-2; Oncogene 24p3; Siderocalin LCN2; p25; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Neutrophil gelatinase-associated lipocalin; NGAL (25 kDa alpha-2-microglobulin-related subunit of MMP-9; Lipocalin-2; Oncogene 24p3; Siderocalin LCN2; p25; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P80188
ID NGAL_HUMAN Reviewed; 198 AA.
AC P80188; A6NII8; B4DWV4; B7ZAA2; P30150; Q5SYV9; Q5SYW0; Q6FGL5;
read moreAC Q92683;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 2.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=Neutrophil gelatinase-associated lipocalin;
DE Short=NGAL;
DE AltName: Full=25 kDa alpha-2-microglobulin-related subunit of MMP-9;
DE AltName: Full=Lipocalin-2;
DE AltName: Full=Oncogene 24p3;
DE AltName: Full=Siderocalin LCN2;
DE AltName: Full=p25;
DE Flags: Precursor;
GN Name=LCN2; Synonyms=HNL, NGAL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8060329; DOI=10.1006/bbrc.1994.2096;
RA Bundgaard J.R., Sengelov H., Borregaard N., Kjeldsen L.;
RT "Molecular cloning and expression of a cDNA encoding NGAL: a lipocalin
RT expressed in human neutrophils.";
RL Biochem. Biophys. Res. Commun. 202:1468-1475(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RC TISSUE=Bone marrow;
RX PubMed=9339356; DOI=10.1006/geno.1997.4896;
RA Cowland J.B., Borregaard N.;
RT "Molecular characterization and pattern of tissue expression of the
RT gene for neutrophil gelatinase-associated lipocalin from humans.";
RL Genomics 45:17-23(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Esophagus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 21-198, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=7835423; DOI=10.1016/0014-5793(94)01303-I;
RA Bartsch S., Tschesche H.;
RT "Cloning and expression of human neutrophil lipocalin cDNA derived
RT from bone marrow and ovarian cancer cells.";
RL FEBS Lett. 357:255-259(1995).
RN [9]
RP PROTEIN SEQUENCE OF 21-198.
RC TISSUE=Neutrophil;
RX PubMed=7683678;
RA Kjeldsen L., Johnsen A.H., Sengelov H., Borregaard N.;
RT "Isolation and primary structure of NGAL, a novel protein associated
RT with human neutrophil gelatinase.";
RL J. Biol. Chem. 268:10425-10432(1993).
RN [10]
RP PROTEIN SEQUENCE OF 51-61; 71-90; 132-136; 152-160 AND 178-192.
RC TISSUE=Neutrophil;
RX PubMed=1281792; DOI=10.1016/0014-5793(92)81511-J;
RA Triebel S., Blaeser J., Reinke H., Tschesche H.;
RT "A 25 kDa alpha 2-microglobulin-related protein is a component of the
RT 125 kDa form of human gelatinase.";
RL FEBS Lett. 314:386-388(1992).
RN [11]
RP FUNCTION, IRON-BINDING, SIDEROPHORE-BINDING, AND SUBCELLULAR LOCATION.
RX PubMed=12453413; DOI=10.1016/S1097-2765(02)00710-4;
RA Yang J., Goetz D., Li J.Y., Wang W., Mori K., Setlik D., Du T.,
RA Erdjument-Bromage H., Tempst P., Strong R., Barasch J.;
RT "An iron delivery pathway mediated by a lipocalin.";
RL Mol. Cell 10:1045-1056(2002).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Bile;
RX PubMed=15084671; DOI=10.1074/mcp.M400015-MCP200;
RA Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H.,
RA Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A.;
RT "A proteomic analysis of human bile.";
RL Mol. Cell. Proteomics 3:715-728(2004).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [15]
RP INDUCTION.
RX PubMed=19229297; DOI=10.1038/emboj.2009.35;
RA Sheng Z., Wang S.Z., Green M.R.;
RT "Transcription and signalling pathways involved in BCR-ABL-mediated
RT misregulation of 24p3 and 24p3R.";
RL EMBO J. 28:866-876(2009).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [17]
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 [18]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 21-298.
RX PubMed=10684642; DOI=10.1021/bi992215v;
RA Goetz D.H., Willie S.T., Armen R.S., Bratt T., Borregaard N.,
RA Strong R.K.;
RT "Ligand preference inferred from the structure of neutrophil
RT gelatinase associated lipocalin.";
RL Biochemistry 39:1935-1941(2000).
RN [19]
RP STRUCTURE BY NMR OF 21-198.
RX PubMed=10339412; DOI=10.1006/jmbi.1999.2755;
RA Coles M., Diercks T., Muehlenweg B., Bartsch S., Zolzer V.,
RA Tschesche H., Kessler H.;
RT "The solution structure and dynamics of human neutrophil gelatinase-
RT associated lipocalin.";
RL J. Mol. Biol. 289:139-157(1999).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 21-198 IN COMPLEX WITH
RP SIDEROPHORE AND IRON, AND SUBUNIT.
RX PubMed=12453412; DOI=10.1016/S1097-2765(02)00708-6;
RA Goetz D.H., Holmes M.A., Borregaard N., Bluhm M.E., Raymond K.N.,
RA Strong R.K.;
RT "The neutrophil lipocalin NGAL is a bacteriostatic agent that
RT interferes with siderophore-mediated iron acquisition.";
RL Mol. Cell 10:1033-1043(2002).
CC -!- FUNCTION: Iron-trafficking protein involved in multiple processes
CC such as apoptosis, innate immunity and renal development. Binds
CC iron through association with 2,5-dihydroxybenzoic acid (2,5-
CC DHBA), a siderophore that shares structural similarities with
CC bacterial enterobactin, and delivers or removes iron from the
CC cell, depending on the context. Iron-bound form (holo-24p3) is
CC internalized following binding to the SLC22A17 (24p3R) receptor,
CC leading to release of iron and subsequent increase of
CC intracellular iron concentration. In contrast, association of the
CC iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is
CC followed by association with an intracellular siderophore, iron
CC chelation and iron transfer to the extracellular medium, thereby
CC reducing intracellular iron concentration. Involved in apoptosis
CC due to interleukin-3 (IL3) deprivation: iron-loaded form increases
CC intracellular iron concentration without promoting apoptosis,
CC while iron-free form decreases intracellular iron levels, inducing
CC expression of the proapoptotic protein BCL2L11/BIM, resulting in
CC apoptosis. Involved in innate immunity, possibly by sequestrating
CC iron, leading to limit bacterial growth.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Heterodimer; disulfide-
CC linked with MMP9.
CC -!- SUBCELLULAR LOCATION: Secreted. Note=Upon binding to the SLC22A17
CC (24p3R) receptor, it is internalized.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P80188-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P80188-2; Sequence=VSP_039780;
CC -!- TISSUE SPECIFICITY: Expressed in bone marrow and in tissues that
CC are prone to exposure to microorganism. High expression is found
CC in bone marrow as well as in uterus, prostate, salivary gland,
CC stomach, appendix, colon, trachea and lung. Not found in the small
CC intestine or peripheral blood leukocytes.
CC -!- INDUCTION: Expression is activated by the oncoprotein BCR-ABL;
CC BCR-ABL misregulates expression via the JAK/STAT pathway and
CC binding of STAT5A to the promoter.
CC -!- SIMILARITY: Belongs to the calycin superfamily. Lipocalin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAI13824.1; Type=Erroneous gene model prediction;
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DR EMBL; X83006; CAA58127.1; -; mRNA.
DR EMBL; X99133; CAA67574.1; -; Genomic_DNA.
DR EMBL; AK301694; BAG63166.1; -; mRNA.
DR EMBL; AK316217; BAH14588.1; -; mRNA.
DR EMBL; CR542092; CAG46889.1; -; mRNA.
DR EMBL; AL590708; CAI13823.1; -; Genomic_DNA.
DR EMBL; AL590708; CAI13824.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471090; EAW87750.1; -; Genomic_DNA.
DR EMBL; BC033089; AAH33089.1; -; mRNA.
DR EMBL; S75256; AAD14168.1; -; mRNA.
DR PIR; JC2339; JC2339.
DR RefSeq; NP_005555.2; NM_005564.3.
DR UniGene; Hs.204238; -.
DR PDB; 1DFV; X-ray; 2.60 A; A/B=21-197.
DR PDB; 1L6M; X-ray; 2.40 A; A/B/C=21-198.
DR PDB; 1NGL; NMR; -; A=21-198.
DR PDB; 1QQS; X-ray; 2.40 A; A=24-197.
DR PDB; 1X71; X-ray; 2.10 A; A/B/C=21-198.
DR PDB; 1X89; X-ray; 2.10 A; A/B/C=21-198.
DR PDB; 1X8U; X-ray; 2.20 A; A/B/C=21-198.
DR PDB; 3BY0; X-ray; 2.57 A; A/B/C=1-198.
DR PDB; 3CBC; X-ray; 2.17 A; A/B/C=1-198.
DR PDB; 3CMP; X-ray; 2.80 A; A/B/C=1-198.
DR PDB; 3DSZ; X-ray; 2.00 A; A/B=21-198.
DR PDB; 3DTQ; X-ray; 2.50 A; A/B/C=21-198.
DR PDB; 3FW4; X-ray; 2.30 A; A/B/C=21-198.
DR PDB; 3FW5; X-ray; 2.30 A; A/B/C=21-198.
DR PDB; 3HWD; X-ray; 2.95 A; A/B/C=1-198.
DR PDB; 3HWE; X-ray; 2.80 A; A/B/C=1-198.
DR PDB; 3HWF; X-ray; 3.20 A; A/B/C=1-198.
DR PDB; 3HWG; X-ray; 2.19 A; A/B/C=1-198.
DR PDB; 3I0A; X-ray; 2.60 A; A/B/C=1-198.
DR PDB; 3K3L; X-ray; 2.62 A; A/B/C=21-198.
DR PDB; 3PEC; X-ray; 2.19 A; A/B/C=21-198.
DR PDB; 3PED; X-ray; 2.30 A; A/B/C=21-198.
DR PDB; 3T1D; X-ray; 2.30 A; A/B/C=1-198.
DR PDB; 3TF6; X-ray; 2.35 A; A/B/C=21-198.
DR PDB; 3TZS; X-ray; 2.45 A; A/B/C=21-198.
DR PDB; 3U03; X-ray; 2.40 A; A/C=1-198.
DR PDB; 3U0D; X-ray; 2.51 A; A/B/C/D=1-198.
DR PDB; 4GH7; X-ray; 2.60 A; A/C=21-198.
DR PDB; 4IAW; X-ray; 2.40 A; A/B/C=21-198.
DR PDB; 4IAX; X-ray; 1.90 A; A=21-198.
DR PDB; 4K19; X-ray; 2.74 A; A/B/C=21-198.
DR PDBsum; 1DFV; -.
DR PDBsum; 1L6M; -.
DR PDBsum; 1NGL; -.
DR PDBsum; 1QQS; -.
DR PDBsum; 1X71; -.
DR PDBsum; 1X89; -.
DR PDBsum; 1X8U; -.
DR PDBsum; 3BY0; -.
DR PDBsum; 3CBC; -.
DR PDBsum; 3CMP; -.
DR PDBsum; 3DSZ; -.
DR PDBsum; 3DTQ; -.
DR PDBsum; 3FW4; -.
DR PDBsum; 3FW5; -.
DR PDBsum; 3HWD; -.
DR PDBsum; 3HWE; -.
DR PDBsum; 3HWF; -.
DR PDBsum; 3HWG; -.
DR PDBsum; 3I0A; -.
DR PDBsum; 3K3L; -.
DR PDBsum; 3PEC; -.
DR PDBsum; 3PED; -.
DR PDBsum; 3T1D; -.
DR PDBsum; 3TF6; -.
DR PDBsum; 3TZS; -.
DR PDBsum; 3U03; -.
DR PDBsum; 3U0D; -.
DR PDBsum; 4GH7; -.
DR PDBsum; 4IAW; -.
DR PDBsum; 4IAX; -.
DR PDBsum; 4K19; -.
DR ProteinModelPortal; P80188; -.
DR SMR; P80188; 24-197.
DR DIP; DIP-29952N; -.
DR STRING; 9606.ENSP00000277480; -.
DR PhosphoSite; P80188; -.
DR DMDM; 1171700; -.
DR PaxDb; P80188; -.
DR PRIDE; P80188; -.
DR DNASU; 3934; -.
DR Ensembl; ENST00000277480; ENSP00000277480; ENSG00000148346.
DR Ensembl; ENST00000373017; ENSP00000362108; ENSG00000148346.
DR Ensembl; ENST00000540948; ENSP00000441666; ENSG00000148346.
DR GeneID; 3934; -.
DR KEGG; hsa:3934; -.
DR UCSC; uc004bto.1; human.
DR CTD; 3934; -.
DR GeneCards; GC09P130911; -.
DR HGNC; HGNC:6526; LCN2.
DR HPA; CAB016549; -.
DR HPA; CAB016550; -.
DR HPA; HPA002695; -.
DR MIM; 600181; gene.
DR neXtProt; NX_P80188; -.
DR PharmGKB; PA30309; -.
DR eggNOG; NOG40148; -.
DR HOVERGEN; HBG106490; -.
DR OrthoDB; EOG78M03G; -.
DR ChiTaRS; LCN2; human.
DR EvolutionaryTrace; P80188; -.
DR GeneWiki; LCN2; -.
DR GenomeRNAi; 3934; -.
DR NextBio; 15451; -.
DR PRO; PR:P80188; -.
DR ArrayExpress; P80188; -.
DR Bgee; P80188; -.
DR CleanEx; HS_LCN2; -.
DR Genevestigator; P80188; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005506; F:iron ion binding; ISS:UniProtKB.
DR GO; GO:0036094; F:small molecule binding; IEA:InterPro.
DR GO; GO:0005215; F:transporter activity; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0031669; P:cellular response to nutrient levels; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0006811; P:ion transport; IEA:UniProtKB-KW.
DR GO; GO:0031346; P:positive regulation of cell projection organization; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0070207; P:protein homotrimerization; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEA:Ensembl.
DR GO; GO:0015891; P:siderophore transport; ISS:UniProtKB.
DR Gene3D; 2.40.128.20; -; 1.
DR InterPro; IPR012674; Calycin.
DR InterPro; IPR011038; Calycin-like.
DR InterPro; IPR002345; Lipocalin.
DR InterPro; IPR022272; Lipocalin_CS.
DR InterPro; IPR000566; Lipocln_cytosolic_FA-bd_dom.
DR InterPro; IPR003087; N_gelatinase.
DR Pfam; PF00061; Lipocalin; 1.
DR PRINTS; PR00179; LIPOCALIN.
DR PRINTS; PR01275; NGELATINASE.
DR SUPFAM; SSF50814; SSF50814; 1.
DR PROSITE; PS00213; LIPOCALIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Immunity;
KW Innate immunity; Ion transport; Iron; Iron transport;
KW Pyrrolidone carboxylic acid; Reference proteome; Secreted; Signal;
KW Transport.
FT SIGNAL 1 20
FT CHAIN 21 198 Neutrophil gelatinase-associated
FT lipocalin.
FT /FTId=PRO_0000017933.
FT BINDING 126 126 Catecholate-type ferric siderophore.
FT BINDING 145 145 Catecholate-type ferric siderophore.
FT BINDING 154 154 Catecholate-type ferric siderophore.
FT MOD_RES 21 21 Pyrrolidone carboxylic acid.
FT CARBOHYD 85 85 N-linked (GlcNAc...).
FT DISULFID 96 195
FT VAR_SEQ 193 198 DQCIDG -> GNGQSG (in isoform 2).
FT /FTId=VSP_039780.
FT CONFLICT 9 9 G -> R (in Ref. 3; BAG63166).
FT CONFLICT 13 13 L -> S (in Ref. 4; CAG46889).
FT CONFLICT 82 82 K -> N (in Ref. 10; AA sequence).
FT CONFLICT 155 155 I -> V (in Ref. 10; AA sequence).
FT CONFLICT 178 178 S -> Y (in Ref. 2; CAA67574).
FT HELIX 33 35
FT HELIX 44 47
FT STRAND 49 60
FT HELIX 66 69
FT STRAND 73 78
FT TURN 80 82
FT STRAND 84 92
FT STRAND 95 105
FT STRAND 111 114
FT HELIX 117 119
FT STRAND 123 133
FT STRAND 135 147
FT STRAND 150 162
FT HELIX 166 178
FT HELIX 183 185
FT TURN 194 196
SQ SEQUENCE 198 AA; 22588 MW; CD761805723FEF1E CRC64;
MPLGLLWLGL ALLGALHAQA QDSTSDLIPA PPLSKVPLQQ NFQDNQFQGK WYVVGLAGNA
ILREDKDPQK MYATIYELKE DKSYNVTSVL FRKKKCDYWI RTFVPGCQPG EFTLGNIKSY
PGLTSYLVRV VSTNYNQHAM VFFKKVSQNR EYFKITLYGR TKELTSELKE NFIRFSKSLG
LPENHIVFPV PIDQCIDG
//
ID NGAL_HUMAN Reviewed; 198 AA.
AC P80188; A6NII8; B4DWV4; B7ZAA2; P30150; Q5SYV9; Q5SYW0; Q6FGL5;
read moreAC Q92683;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 2.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=Neutrophil gelatinase-associated lipocalin;
DE Short=NGAL;
DE AltName: Full=25 kDa alpha-2-microglobulin-related subunit of MMP-9;
DE AltName: Full=Lipocalin-2;
DE AltName: Full=Oncogene 24p3;
DE AltName: Full=Siderocalin LCN2;
DE AltName: Full=p25;
DE Flags: Precursor;
GN Name=LCN2; Synonyms=HNL, NGAL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8060329; DOI=10.1006/bbrc.1994.2096;
RA Bundgaard J.R., Sengelov H., Borregaard N., Kjeldsen L.;
RT "Molecular cloning and expression of a cDNA encoding NGAL: a lipocalin
RT expressed in human neutrophils.";
RL Biochem. Biophys. Res. Commun. 202:1468-1475(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RC TISSUE=Bone marrow;
RX PubMed=9339356; DOI=10.1006/geno.1997.4896;
RA Cowland J.B., Borregaard N.;
RT "Molecular characterization and pattern of tissue expression of the
RT gene for neutrophil gelatinase-associated lipocalin from humans.";
RL Genomics 45:17-23(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Esophagus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 21-198, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=7835423; DOI=10.1016/0014-5793(94)01303-I;
RA Bartsch S., Tschesche H.;
RT "Cloning and expression of human neutrophil lipocalin cDNA derived
RT from bone marrow and ovarian cancer cells.";
RL FEBS Lett. 357:255-259(1995).
RN [9]
RP PROTEIN SEQUENCE OF 21-198.
RC TISSUE=Neutrophil;
RX PubMed=7683678;
RA Kjeldsen L., Johnsen A.H., Sengelov H., Borregaard N.;
RT "Isolation and primary structure of NGAL, a novel protein associated
RT with human neutrophil gelatinase.";
RL J. Biol. Chem. 268:10425-10432(1993).
RN [10]
RP PROTEIN SEQUENCE OF 51-61; 71-90; 132-136; 152-160 AND 178-192.
RC TISSUE=Neutrophil;
RX PubMed=1281792; DOI=10.1016/0014-5793(92)81511-J;
RA Triebel S., Blaeser J., Reinke H., Tschesche H.;
RT "A 25 kDa alpha 2-microglobulin-related protein is a component of the
RT 125 kDa form of human gelatinase.";
RL FEBS Lett. 314:386-388(1992).
RN [11]
RP FUNCTION, IRON-BINDING, SIDEROPHORE-BINDING, AND SUBCELLULAR LOCATION.
RX PubMed=12453413; DOI=10.1016/S1097-2765(02)00710-4;
RA Yang J., Goetz D., Li J.Y., Wang W., Mori K., Setlik D., Du T.,
RA Erdjument-Bromage H., Tempst P., Strong R., Barasch J.;
RT "An iron delivery pathway mediated by a lipocalin.";
RL Mol. Cell 10:1045-1056(2002).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Bile;
RX PubMed=15084671; DOI=10.1074/mcp.M400015-MCP200;
RA Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H.,
RA Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A.;
RT "A proteomic analysis of human bile.";
RL Mol. Cell. Proteomics 3:715-728(2004).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [15]
RP INDUCTION.
RX PubMed=19229297; DOI=10.1038/emboj.2009.35;
RA Sheng Z., Wang S.Z., Green M.R.;
RT "Transcription and signalling pathways involved in BCR-ABL-mediated
RT misregulation of 24p3 and 24p3R.";
RL EMBO J. 28:866-876(2009).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [17]
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 [18]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 21-298.
RX PubMed=10684642; DOI=10.1021/bi992215v;
RA Goetz D.H., Willie S.T., Armen R.S., Bratt T., Borregaard N.,
RA Strong R.K.;
RT "Ligand preference inferred from the structure of neutrophil
RT gelatinase associated lipocalin.";
RL Biochemistry 39:1935-1941(2000).
RN [19]
RP STRUCTURE BY NMR OF 21-198.
RX PubMed=10339412; DOI=10.1006/jmbi.1999.2755;
RA Coles M., Diercks T., Muehlenweg B., Bartsch S., Zolzer V.,
RA Tschesche H., Kessler H.;
RT "The solution structure and dynamics of human neutrophil gelatinase-
RT associated lipocalin.";
RL J. Mol. Biol. 289:139-157(1999).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 21-198 IN COMPLEX WITH
RP SIDEROPHORE AND IRON, AND SUBUNIT.
RX PubMed=12453412; DOI=10.1016/S1097-2765(02)00708-6;
RA Goetz D.H., Holmes M.A., Borregaard N., Bluhm M.E., Raymond K.N.,
RA Strong R.K.;
RT "The neutrophil lipocalin NGAL is a bacteriostatic agent that
RT interferes with siderophore-mediated iron acquisition.";
RL Mol. Cell 10:1033-1043(2002).
CC -!- FUNCTION: Iron-trafficking protein involved in multiple processes
CC such as apoptosis, innate immunity and renal development. Binds
CC iron through association with 2,5-dihydroxybenzoic acid (2,5-
CC DHBA), a siderophore that shares structural similarities with
CC bacterial enterobactin, and delivers or removes iron from the
CC cell, depending on the context. Iron-bound form (holo-24p3) is
CC internalized following binding to the SLC22A17 (24p3R) receptor,
CC leading to release of iron and subsequent increase of
CC intracellular iron concentration. In contrast, association of the
CC iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is
CC followed by association with an intracellular siderophore, iron
CC chelation and iron transfer to the extracellular medium, thereby
CC reducing intracellular iron concentration. Involved in apoptosis
CC due to interleukin-3 (IL3) deprivation: iron-loaded form increases
CC intracellular iron concentration without promoting apoptosis,
CC while iron-free form decreases intracellular iron levels, inducing
CC expression of the proapoptotic protein BCL2L11/BIM, resulting in
CC apoptosis. Involved in innate immunity, possibly by sequestrating
CC iron, leading to limit bacterial growth.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Heterodimer; disulfide-
CC linked with MMP9.
CC -!- SUBCELLULAR LOCATION: Secreted. Note=Upon binding to the SLC22A17
CC (24p3R) receptor, it is internalized.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P80188-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P80188-2; Sequence=VSP_039780;
CC -!- TISSUE SPECIFICITY: Expressed in bone marrow and in tissues that
CC are prone to exposure to microorganism. High expression is found
CC in bone marrow as well as in uterus, prostate, salivary gland,
CC stomach, appendix, colon, trachea and lung. Not found in the small
CC intestine or peripheral blood leukocytes.
CC -!- INDUCTION: Expression is activated by the oncoprotein BCR-ABL;
CC BCR-ABL misregulates expression via the JAK/STAT pathway and
CC binding of STAT5A to the promoter.
CC -!- SIMILARITY: Belongs to the calycin superfamily. Lipocalin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAI13824.1; Type=Erroneous gene model prediction;
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DR EMBL; X83006; CAA58127.1; -; mRNA.
DR EMBL; X99133; CAA67574.1; -; Genomic_DNA.
DR EMBL; AK301694; BAG63166.1; -; mRNA.
DR EMBL; AK316217; BAH14588.1; -; mRNA.
DR EMBL; CR542092; CAG46889.1; -; mRNA.
DR EMBL; AL590708; CAI13823.1; -; Genomic_DNA.
DR EMBL; AL590708; CAI13824.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471090; EAW87750.1; -; Genomic_DNA.
DR EMBL; BC033089; AAH33089.1; -; mRNA.
DR EMBL; S75256; AAD14168.1; -; mRNA.
DR PIR; JC2339; JC2339.
DR RefSeq; NP_005555.2; NM_005564.3.
DR UniGene; Hs.204238; -.
DR PDB; 1DFV; X-ray; 2.60 A; A/B=21-197.
DR PDB; 1L6M; X-ray; 2.40 A; A/B/C=21-198.
DR PDB; 1NGL; NMR; -; A=21-198.
DR PDB; 1QQS; X-ray; 2.40 A; A=24-197.
DR PDB; 1X71; X-ray; 2.10 A; A/B/C=21-198.
DR PDB; 1X89; X-ray; 2.10 A; A/B/C=21-198.
DR PDB; 1X8U; X-ray; 2.20 A; A/B/C=21-198.
DR PDB; 3BY0; X-ray; 2.57 A; A/B/C=1-198.
DR PDB; 3CBC; X-ray; 2.17 A; A/B/C=1-198.
DR PDB; 3CMP; X-ray; 2.80 A; A/B/C=1-198.
DR PDB; 3DSZ; X-ray; 2.00 A; A/B=21-198.
DR PDB; 3DTQ; X-ray; 2.50 A; A/B/C=21-198.
DR PDB; 3FW4; X-ray; 2.30 A; A/B/C=21-198.
DR PDB; 3FW5; X-ray; 2.30 A; A/B/C=21-198.
DR PDB; 3HWD; X-ray; 2.95 A; A/B/C=1-198.
DR PDB; 3HWE; X-ray; 2.80 A; A/B/C=1-198.
DR PDB; 3HWF; X-ray; 3.20 A; A/B/C=1-198.
DR PDB; 3HWG; X-ray; 2.19 A; A/B/C=1-198.
DR PDB; 3I0A; X-ray; 2.60 A; A/B/C=1-198.
DR PDB; 3K3L; X-ray; 2.62 A; A/B/C=21-198.
DR PDB; 3PEC; X-ray; 2.19 A; A/B/C=21-198.
DR PDB; 3PED; X-ray; 2.30 A; A/B/C=21-198.
DR PDB; 3T1D; X-ray; 2.30 A; A/B/C=1-198.
DR PDB; 3TF6; X-ray; 2.35 A; A/B/C=21-198.
DR PDB; 3TZS; X-ray; 2.45 A; A/B/C=21-198.
DR PDB; 3U03; X-ray; 2.40 A; A/C=1-198.
DR PDB; 3U0D; X-ray; 2.51 A; A/B/C/D=1-198.
DR PDB; 4GH7; X-ray; 2.60 A; A/C=21-198.
DR PDB; 4IAW; X-ray; 2.40 A; A/B/C=21-198.
DR PDB; 4IAX; X-ray; 1.90 A; A=21-198.
DR PDB; 4K19; X-ray; 2.74 A; A/B/C=21-198.
DR PDBsum; 1DFV; -.
DR PDBsum; 1L6M; -.
DR PDBsum; 1NGL; -.
DR PDBsum; 1QQS; -.
DR PDBsum; 1X71; -.
DR PDBsum; 1X89; -.
DR PDBsum; 1X8U; -.
DR PDBsum; 3BY0; -.
DR PDBsum; 3CBC; -.
DR PDBsum; 3CMP; -.
DR PDBsum; 3DSZ; -.
DR PDBsum; 3DTQ; -.
DR PDBsum; 3FW4; -.
DR PDBsum; 3FW5; -.
DR PDBsum; 3HWD; -.
DR PDBsum; 3HWE; -.
DR PDBsum; 3HWF; -.
DR PDBsum; 3HWG; -.
DR PDBsum; 3I0A; -.
DR PDBsum; 3K3L; -.
DR PDBsum; 3PEC; -.
DR PDBsum; 3PED; -.
DR PDBsum; 3T1D; -.
DR PDBsum; 3TF6; -.
DR PDBsum; 3TZS; -.
DR PDBsum; 3U03; -.
DR PDBsum; 3U0D; -.
DR PDBsum; 4GH7; -.
DR PDBsum; 4IAW; -.
DR PDBsum; 4IAX; -.
DR PDBsum; 4K19; -.
DR ProteinModelPortal; P80188; -.
DR SMR; P80188; 24-197.
DR DIP; DIP-29952N; -.
DR STRING; 9606.ENSP00000277480; -.
DR PhosphoSite; P80188; -.
DR DMDM; 1171700; -.
DR PaxDb; P80188; -.
DR PRIDE; P80188; -.
DR DNASU; 3934; -.
DR Ensembl; ENST00000277480; ENSP00000277480; ENSG00000148346.
DR Ensembl; ENST00000373017; ENSP00000362108; ENSG00000148346.
DR Ensembl; ENST00000540948; ENSP00000441666; ENSG00000148346.
DR GeneID; 3934; -.
DR KEGG; hsa:3934; -.
DR UCSC; uc004bto.1; human.
DR CTD; 3934; -.
DR GeneCards; GC09P130911; -.
DR HGNC; HGNC:6526; LCN2.
DR HPA; CAB016549; -.
DR HPA; CAB016550; -.
DR HPA; HPA002695; -.
DR MIM; 600181; gene.
DR neXtProt; NX_P80188; -.
DR PharmGKB; PA30309; -.
DR eggNOG; NOG40148; -.
DR HOVERGEN; HBG106490; -.
DR OrthoDB; EOG78M03G; -.
DR ChiTaRS; LCN2; human.
DR EvolutionaryTrace; P80188; -.
DR GeneWiki; LCN2; -.
DR GenomeRNAi; 3934; -.
DR NextBio; 15451; -.
DR PRO; PR:P80188; -.
DR ArrayExpress; P80188; -.
DR Bgee; P80188; -.
DR CleanEx; HS_LCN2; -.
DR Genevestigator; P80188; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005506; F:iron ion binding; ISS:UniProtKB.
DR GO; GO:0036094; F:small molecule binding; IEA:InterPro.
DR GO; GO:0005215; F:transporter activity; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0031669; P:cellular response to nutrient levels; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0006811; P:ion transport; IEA:UniProtKB-KW.
DR GO; GO:0031346; P:positive regulation of cell projection organization; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0070207; P:protein homotrimerization; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEA:Ensembl.
DR GO; GO:0015891; P:siderophore transport; ISS:UniProtKB.
DR Gene3D; 2.40.128.20; -; 1.
DR InterPro; IPR012674; Calycin.
DR InterPro; IPR011038; Calycin-like.
DR InterPro; IPR002345; Lipocalin.
DR InterPro; IPR022272; Lipocalin_CS.
DR InterPro; IPR000566; Lipocln_cytosolic_FA-bd_dom.
DR InterPro; IPR003087; N_gelatinase.
DR Pfam; PF00061; Lipocalin; 1.
DR PRINTS; PR00179; LIPOCALIN.
DR PRINTS; PR01275; NGELATINASE.
DR SUPFAM; SSF50814; SSF50814; 1.
DR PROSITE; PS00213; LIPOCALIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Immunity;
KW Innate immunity; Ion transport; Iron; Iron transport;
KW Pyrrolidone carboxylic acid; Reference proteome; Secreted; Signal;
KW Transport.
FT SIGNAL 1 20
FT CHAIN 21 198 Neutrophil gelatinase-associated
FT lipocalin.
FT /FTId=PRO_0000017933.
FT BINDING 126 126 Catecholate-type ferric siderophore.
FT BINDING 145 145 Catecholate-type ferric siderophore.
FT BINDING 154 154 Catecholate-type ferric siderophore.
FT MOD_RES 21 21 Pyrrolidone carboxylic acid.
FT CARBOHYD 85 85 N-linked (GlcNAc...).
FT DISULFID 96 195
FT VAR_SEQ 193 198 DQCIDG -> GNGQSG (in isoform 2).
FT /FTId=VSP_039780.
FT CONFLICT 9 9 G -> R (in Ref. 3; BAG63166).
FT CONFLICT 13 13 L -> S (in Ref. 4; CAG46889).
FT CONFLICT 82 82 K -> N (in Ref. 10; AA sequence).
FT CONFLICT 155 155 I -> V (in Ref. 10; AA sequence).
FT CONFLICT 178 178 S -> Y (in Ref. 2; CAA67574).
FT HELIX 33 35
FT HELIX 44 47
FT STRAND 49 60
FT HELIX 66 69
FT STRAND 73 78
FT TURN 80 82
FT STRAND 84 92
FT STRAND 95 105
FT STRAND 111 114
FT HELIX 117 119
FT STRAND 123 133
FT STRAND 135 147
FT STRAND 150 162
FT HELIX 166 178
FT HELIX 183 185
FT TURN 194 196
SQ SEQUENCE 198 AA; 22588 MW; CD761805723FEF1E CRC64;
MPLGLLWLGL ALLGALHAQA QDSTSDLIPA PPLSKVPLQQ NFQDNQFQGK WYVVGLAGNA
ILREDKDPQK MYATIYELKE DKSYNVTSVL FRKKKCDYWI RTFVPGCQPG EFTLGNIKSY
PGLTSYLVRV VSTNYNQHAM VFFKKVSQNR EYFKITLYGR TKELTSELKE NFIRFSKSLG
LPENHIVFPV PIDQCIDG
//
MIM
600181
*RECORD*
*FIELD* NO
600181
*FIELD* TI
*600181 LIPOCALIN 2; LCN2
;;NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN; NGAL;;
ONCOGENIC LIPOCALIN 24P3;;
read moreUTEROCALIN
*FIELD* TX
CLONING
Lipocalin-2 (LCN2), also known as NGAL, is a protein associated with
neutrophil gelatinase (Kjeldsen et al., 1993). The 25-kD LCN2 protein is
believed to bind small lipophilic substances such as bacteria-derived
lipopolysaccharide (LPS) and formylpeptides and may function as a
modulator of inflammation. By screening a human genomic library with an
LCN2 cDNA, Cowland and Borregaard (1997) isolated the LCN2 genomic
sequence. The primary LCN2 transcript is 3,696 nucleotides long, and the
processed transcript is 809 nucleotides long. RNA dot blot analysis of
50 human tissues detected LCN2 expression in adult bone marrow, uterus,
prostate, salivary gland, stomach, appendix, colon, trachea, and lung,
and in fetal spleen and lung.
GENE FUNCTION
Using DNA microarrays to analyze IL3 (147740)-dependent murine FL5.12
pro-B cells, Devireddy et al. (2001) found that the gene undergoing
maximal transcriptional induction after cytokine withdrawal is 24p3,
which encodes a secreted lipocalin (lipocalin-2). Conditioned medium
from IL3-deprived cells contained 24p3 and induced apoptosis in naive
cells, even when IL3 was present. 24p3 also induced apoptosis in a wide
variety of leukocytes but not other cell types. Apoptotic sensitivity
correlated with the presence of a putative 24p3 cell surface receptor.
Devireddy et al. (2001) concluded that IL3 deprivation activates 24p3
transcription, leading to synthesis and secretion of 24p3, which induces
apoptosis through an autocrine pathway. In addition to murine FL5.12
pro-B cells, many other cell types were sensitive to 24p3-mediated
apoptosis: murine primary thymocytes, murine primary splenocytes, murine
primary bone marrow cells, human primary neutrophils, and human
peripheral blood lymphocytes. In contrast, human primary macrophages,
HeLa cells, and Jurkat cells were not susceptible to 24p3-mediated
apoptosis.
Goetz et al. (2002) reported that NGAL tightly binds bacterial
catecholate-type ferric siderophores through a cyclically permuted,
hybrid electrostatic/cation-pi interaction and is a potent
bacteriostatic agent in iron-limiting conditions. They proposed that
NGAL participates in the antibacterial iron depletion strategy of the
innate immune system.
Yang et al. (2002) showed that NGAL delivers iron to the cytoplasm,
where it activates or represses iron-responsive genes. Iron unloading
depended on the cycling of NGAL through acidic endosomes, but its pH
sensitivity and its subcellular targeting differed from transferrin
(190000). During the conversion of mesenchyme into epithelia, NGAL and
transferrin were endocytosed by different cells that characterize
different stages of development, and they triggered unique responses.
These studies identified an iron delivery pathway active in development
and cell physiology.
Flo et al. (2004) demonstrated that the binding of lipocalin-2 to
bacterial siderophores is pivotal in the innate immune response to
bacterial infection. Upon encountering invading bacteria the Toll-like
receptors on immune cells stimulate the transcription, translation, and
secretion of lipocalin-2. Secreted lipocalin-2 then limits bacterial
growth by sequestrating the iron-laden siderophore. Flo et al. (2004)
concluded that their findings represent a new component of the innate
immune system and the acute phase response to infection.
Using healthy human skin fragments obtained as surgical residua,
Sorensen et al. (2006) demonstrated that sterile wounding of human skin
induces epidermal expression of the antimicrobial polypeptides
beta-defensin-103 (DEFB103; 606611), LCN2, and secretory leukocyte
protease inhibitor (SLPI; 107285) through activation of EGFR (131550) by
heparin-binding EGF (HBEGF; 126150).
Yang et al. (2009) found that overexpression of LCN2 in clones of human
MFC-7 breast cancer (114480) cells induced expression of mesenchymal
markers on these cells, including vimentin (VIM; 193060) and fibronectin
(FN1; 135600), and downregulated the epithelial cell marker E-cadherin
(CDH1; 192090), consistent with an epithelial to mesenchymal transition.
Cell motility and invasiveness were also increased. The cancer cell
clones with increased LCN2 expression also showed decreased estrogen
receptor (ESR1; 133430) expression and increased SLUG (SNAI2; 602150)
expression. Inhibition of LCN2 in aggressive breast cancer cells
(MDA-MB-231) reduced migration and suppressed the mesenchymal phenotype.
Studies in mice showed that breast cancer cells with high LCN2
expression resulted in increased local invasion and lymph node
metastases compared to those with low LCN2 expression. In humans,
increased urinary LCN2 levels correlated with invasive breast cancer.
Estrogen receptor-alpha (ERA, or ESR1)-positive breast cancer cells are
less invasive than ERA-negative breast cancer cells. Fougere et al.
(2010) found that ERA-positive breast cancer cells had upregulated
expression of NFAT3 (NFATC4; 602699) and downregulated expression of
LCN2 compared with ERA-negative breast cancer cells. Overexpression and
knockdown studies suggested that NFAT3 cooperated with ERA in
downregulation of LCN2, although indirectly, and downregulated LCN2
expression correlated with reduced invasiveness and metastasis.
GENE STRUCTURE
By genomic sequence analysis, Cowland and Borregaard (1997) determined
that the LCN2 gene contains 7 exons.
MAPPING
LCN1 (151675) and LCN2 map to 9q34 by in situ hybridization (Chan et
al., 1994). By linkage analyses in an interspecific backcross progeny in
the mouse, Chan et al. (1994) mapped the Lcn2 gene to mouse chromosome
2.
ANIMAL MODEL
Berger et al. (2006) found that Lcn2 -/- mice had increased
susceptibility to bacterial infection. Neutrophils from Lcn2 -/- mice
were significantly less bacteriostatic than neutrophils from wildtype
mice. Bacteriostatic activity of wildtype mice was abolished by addition
of exogenous iron, suggesting that LCN2 limits iron for bacteria. Lcn2
-/- females, but not males, were significantly less fertile than
wildtype mice. Otherwise, Lcn2 -/- mice appeared healthy, including
normal kidney development, immune cell types, and susceptibility to
apoptosis. Deficiency of Lcn2 had no impact on severity of ischemic
kidney damage. Berger et al. (2006) concluded that LCN2 has an essential
role in the early stages of the immune response to bacterial infection,
with its loss leading to host mortality due to accelerated bacterial
growth.
Nairz et al. (2009) found that mice lacking 1 or both Hfe (613609)
alleles were protected from Salmonella typhimurium septicemia,
displaying reduced bacterial replication and prolonged host survival.
Increased resistance was associated with enhanced production of the
enterochelin-binding protein Lcn2, which reduced iron availability for
Salmonella. Macrophages lacking both Hfe and Lcn2 were unable to
efficiently control S. typhimurium or to withhold iron from the
bacterium. Salmonella lacking enterochelin overcame protection in Hfe
-/- mice, as did wildtype bacteria in Hfe -/- Lcn2 -/- double-knockout
mice. Nairz et al. (2009) concluded that loss of HFE confers host
resistance to systemic Salmonella infection by inducing the
iron-capturing peptide LCN2, thereby providing an evolutionary advantage
that may account for the high prevalence of genetic hemochromatosis
(235200).
Liu et al. (2011) found an abnormal increase in myeloid, B-cell, and
erythroid precursors in bone marrow of 24p3 -/- mice. The number of
leukocytes of all types, except for basophils, was also elevated in
peripheral blood of 24p3 -/- mice. Liu et al. (2011) found that the
abnormal hematologic profile in 24p3 -/- mice was due to their
resistance to an apoptotic pathway involving Bim (BCL2L11; 603827) and
intracellular iron content, in addition to 24p3, and was specific to
relatively mature committed progenitors and precursor cells.
Srinivasan et al. (2012) found that LPS induced a 150-fold increase in
Lcn2 in wildtype mice. Lcn2 -/- mice were markedly more sensitive to
endotoxemia compared with wildtype littermates, with increased organ
damage, as assessed by transaminasemia and lactate dehydrogenase, and
mortality. Severe endotoxemia was associated with elevated Casp3
(600636) cleavage and immune cell apoptosis. Lcn2 -/- cells were
hyperresponsive to LPS ex vivo, as determined by elevated cytokine
secretion. Lcn2 -/- mice exhibited delayed LPS-induced hypoferremia,
despite having normal hepatic hepcidin (HAMP; 606464) expression, and
decreased levels of the tissue redox state indicators cysteine and
glutathione in liver and plasma. Lcn2 -/- mice were significantly
protected from LPS-induced toxicity and mortality by the iron chelator
desferroxamine. Srinivasan et al. (2012) proposed that LCN2 acts as an
antioxidant in vivo by regulating iron hemostasis and thereby protects
against sepsis.
*FIELD* RF
1. Berger, T.; Togawa, A.; Duncan, G. S.; Elia, A. J.; You-Ten, A.;
Wakeham, A.; Fong, H. E. H.; Cheung, C. C.; Mak, T. W.: Lipocalin
2-deficient mice exhibit increased sensitivity to Escherichia coli
infection but not to ischemia-reperfusion injury. Proc. Nat. Acad.
Sci. 103: 1834-1839, 2006.
2. Chan, P.; Simon-Chazottes, D.; Mattei, M. G.; Guenet, J. L.; Salier,
J. P.: Comparative mapping of lipocalin genes in human and mouse:
the four genes for complement C8 gamma chain, prostaglandin-D-synthase,
oncogene-24P3, and progestagen-associated endometrial protein map
to HSA9 and MMU2. Genomics 23: 145-150, 1994.
3. Cowland, J. B.; Borregaard, N.: Molecular characterization and
pattern of tissue expression of the gene for neutrophil gelatinase-associated
lipocalin from humans. Genomics 45: 17-23, 1997.
4. Devireddy, L. R.; Teodoro, J. G.; Richard, F. A.; Green, M. R.
: Induction of apoptosis by a secreted lipocalin that is transcriptionally
regulated by IL-3 deprivation. Science 293: 829-834, 2001.
5. Flo, T. H.; Smith, K. D.; Sato, S.; Rodriguez, D. J.; Holmes, M.
A.; Strong, R. K.; Akira, S.; Aderem, A.: Lipocalin 2 mediates an
innate immune response to bacterial infection by sequestrating iron. Nature 432:
917-921, 2004.
6. Fougere, M.; Gaudineau, B.; Barbier, J.; Guaddachi, F.; Feugeas,
J.-P.; Auboeuf, D.; Jauliac, S.: NFAT3 transcription factor inhibits
breast cancer cell motility by targeting the lipocalin 2 gene. Oncogene 29:
2292-2301, 2010.
7. Goetz, D. H.; Holmes, M. A.; Borregaard, N.; Bluhm, M. E.; Raymond,
K. N.; Strong, R. K.: The neutrophil lipocalin NGAL is a bacteriostatic
agent that interferes with siderophore-mediated iron acquisition. Molec.
Cell 10: 1033-1043, 2002.
8. Kjeldsen, L.; Johnsen, A. H.; Sengelov, H.; Borregaard, N.: Isolation
and primary structure of NGAL, a novel protein associated with human
neutrophil gelatinase. J. Biol. Chem. 268: 10425-10432, 1993.
9. Liu, Z.; Yang, A.; Wang, Z.; Bunting, K. D.; Davuluri, G.; Green,
M. R.; Devireddy, L. R.: Multiple apoptotic defects in hematopoietic
cells from mice lacking lipocalin 24p3. J. Biol. Chem. 286: 20606-20614,
2011.
10. Nairz, M.; Theurl, I.; Schroll, A.; Theurl, M.; Fritsche, G.;
Lindner, E.; Seifert, M.; Crouch, M.-L. V.; Hantke, K.; Akira, S.;
Fang, F. C.; Weiss, G.: Absence of functional Hfe protects mice from
invasive Salmonella enterica serovar typhimurium infection via induction
of lipocalin-2. Blood 114: 3642-3651, 2009.
11. Sorensen, O. E.; Thapa, D. R.; Roupe, K. M.; Valore, E. V.; Sjobring,
U.; Roberts, A. A.; Schmidtchen, A.; Ganz, T.: Injury-induced innate
immune response in human skin mediated by transactivation of the epidermal
growth factor receptor. J. Clin. Invest. 116: 1878-1885, 2006.
12. Srinivasan, G.; Aitken, J. D.; Zhang, B.; Carvalho, F. A.; Chassaing,
B.; Shashidharamurthy, R.; Borregaard, N.; Jones, D. P.; Gewirtz,
A. T.; Vijay-Kumar, M.: Lipocalin 2 deficiency dysregulates iron
homeostasis and exacerbates endotoxin-induced sepsis. J. Immun. 189:
1911-1919, 2012.
13. Yang, J.; Bielenberg, D. R.; Rodig, S. J.; Doiron, R.; Clifton,
M. C.; Kung, A. L.; Strong, R. K.; Zurakowski, D.; Moses, M. A.:
Lipocalin 2 promotes breast cancer progression. Proc. Nat. Acad.
Sci. 106: 3913-3918, 2009.
14. Yang, J.; Goetz, D.; Li, J.-Y.; Wang, W.; Mori, K.; Setlik, D.;
Du, T.; Erdjument-Bromage, H.; Tempst, P.; Strong, R.; Barasch, J.
: An iron delivery pathway mediated by lipocalin. Molec. Cell 10:
1045-1056, 2002.
*FIELD* CN
Paul J. Converse - updated: 06/25/2013
Patricia A. Hartz - updated: 2/23/2012
Patricia A. Hartz - updated: 10/21/2011
Paul J. Converse - updated: 7/1/2011
Cassandra L. Kniffin - updated: 6/25/2009
Marla J. F. O'Neill - updated: 11/17/2006
Paul J. Converse - updated: 3/24/2006
Ada Hamosh - updated: 12/29/2004
Stylianos E. Antonarakis - updated: 4/29/2003
Ada Hamosh - updated: 8/27/2001
Patti M. Sherman - updated: 5/24/2000
*FIELD* CD
Victor A. McKusick: 11/8/1994
*FIELD* ED
mgross: 06/25/2013
mgross: 3/6/2012
terry: 2/23/2012
terry: 1/17/2012
mgross: 10/27/2011
terry: 10/21/2011
mgross: 7/7/2011
terry: 7/1/2011
wwang: 7/23/2009
ckniffin: 6/25/2009
wwang: 11/17/2006
mgross: 5/3/2006
terry: 3/24/2006
alopez: 12/30/2004
terry: 12/29/2004
mgross: 4/29/2003
alopez: 8/30/2001
terry: 8/27/2001
mcapotos: 6/16/2000
psherman: 5/24/2000
carol: 9/16/1998
psherman: 4/7/1998
alopez: 10/3/1997
jamie: 1/17/1997
carol: 11/18/1994
terry: 11/8/1994
*RECORD*
*FIELD* NO
600181
*FIELD* TI
*600181 LIPOCALIN 2; LCN2
;;NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN; NGAL;;
ONCOGENIC LIPOCALIN 24P3;;
read moreUTEROCALIN
*FIELD* TX
CLONING
Lipocalin-2 (LCN2), also known as NGAL, is a protein associated with
neutrophil gelatinase (Kjeldsen et al., 1993). The 25-kD LCN2 protein is
believed to bind small lipophilic substances such as bacteria-derived
lipopolysaccharide (LPS) and formylpeptides and may function as a
modulator of inflammation. By screening a human genomic library with an
LCN2 cDNA, Cowland and Borregaard (1997) isolated the LCN2 genomic
sequence. The primary LCN2 transcript is 3,696 nucleotides long, and the
processed transcript is 809 nucleotides long. RNA dot blot analysis of
50 human tissues detected LCN2 expression in adult bone marrow, uterus,
prostate, salivary gland, stomach, appendix, colon, trachea, and lung,
and in fetal spleen and lung.
GENE FUNCTION
Using DNA microarrays to analyze IL3 (147740)-dependent murine FL5.12
pro-B cells, Devireddy et al. (2001) found that the gene undergoing
maximal transcriptional induction after cytokine withdrawal is 24p3,
which encodes a secreted lipocalin (lipocalin-2). Conditioned medium
from IL3-deprived cells contained 24p3 and induced apoptosis in naive
cells, even when IL3 was present. 24p3 also induced apoptosis in a wide
variety of leukocytes but not other cell types. Apoptotic sensitivity
correlated with the presence of a putative 24p3 cell surface receptor.
Devireddy et al. (2001) concluded that IL3 deprivation activates 24p3
transcription, leading to synthesis and secretion of 24p3, which induces
apoptosis through an autocrine pathway. In addition to murine FL5.12
pro-B cells, many other cell types were sensitive to 24p3-mediated
apoptosis: murine primary thymocytes, murine primary splenocytes, murine
primary bone marrow cells, human primary neutrophils, and human
peripheral blood lymphocytes. In contrast, human primary macrophages,
HeLa cells, and Jurkat cells were not susceptible to 24p3-mediated
apoptosis.
Goetz et al. (2002) reported that NGAL tightly binds bacterial
catecholate-type ferric siderophores through a cyclically permuted,
hybrid electrostatic/cation-pi interaction and is a potent
bacteriostatic agent in iron-limiting conditions. They proposed that
NGAL participates in the antibacterial iron depletion strategy of the
innate immune system.
Yang et al. (2002) showed that NGAL delivers iron to the cytoplasm,
where it activates or represses iron-responsive genes. Iron unloading
depended on the cycling of NGAL through acidic endosomes, but its pH
sensitivity and its subcellular targeting differed from transferrin
(190000). During the conversion of mesenchyme into epithelia, NGAL and
transferrin were endocytosed by different cells that characterize
different stages of development, and they triggered unique responses.
These studies identified an iron delivery pathway active in development
and cell physiology.
Flo et al. (2004) demonstrated that the binding of lipocalin-2 to
bacterial siderophores is pivotal in the innate immune response to
bacterial infection. Upon encountering invading bacteria the Toll-like
receptors on immune cells stimulate the transcription, translation, and
secretion of lipocalin-2. Secreted lipocalin-2 then limits bacterial
growth by sequestrating the iron-laden siderophore. Flo et al. (2004)
concluded that their findings represent a new component of the innate
immune system and the acute phase response to infection.
Using healthy human skin fragments obtained as surgical residua,
Sorensen et al. (2006) demonstrated that sterile wounding of human skin
induces epidermal expression of the antimicrobial polypeptides
beta-defensin-103 (DEFB103; 606611), LCN2, and secretory leukocyte
protease inhibitor (SLPI; 107285) through activation of EGFR (131550) by
heparin-binding EGF (HBEGF; 126150).
Yang et al. (2009) found that overexpression of LCN2 in clones of human
MFC-7 breast cancer (114480) cells induced expression of mesenchymal
markers on these cells, including vimentin (VIM; 193060) and fibronectin
(FN1; 135600), and downregulated the epithelial cell marker E-cadherin
(CDH1; 192090), consistent with an epithelial to mesenchymal transition.
Cell motility and invasiveness were also increased. The cancer cell
clones with increased LCN2 expression also showed decreased estrogen
receptor (ESR1; 133430) expression and increased SLUG (SNAI2; 602150)
expression. Inhibition of LCN2 in aggressive breast cancer cells
(MDA-MB-231) reduced migration and suppressed the mesenchymal phenotype.
Studies in mice showed that breast cancer cells with high LCN2
expression resulted in increased local invasion and lymph node
metastases compared to those with low LCN2 expression. In humans,
increased urinary LCN2 levels correlated with invasive breast cancer.
Estrogen receptor-alpha (ERA, or ESR1)-positive breast cancer cells are
less invasive than ERA-negative breast cancer cells. Fougere et al.
(2010) found that ERA-positive breast cancer cells had upregulated
expression of NFAT3 (NFATC4; 602699) and downregulated expression of
LCN2 compared with ERA-negative breast cancer cells. Overexpression and
knockdown studies suggested that NFAT3 cooperated with ERA in
downregulation of LCN2, although indirectly, and downregulated LCN2
expression correlated with reduced invasiveness and metastasis.
GENE STRUCTURE
By genomic sequence analysis, Cowland and Borregaard (1997) determined
that the LCN2 gene contains 7 exons.
MAPPING
LCN1 (151675) and LCN2 map to 9q34 by in situ hybridization (Chan et
al., 1994). By linkage analyses in an interspecific backcross progeny in
the mouse, Chan et al. (1994) mapped the Lcn2 gene to mouse chromosome
2.
ANIMAL MODEL
Berger et al. (2006) found that Lcn2 -/- mice had increased
susceptibility to bacterial infection. Neutrophils from Lcn2 -/- mice
were significantly less bacteriostatic than neutrophils from wildtype
mice. Bacteriostatic activity of wildtype mice was abolished by addition
of exogenous iron, suggesting that LCN2 limits iron for bacteria. Lcn2
-/- females, but not males, were significantly less fertile than
wildtype mice. Otherwise, Lcn2 -/- mice appeared healthy, including
normal kidney development, immune cell types, and susceptibility to
apoptosis. Deficiency of Lcn2 had no impact on severity of ischemic
kidney damage. Berger et al. (2006) concluded that LCN2 has an essential
role in the early stages of the immune response to bacterial infection,
with its loss leading to host mortality due to accelerated bacterial
growth.
Nairz et al. (2009) found that mice lacking 1 or both Hfe (613609)
alleles were protected from Salmonella typhimurium septicemia,
displaying reduced bacterial replication and prolonged host survival.
Increased resistance was associated with enhanced production of the
enterochelin-binding protein Lcn2, which reduced iron availability for
Salmonella. Macrophages lacking both Hfe and Lcn2 were unable to
efficiently control S. typhimurium or to withhold iron from the
bacterium. Salmonella lacking enterochelin overcame protection in Hfe
-/- mice, as did wildtype bacteria in Hfe -/- Lcn2 -/- double-knockout
mice. Nairz et al. (2009) concluded that loss of HFE confers host
resistance to systemic Salmonella infection by inducing the
iron-capturing peptide LCN2, thereby providing an evolutionary advantage
that may account for the high prevalence of genetic hemochromatosis
(235200).
Liu et al. (2011) found an abnormal increase in myeloid, B-cell, and
erythroid precursors in bone marrow of 24p3 -/- mice. The number of
leukocytes of all types, except for basophils, was also elevated in
peripheral blood of 24p3 -/- mice. Liu et al. (2011) found that the
abnormal hematologic profile in 24p3 -/- mice was due to their
resistance to an apoptotic pathway involving Bim (BCL2L11; 603827) and
intracellular iron content, in addition to 24p3, and was specific to
relatively mature committed progenitors and precursor cells.
Srinivasan et al. (2012) found that LPS induced a 150-fold increase in
Lcn2 in wildtype mice. Lcn2 -/- mice were markedly more sensitive to
endotoxemia compared with wildtype littermates, with increased organ
damage, as assessed by transaminasemia and lactate dehydrogenase, and
mortality. Severe endotoxemia was associated with elevated Casp3
(600636) cleavage and immune cell apoptosis. Lcn2 -/- cells were
hyperresponsive to LPS ex vivo, as determined by elevated cytokine
secretion. Lcn2 -/- mice exhibited delayed LPS-induced hypoferremia,
despite having normal hepatic hepcidin (HAMP; 606464) expression, and
decreased levels of the tissue redox state indicators cysteine and
glutathione in liver and plasma. Lcn2 -/- mice were significantly
protected from LPS-induced toxicity and mortality by the iron chelator
desferroxamine. Srinivasan et al. (2012) proposed that LCN2 acts as an
antioxidant in vivo by regulating iron hemostasis and thereby protects
against sepsis.
*FIELD* RF
1. Berger, T.; Togawa, A.; Duncan, G. S.; Elia, A. J.; You-Ten, A.;
Wakeham, A.; Fong, H. E. H.; Cheung, C. C.; Mak, T. W.: Lipocalin
2-deficient mice exhibit increased sensitivity to Escherichia coli
infection but not to ischemia-reperfusion injury. Proc. Nat. Acad.
Sci. 103: 1834-1839, 2006.
2. Chan, P.; Simon-Chazottes, D.; Mattei, M. G.; Guenet, J. L.; Salier,
J. P.: Comparative mapping of lipocalin genes in human and mouse:
the four genes for complement C8 gamma chain, prostaglandin-D-synthase,
oncogene-24P3, and progestagen-associated endometrial protein map
to HSA9 and MMU2. Genomics 23: 145-150, 1994.
3. Cowland, J. B.; Borregaard, N.: Molecular characterization and
pattern of tissue expression of the gene for neutrophil gelatinase-associated
lipocalin from humans. Genomics 45: 17-23, 1997.
4. Devireddy, L. R.; Teodoro, J. G.; Richard, F. A.; Green, M. R.
: Induction of apoptosis by a secreted lipocalin that is transcriptionally
regulated by IL-3 deprivation. Science 293: 829-834, 2001.
5. Flo, T. H.; Smith, K. D.; Sato, S.; Rodriguez, D. J.; Holmes, M.
A.; Strong, R. K.; Akira, S.; Aderem, A.: Lipocalin 2 mediates an
innate immune response to bacterial infection by sequestrating iron. Nature 432:
917-921, 2004.
6. Fougere, M.; Gaudineau, B.; Barbier, J.; Guaddachi, F.; Feugeas,
J.-P.; Auboeuf, D.; Jauliac, S.: NFAT3 transcription factor inhibits
breast cancer cell motility by targeting the lipocalin 2 gene. Oncogene 29:
2292-2301, 2010.
7. Goetz, D. H.; Holmes, M. A.; Borregaard, N.; Bluhm, M. E.; Raymond,
K. N.; Strong, R. K.: The neutrophil lipocalin NGAL is a bacteriostatic
agent that interferes with siderophore-mediated iron acquisition. Molec.
Cell 10: 1033-1043, 2002.
8. Kjeldsen, L.; Johnsen, A. H.; Sengelov, H.; Borregaard, N.: Isolation
and primary structure of NGAL, a novel protein associated with human
neutrophil gelatinase. J. Biol. Chem. 268: 10425-10432, 1993.
9. Liu, Z.; Yang, A.; Wang, Z.; Bunting, K. D.; Davuluri, G.; Green,
M. R.; Devireddy, L. R.: Multiple apoptotic defects in hematopoietic
cells from mice lacking lipocalin 24p3. J. Biol. Chem. 286: 20606-20614,
2011.
10. Nairz, M.; Theurl, I.; Schroll, A.; Theurl, M.; Fritsche, G.;
Lindner, E.; Seifert, M.; Crouch, M.-L. V.; Hantke, K.; Akira, S.;
Fang, F. C.; Weiss, G.: Absence of functional Hfe protects mice from
invasive Salmonella enterica serovar typhimurium infection via induction
of lipocalin-2. Blood 114: 3642-3651, 2009.
11. Sorensen, O. E.; Thapa, D. R.; Roupe, K. M.; Valore, E. V.; Sjobring,
U.; Roberts, A. A.; Schmidtchen, A.; Ganz, T.: Injury-induced innate
immune response in human skin mediated by transactivation of the epidermal
growth factor receptor. J. Clin. Invest. 116: 1878-1885, 2006.
12. Srinivasan, G.; Aitken, J. D.; Zhang, B.; Carvalho, F. A.; Chassaing,
B.; Shashidharamurthy, R.; Borregaard, N.; Jones, D. P.; Gewirtz,
A. T.; Vijay-Kumar, M.: Lipocalin 2 deficiency dysregulates iron
homeostasis and exacerbates endotoxin-induced sepsis. J. Immun. 189:
1911-1919, 2012.
13. Yang, J.; Bielenberg, D. R.; Rodig, S. J.; Doiron, R.; Clifton,
M. C.; Kung, A. L.; Strong, R. K.; Zurakowski, D.; Moses, M. A.:
Lipocalin 2 promotes breast cancer progression. Proc. Nat. Acad.
Sci. 106: 3913-3918, 2009.
14. Yang, J.; Goetz, D.; Li, J.-Y.; Wang, W.; Mori, K.; Setlik, D.;
Du, T.; Erdjument-Bromage, H.; Tempst, P.; Strong, R.; Barasch, J.
: An iron delivery pathway mediated by lipocalin. Molec. Cell 10:
1045-1056, 2002.
*FIELD* CN
Paul J. Converse - updated: 06/25/2013
Patricia A. Hartz - updated: 2/23/2012
Patricia A. Hartz - updated: 10/21/2011
Paul J. Converse - updated: 7/1/2011
Cassandra L. Kniffin - updated: 6/25/2009
Marla J. F. O'Neill - updated: 11/17/2006
Paul J. Converse - updated: 3/24/2006
Ada Hamosh - updated: 12/29/2004
Stylianos E. Antonarakis - updated: 4/29/2003
Ada Hamosh - updated: 8/27/2001
Patti M. Sherman - updated: 5/24/2000
*FIELD* CD
Victor A. McKusick: 11/8/1994
*FIELD* ED
mgross: 06/25/2013
mgross: 3/6/2012
terry: 2/23/2012
terry: 1/17/2012
mgross: 10/27/2011
terry: 10/21/2011
mgross: 7/7/2011
terry: 7/1/2011
wwang: 7/23/2009
ckniffin: 6/25/2009
wwang: 11/17/2006
mgross: 5/3/2006
terry: 3/24/2006
alopez: 12/30/2004
terry: 12/29/2004
mgross: 4/29/2003
alopez: 8/30/2001
terry: 8/27/2001
mcapotos: 6/16/2000
psherman: 5/24/2000
carol: 9/16/1998
psherman: 4/7/1998
alopez: 10/3/1997
jamie: 1/17/1997
carol: 11/18/1994
terry: 11/8/1994