ID MIF_HUMAN Reviewed; 115 AA. AC P14174; A5Z1R8; B2R4S3; Q2V4Y5; Q6FHV0; DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 4. DT 11-NOV-2015, entry version 188. DE RecName: Full=Macrophage migration inhibitory factor; DE Short=MIF; DE EC=5.3.2.1; DE AltName: Full=Glycosylation-inhibiting factor; DE Short=GIF; DE AltName: Full=L-dopachrome isomerase; DE AltName: Full=L-dopachrome tautomerase; DE EC=5.3.3.12; DE AltName: Full=Phenylpyruvate tautomerase; GN Name=MIF; Synonyms=GLIF, MMIF; 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], INDUCTION, AND SUBCELLULAR LOCATION. RX PubMed=2552447; DOI=10.1073/pnas.86.19.7522; RA Weiser W.Y., Temple P.A., Witek-Giannotti J.S., Remold H.G., RA Clark S.C., David J.R.; RT "Molecular cloning of a cDNA encoding a human macrophage migration RT inhibitory factor."; RL Proc. Natl. Acad. Sci. U.S.A. 86:7522-7526(1989). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION. RX PubMed=8234256; DOI=10.1073/pnas.90.21.10056; RA Mikayama T., Nakano T., Gomi H., Nakagawa Y., Liu Y.C., Iwamatsu A., RA Weiser W.Y., Ishizaka K., Sato M., Ishii Y.; RT "Molecular cloning and functional expression of a cDNA encoding RT glycosylation-inhibiting factor."; RL Proc. Natl. Acad. Sci. U.S.A. 90:10056-10060(1993). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=7947826; DOI=10.1021/bi00251a025; RA Bernhagen J., Mitchell R.A., Calandra T., Voelter W., Cerami A., RA Bucala R.; RT "Purification, bioactivity, and secondary structure analysis of mouse RT and human macrophage migration inhibitory factor (MIF)."; RL Biochemistry 33:14144-14155(1994). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8188240; DOI=10.1006/geno.1994.1011; RA Paralkar V., Wistow G.J.; RT "Cloning the human gene for macrophage migration inhibitory factor RT (MIF)."; RL Genomics 19:48-51(1994). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Shan Z.X., Yu X.Y., Lin S.G., Lin Q.X., Fu Y.H., Tan H.H.; RT "The effect of macrophage migration inhibitory factor in the RT atherogenesis process."; RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Wu S.H., Xie J., Shang H.X., Li Y., Zhang Z.; RT "Amplification and expression of macrophage migration inhibitory RT factor (MIF) in tissue of squamous carcinoma of the cervix."; RL Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84; RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A., RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J., RA Beare D.M., Dunham I.; RT "A genome annotation-driven approach to cloning the human ORFeome."; RL Genome Biol. 5:R84.1-R84.11(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor RT vector."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases. RN [12] 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 [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, Lung, Skin, and Uterus; 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 [14] RP PROTEIN SEQUENCE OF 2-12. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., RA Thomas G.R., Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass RT spectrometric identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [15] RP PROTEIN SEQUENCE OF 2-11. RC TISSUE=Liver; RX PubMed=1286669; DOI=10.1002/elps.11501301201; RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F., RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R., RA Appel R.D., Hughes G.J.; RT "Human liver protein map: a reference database established by RT microsequencing and gel comparison."; RL Electrophoresis 13:992-1001(1992). RN [16] RP PROTEIN SEQUENCE OF 3-24. RX PubMed=7683862; DOI=10.1006/abbi.1993.1257; RA Zeng F.Y., Weiser W.Y., Kratzin H., Stahl B., Karas M., Gabius H.J.; RT "The major binding protein of the interferon antagonist sarcolectin in RT human placenta is a macrophage migration inhibitory factor."; RL Arch. Biochem. Biophys. 303:74-80(1993). RN [17] RP NUCLEOTIDE SEQUENCE [MRNA] OF 10-115. RC TISSUE=Lens; RX PubMed=7679497; DOI=10.1073/pnas.90.4.1272; RA Wistow G.J., Shaughnessy M., Lee D.C., Hodin J., Zelenka P.S.; RT "A macrophage migration inhibitory factor is expressed in the RT differentiating cells of the eye lens."; RL Proc. Natl. Acad. Sci. U.S.A. 90:1272-1275(1993). RN [18] RP INTERACTION WITH COPS5, AND SUBCELLULAR LOCATION. RX PubMed=11089976; DOI=10.1038/35041591; RA Kleemann R., Hausser A., Geiger G., Mischke R., Burger-Kentischer A., RA Flieger O., Johannes F.-J., Roger T., Calandra T., Kapurniotu A., RA Grell M., Finkelmeier D., Brunner H., Bernhagen J.; RT "Intracellular action of the cytokine MIF to modulate AP-1 activity RT and the cell cycle through Jab1."; RL Nature 408:211-216(2000). RN [19] RP INVOLVEMENT IN SUSCEPTIBILITY TO SYSTEMIC JUVENILE RHEUMATOID RP ARTHRITIS. RX PubMed=11508429; RX DOI=10.1002/1529-0131(200108)44:8<1782::AID-ART314>3.0.CO;2-#; RG The British peadiatric rheumatology study group; RA Donn R.P., Shelley E., Ollier W.E.R., Thomson W.; RT "A novel 5'-flanking region polymorphism of macrophage migration RT inhibitory factor is associated with systemic-onset juvenile RT idiopathic arthritis."; RL Arthritis Rheum. 44:1782-1785(2001). RN [20] RP BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=11439086; DOI=10.1042/0264-6021:3570373; RA Tan T.H.P., Edgerton S.A.V., Kumari R., McAlister M.S.B., Roe S.M., RA Nagl S., Pearl L.H., Selkirk M.E., Bianco A.E., Totty N.F., RA Engwerda C., Gray C.A., Meyer D.J., Rowe S.M.; RT "Macrophage migration inhibitory factor of the parasitic nematode RT Trichinella spiralis."; RL Biochem. J. 357:373-383(2001). RN [21] RP INTERACTION WITH BNIPL. RX PubMed=12681488; DOI=10.1016/S0014-5793(03)00229-1; RA Shen L., Hu J., Lu H., Wu M., Qin W., Wan D., Li Y.-Y., Gu J.; RT "The apoptosis-associated protein BNIPL interacts with two cell RT proliferation-related proteins, MIF and GFER."; RL FEBS Lett. 540:86-90(2003). RN [22] RP INTERACTION WITH CD74. RX PubMed=12782713; DOI=10.1084/jem.20030286; RA Leng L., Metz C.N., Fang Y., Xu J., Donnelly S., Baugh J., RA Delohery T., Chen Y., Mitchell R.A., Bucala R.; RT "MIF signal transduction initiated by binding to CD74."; RL J. Exp. Med. 197:1467-1476(2003). RN [23] RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION. RX PubMed=15908412; DOI=10.1128/IAI.73.6.3783-3786.2005; RA Oddo M., Calandra T., Bucala R., Meylan P.R.A.; RT "Macrophage migration inhibitory factor reduces the growth of virulent RT Mycobacterium tuberculosis in human macrophages."; RL Infect. Immun. 73:3783-3786(2005). RN [24] RP ROLE IN SEPSIS-RELATED DEATH. RX PubMed=17443469; DOI=10.1086/514344; RA Emonts M., Sweep F.C.G.J., Grebenchtchikov N., Geurts-Moespot A., RA Knaup M., Chanson A.L., Erard V., Renner P., Hermans P.W.M., RA Hazelzet J.A., Calandra T.; RT "Association between high levels of blood macrophage migration RT inhibitory factor, inappropriate adrenal response, and early death in RT patients with severe sepsis."; RL Clin. Infect. Dis. 44:1321-1328(2007). RN [25] RP SUBCELLULAR LOCATION, AND INTERACTION WITH USO1. RX PubMed=19454686; DOI=10.4049/jimmunol.0803710; RA Merk M., Baugh J., Zierow S., Leng L., Pal U., Lee S.J., Ebert A.D., RA Mizue Y., Trent J.O., Mitchell R., Nickel W., Kavathas P.B., RA Bernhagen J., Bucala R.; RT "The Golgi-associated protein p115 mediates the secretion of RT macrophage migration inhibitory factor."; RL J. Immunol. 182:6896-6906(2009). RN [26] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-78, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. 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 [27] 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 [28] RP CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS], AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.M111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., RA Meinnel T., Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [29] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. 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 [30] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [31] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., RA Ayoub D., Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS). RX PubMed=8766818; DOI=10.1016/0014-5793(96)00553-4; RA Sugimoto H., Suzuki M., Nakagawa A., Tanaka I., Nishihira J.; RT "Crystal structure of macrophage migration inhibitory factor from RT human lymphocyte at 2.1-A resolution."; RL FEBS Lett. 389:145-148(1996). RN [33] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS). RX PubMed=8610159; DOI=10.1073/pnas.93.7.3007; RA Kato Y., Muto T., Tomura T., Tsumura H., Watarai H., Mikayama T., RA Ishizaka K., Kuroki R.; RT "The crystal structure of human glycosylation-inhibiting factor is a RT trimeric barrel with three 6-stranded beta-sheets."; RL Proc. Natl. Acad. Sci. U.S.A. 93:3007-3010(1996). RN [34] RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS). RX PubMed=8643551; DOI=10.1073/pnas.93.11.5191; RA Sun H.W., Bernhagen J., Bucala R., Lolis E.; RT "Crystal structure at 2.6-A resolution of human macrophage migration RT inhibitory factor."; RL Proc. Natl. Acad. Sci. U.S.A. 93:5191-5196(1996). RN [35] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS). RX PubMed=10353846; DOI=10.1021/bi990306m; RA Lubetsky J.B., Swope M., Dealwis C., Blake P., Lolis E.; RT "Pro-1 of macrophage migration inhibitory factor functions as a RT catalytic base in the phenylpyruvate tautomerase activity."; RL Biochemistry 38:7346-7354(1999). RN [36] RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) IN COMPLEX WITH TAUTOMERASE RP INHIBITOR, AND CATALYTIC ACTIVITY. RX PubMed=11170644; DOI=10.1021/jm000386o; RA Orita M., Yamamoto S., Katayama N., Aoki M., Takayama K., Yamagiwa Y., RA Seki N., Suzuki H., Kurihara H., Sakashita H., Takeuchi M., Fujita S., RA Yamada T., Tanaka A.; RT "Coumarin and chromen-4-one analogues as tautomerase inhibitors of RT macrophage migration inhibitory factor: discovery and X-ray RT crystallography."; RL J. Med. Chem. 44:540-547(2001). RN [37] RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) IN COMPLEX WITH RP CARBONYLOXIME-BASED INHIBITORS, AND SUBUNIT. RX PubMed=17526494; DOI=10.1074/jbc.M701825200; RA Crichlow G.V., Cheng K.F., Dabideen D., Ochani M., Aljabari B., RA Pavlov V.A., Miller E.J., Lolis E., Al-Abed Y.; RT "Alternative chemical modifications reverse the binding orientation of RT a pharmacophore scaffold in the active site of macrophage migration RT inhibitory factor."; RL J. Biol. Chem. 282:23089-23095(2007). RN [38] RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) IN COMPLEX WITH THE INHIBITOR RP N-ACETYL-P-BENZOQUINONE IMINE, SUBUNIT, AND CATALYTIC ACTIVITY. RX PubMed=19090677; DOI=10.1021/bi8014423; RA Crichlow G.V., Lubetsky J.B., Leng L., Bucala R., Lolis E.J.; RT "Structural and kinetic analyses of macrophage migration inhibitory RT factor active site interactions."; RL Biochemistry 48:132-139(2009). RN [39] RP X-RAY CRYSTALLOGRAPHY (2.33 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY, RP INTERACTION WITH CD74, MUTAGENESIS OF ASN-111, AND SUBUNIT. RX PubMed=23776208; DOI=10.1073/pnas.1221817110; RA Fan C., Rajasekaran D., Syed M.A., Leng L., Loria J.P., Bhandari V., RA Bucala R., Lolis E.J.; RT "MIF intersubunit disulfide mutant antagonist supports activation of RT CD74 by endogenous MIF trimer at physiologic concentrations."; RL Proc. Natl. Acad. Sci. U.S.A. 110:10994-10999(2013). CC -!- FUNCTION: Pro-inflammatory cytokine. Involved in the innate immune CC response to bacterial pathogens. The expression of MIF at sites of CC inflammation suggests a role as mediator in regulating the CC function of macrophages in host defense. Counteracts the anti- CC inflammatory activity of glucocorticoids. Has phenylpyruvate CC tautomerase and dopachrome tautomerase activity (in vitro), but CC the physiological substrate is not known. It is not clear whether CC the tautomerase activity has any physiological relevance, and CC whether it is important for cytokine activity. CC {ECO:0000269|PubMed:15908412, ECO:0000269|PubMed:17443469, CC ECO:0000269|PubMed:23776208}. CC -!- CATALYTIC ACTIVITY: Keto-phenylpyruvate = enol-phenylpyruvate. CC -!- CATALYTIC ACTIVITY: L-dopachrome = 5,6-dihydroxyindole-2- CC carboxylate. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=249 uM for phenylpyruvate {ECO:0000269|PubMed:11439086}; CC KM=168 uM for p-hydroxyphenylpyruvate CC {ECO:0000269|PubMed:11439086}; CC Vmax=2113 umol/min/mg enzyme toward phenylpyruvate CC {ECO:0000269|PubMed:11439086}; CC Vmax=524 umol/min/mg enzyme toward p-hydroxyphenylpyruvate CC {ECO:0000269|PubMed:11439086}; CC -!- SUBUNIT: Homotrimer. Interacts with CXCR2 extracellular domain (By CC similarity). Interacts with the CD74 extracellular domain, COPS5 CC and BNIPL. {ECO:0000250, ECO:0000269|PubMed:11089976, CC ECO:0000269|PubMed:11170644, ECO:0000269|PubMed:12681488, CC ECO:0000269|PubMed:12782713, ECO:0000269|PubMed:17526494, CC ECO:0000269|PubMed:19090677, ECO:0000269|PubMed:19454686, CC ECO:0000269|PubMed:23776208}. CC -!- INTERACTION: CC O43521-2:BCL2L11; NbExp=5; IntAct=EBI-372712, EBI-526420; CC -!- SUBCELLULAR LOCATION: Secreted. Cytoplasm. Note=Does not have a CC cleavable signal sequence and is secreted via a specialized, non- CC classical pathway. Secreted by macrophages upon stimulation by CC bacterial lipopolysaccharide (LPS), or by M.tuberculosis antigens. CC -!- INDUCTION: Up-regulated in concanavalin-A-treated lymphocytes. Up- CC regulated in macrophages upon exposure to M.tuberculosis antigens. CC {ECO:0000269|PubMed:15908412, ECO:0000269|PubMed:2552447}. CC -!- DISEASE: Rheumatoid arthritis systemic juvenile (RASJ) CC [MIM:604302]: An inflammatory articular disorder with systemic- CC onset beginning before the age of 16. It represents a subgroup of CC juvenile arthritis associated with severe extraarticular features CC and occasionally fatal complications. During active phases of the CC disorder, patients display a typical daily spiking fever, an CC evanescent macular rash, lymphadenopathy, hepatosplenomegaly, CC serositis, myalgia and arthritis. Note=Disease susceptibility is CC associated with variations affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: Serum levels of MIF are elevated in patients with CC severe sepsis or septic shock. High levels of MIF are correlated CC with low survival. Drugs that inhibit tautomerase activity protect CC against death due to sepsis. CC -!- SIMILARITY: Belongs to the MIF family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/mif/"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/MIFID41365ch22q11.html"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M25639; AAA36315.1; -; mRNA. DR EMBL; L10612; AAA35892.1; -; mRNA. DR EMBL; Z23063; CAA80598.1; -; mRNA. DR EMBL; L19686; AAA21814.1; -; Genomic_DNA. DR EMBL; AF469046; AAL78635.1; -; mRNA. DR EMBL; EF611126; ABQ95571.1; -; mRNA. DR EMBL; CR456520; CAG30406.1; -; mRNA. DR EMBL; AK311929; BAG34870.1; -; mRNA. DR EMBL; CR407644; CAG28572.1; -; mRNA. DR EMBL; CR541651; CAG46452.1; -; mRNA. DR EMBL; BT007148; AAP35812.1; -; mRNA. DR EMBL; DQ307455; ABB96245.1; -; Genomic_DNA. DR EMBL; CH471095; EAW59620.1; -; Genomic_DNA. DR EMBL; BC000447; AAH00447.1; -; mRNA. DR EMBL; BC007676; AAH07676.1; -; mRNA. DR EMBL; BC008914; AAH08914.1; -; mRNA. DR EMBL; BC013976; AAH13976.1; -; mRNA. DR EMBL; BC022414; AAH22414.1; -; mRNA. DR EMBL; BC053376; AAH53376.1; -; mRNA. DR EMBL; M95775; AAA36179.1; -; mRNA. DR CCDS; CCDS13819.1; -. DR PIR; A48793; A48793. DR RefSeq; NP_002406.1; NM_002415.1. DR UniGene; Hs.407995; -. DR PDB; 1CA7; X-ray; 2.50 A; A/B/C=2-115. DR PDB; 1CGQ; X-ray; 2.00 A; A/B/C=2-115. DR PDB; 1GCZ; X-ray; 1.90 A; A/B/C=2-115. DR PDB; 1GD0; X-ray; 1.50 A; A/B/C=2-115. DR PDB; 1GIF; X-ray; 1.90 A; A/B/C=1-115. DR PDB; 1LJT; X-ray; 2.00 A; A/B/C=2-115. DR PDB; 1MIF; X-ray; 2.60 A; A/B/C=1-115. DR PDB; 1P1G; X-ray; 2.50 A; A/B/C=2-115. DR PDB; 2OOH; X-ray; 1.85 A; A/B/C=2-115. DR PDB; 2OOW; X-ray; 1.75 A; A/B/C=2-115. DR PDB; 2OOZ; X-ray; 1.80 A; A/B/C=2-115. DR PDB; 3B9S; X-ray; 1.80 A; A/B/C=2-115. DR PDB; 3CE4; X-ray; 1.55 A; A/B/C=2-115. DR PDB; 3DJH; X-ray; 1.25 A; A/B/C=2-115. DR PDB; 3DJI; X-ray; 1.95 A; A/B/C/D/E/F=2-115. DR PDB; 3HOF; X-ray; 1.90 A; A/B/C=1-115. DR PDB; 3IJG; X-ray; 1.70 A; A/B/C=2-115. DR PDB; 3IJJ; X-ray; 1.25 A; A/B/C=2-115. DR PDB; 3JSF; X-ray; 1.93 A; A/B/C=2-115. DR PDB; 3JSG; X-ray; 1.58 A; A/B/C=2-115. DR PDB; 3JTU; X-ray; 1.86 A; A/B/C=2-115. DR PDB; 3L5P; X-ray; 1.80 A; A/B/C=2-115. DR PDB; 3L5R; X-ray; 1.94 A; A/B/C=2-115. DR PDB; 3L5S; X-ray; 1.86 A; A/B/C=2-115. DR PDB; 3L5T; X-ray; 1.86 A; A/B/C=2-115. DR PDB; 3L5U; X-ray; 1.90 A; A/B/C=2-115. DR PDB; 3L5V; X-ray; 1.70 A; A/B/C=2-115. DR PDB; 3SMB; X-ray; 1.60 A; A/B/C=2-115. DR PDB; 3SMC; X-ray; 1.80 A; A/B/C=2-115. DR PDB; 3U18; X-ray; 1.90 A; A/B/C=2-115. DR PDB; 3WNR; X-ray; 2.01 A; A/B/C=2-115. DR PDB; 3WNS; X-ray; 1.66 A; A/B/C=2-115. DR PDB; 3WNT; X-ray; 2.07 A; A/B/C=2-115. DR PDB; 4ETG; X-ray; 1.61 A; A/B/C=2-115. DR PDB; 4EUI; X-ray; 1.70 A; A/B/C=2-115. DR PDB; 4EVG; X-ray; 1.70 A; A/B/C=2-115. DR PDB; 4F2K; X-ray; 1.53 A; A/B/C=2-115. DR PDB; 4GRN; X-ray; 1.25 A; A/B/C=2-115. DR PDB; 4GRO; X-ray; 2.00 A; A/B/C/D/E/F/G/H=2-115. DR PDB; 4GRP; X-ray; 1.27 A; A/B/C=2-115. DR PDB; 4GRQ; X-ray; 1.65 A; A/B/C=2-115. DR PDB; 4GRR; X-ray; 1.47 A; A/B/C=3-115. DR PDB; 4GRU; X-ray; 1.92 A; A/B/C=2-115. DR PDB; 4GUM; X-ray; 2.33 A; A/B/C/D/E/F/G/H/I=2-115. DR PDB; 4K9G; X-ray; 1.55 A; A/B/C=2-115. DR PDB; 4OSF; X-ray; 1.62 A; A/B/C=2-115. DR PDB; 4OYQ; X-ray; 1.70 A; A/B/C=2-115. DR PDB; 4P01; X-ray; 2.07 A; A/B/C=2-115. DR PDB; 4P0H; X-ray; 1.93 A; A/B/C=2-115. DR PDB; 4WR8; X-ray; 2.60 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=2-115. DR PDB; 4WRB; X-ray; 1.81 A; A/B/C=2-115. DR PDBsum; 1CA7; -. DR PDBsum; 1CGQ; -. DR PDBsum; 1GCZ; -. DR PDBsum; 1GD0; -. DR PDBsum; 1GIF; -. DR PDBsum; 1LJT; -. DR PDBsum; 1MIF; -. DR PDBsum; 1P1G; -. DR PDBsum; 2OOH; -. DR PDBsum; 2OOW; -. DR PDBsum; 2OOZ; -. DR PDBsum; 3B9S; -. DR PDBsum; 3CE4; -. DR PDBsum; 3DJH; -. DR PDBsum; 3DJI; -. DR PDBsum; 3HOF; -. DR PDBsum; 3IJG; -. DR PDBsum; 3IJJ; -. DR PDBsum; 3JSF; -. DR PDBsum; 3JSG; -. DR PDBsum; 3JTU; -. DR PDBsum; 3L5P; -. DR PDBsum; 3L5R; -. DR PDBsum; 3L5S; -. DR PDBsum; 3L5T; -. DR PDBsum; 3L5U; -. DR PDBsum; 3L5V; -. DR PDBsum; 3SMB; -. DR PDBsum; 3SMC; -. DR PDBsum; 3U18; -. DR PDBsum; 3WNR; -. DR PDBsum; 3WNS; -. DR PDBsum; 3WNT; -. DR PDBsum; 4ETG; -. DR PDBsum; 4EUI; -. DR PDBsum; 4EVG; -. DR PDBsum; 4F2K; -. DR PDBsum; 4GRN; -. DR PDBsum; 4GRO; -. DR PDBsum; 4GRP; -. DR PDBsum; 4GRQ; -. DR PDBsum; 4GRR; -. DR PDBsum; 4GRU; -. DR PDBsum; 4GUM; -. DR PDBsum; 4K9G; -. DR PDBsum; 4OSF; -. DR PDBsum; 4OYQ; -. DR PDBsum; 4P01; -. DR PDBsum; 4P0H; -. DR PDBsum; 4WR8; -. DR PDBsum; 4WRB; -. DR ProteinModelPortal; P14174; -. DR SMR; P14174; 2-115. DR BioGrid; 110428; 25. DR DIP; DIP-31137N; -. DR IntAct; P14174; 17. DR MINT; MINT-5000040; -. DR STRING; 9606.ENSP00000215754; -. DR BindingDB; P14174; -. DR ChEMBL; CHEMBL2111430; -. DR PhosphoSite; P14174; -. DR DMDM; 1170955; -. DR SWISS-2DPAGE; P14174; -. DR MaxQB; P14174; -. DR PaxDb; P14174; -. DR PeptideAtlas; P14174; -. DR PRIDE; P14174; -. DR DNASU; 4282; -. DR Ensembl; ENST00000215754; ENSP00000215754; ENSG00000240972. DR Ensembl; ENST00000613839; ENSP00000482779; ENSG00000276701. DR GeneID; 4282; -. DR KEGG; hsa:4282; -. DR UCSC; uc002zyr.1; human. DR CTD; 4282; -. DR GeneCards; MIF; -. DR H-InvDB; HIX0041297; -. DR HGNC; HGNC:7097; MIF. DR HPA; CAB005284; -. DR HPA; HPA003868; -. DR MIM; 153620; gene. DR MIM; 604302; phenotype. DR neXtProt; NX_P14174; -. DR Orphanet; 85414; Systemic-onset juvenile idiopathic arthritis. DR PharmGKB; PA30819; -. DR eggNOG; KOG1759; Eukaryota. DR eggNOG; ENOG41122MF; LUCA. DR GeneTree; ENSGT00730000111101; -. DR HOGENOM; HOG000112325; -. DR HOVERGEN; HBG003240; -. DR InParanoid; P14174; -. DR KO; K07253; -. DR OMA; MGKPAQY; -. DR OrthoDB; EOG7GXPDN; -. DR PhylomeDB; P14174; -. DR TreeFam; TF313853; -. DR BRENDA; 5.3.2.1; 2681. DR BRENDA; 5.3.3.12; 2681. DR EvolutionaryTrace; P14174; -. DR GeneWiki; Macrophage_migration_inhibitory_factor; -. DR GenomeRNAi; 4282; -. DR NextBio; 16845; -. DR PRO; PR:P14174; -. DR Proteomes; UP000005640; Chromosome 22. DR Bgee; P14174; -. DR CleanEx; HS_MIF; -. DR ExpressionAtlas; P14174; baseline and differential. DR Genevisible; P14174; HS. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW. DR GO; GO:0043209; C:myelin sheath; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0031982; C:vesicle; IDA:UniProtKB. DR GO; GO:0042056; F:chemoattractant activity; IDA:BHF-UCL. DR GO; GO:0005125; F:cytokine activity; IDA:UniProtKB. DR GO; GO:0005126; F:cytokine receptor binding; IPI:BHF-UCL. DR GO; GO:0004167; F:dopachrome isomerase activity; IDA:UniProtKB. DR GO; GO:0050178; F:phenylpyruvate tautomerase activity; IDA:MGI. DR GO; GO:0005102; F:receptor binding; IPI:BHF-UCL. DR GO; GO:0019752; P:carboxylic acid metabolic process; IDA:BHF-UCL. DR GO; GO:0007569; P:cell aging; IEA:Ensembl. DR GO; GO:0008283; P:cell proliferation; IDA:UniProtKB. DR GO; GO:0007166; P:cell surface receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; IEA:Ensembl. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0090344; P:negative regulation of cell aging; IDA:BHF-UCL. DR GO; GO:0071157; P:negative regulation of cell cycle arrest; IDA:BHF-UCL. DR GO; GO:0032269; P:negative regulation of cellular protein metabolic process; IEA:Ensembl. DR GO; GO:0043518; P:negative regulation of DNA damage response, signal transduction by p53 class mediator; IDA:BHF-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:BHF-UCL. DR GO; GO:1902166; P:negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IDA:BHF-UCL. DR GO; GO:0002906; P:negative regulation of mature B cell apoptotic process; IEA:Ensembl. DR GO; GO:0033033; P:negative regulation of myeloid cell apoptotic process; IEA:Ensembl. DR GO; GO:0050918; P:positive chemotaxis; IDA:GOC. DR GO; GO:0090238; P:positive regulation of arachidonic acid secretion; IEA:Ensembl. DR GO; GO:0030890; P:positive regulation of B cell proliferation; IDA:BHF-UCL. DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IEA:Ensembl. DR GO; GO:0050715; P:positive regulation of cytokine secretion; IDA:BHF-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL. DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IDA:BHF-UCL. DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl. DR GO; GO:0061081; P:positive regulation of myeloid leukocyte cytokine production involved in immune response; IEA:Ensembl. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:BHF-UCL. DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:BHF-UCL. DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:BHF-UCL. DR GO; GO:0061078; P:positive regulation of prostaglandin secretion involved in immune response; IEA:Ensembl. DR GO; GO:0010739; P:positive regulation of protein kinase A signaling; IDA:BHF-UCL. DR GO; GO:0001516; P:prostaglandin biosynthetic process; IDA:UniProtKB. DR GO; GO:0070207; P:protein homotrimerization; IPI:UniProtKB. DR GO; GO:0043030; P:regulation of macrophage activation; NAS:UniProtKB. DR InterPro; IPR001398; Macrophage_inhib_fac. DR InterPro; IPR019829; Macrophage_inhib_fac_CS. DR InterPro; IPR014347; Tautomerase/MIF_sf. DR PANTHER; PTHR11954; PTHR11954; 1. DR Pfam; PF01187; MIF; 1. DR ProDom; PD004816; Macrophage_inhib_fac; 1. DR SUPFAM; SSF55331; SSF55331; 1. DR PROSITE; PS01158; MIF; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Complete proteome; Cytokine; Cytoplasm; KW Direct protein sequencing; Immunity; Inflammatory response; KW Innate immunity; Isomerase; Reference proteome; Secreted. FT INIT_MET 1 1 Removed. {ECO:0000244|PubMed:22223895, FT ECO:0000269|PubMed:12665801, FT ECO:0000269|PubMed:1286669}. FT CHAIN 2 115 Macrophage migration inhibitory factor. FT /FTId=PRO_0000158062. FT ACT_SITE 2 2 Proton acceptor; via imino nitrogen. FT BINDING 33 33 Substrate. FT BINDING 65 65 Substrate; via amide nitrogen. FT BINDING 98 98 Substrate. FT MOD_RES 78 78 N6-acetyllysine; alternate. FT {ECO:0000244|PubMed:19608861}. FT MOD_RES 78 78 N6-succinyllysine; alternate. FT {ECO:0000250|UniProtKB:P34884}. FT MUTAGEN 111 111 N->C: Causes formation of interchain FT disulfide bonds with Cys-81 from another FT subunit. {ECO:0000269|PubMed:23776208}. FT CONFLICT 57 59 CAL -> WAF (in Ref. 6; ABQ95571). FT {ECO:0000305}. FT CONFLICT 67 67 K -> R (in Ref. 9; CAG46452). FT {ECO:0000305}. FT CONFLICT 79 79 L -> Q (in Ref. 9; CAG46452). FT {ECO:0000305}. FT CONFLICT 81 81 C -> F (in Ref. 6; ABQ95571). FT {ECO:0000305}. FT CONFLICT 106 106 N -> S (in Ref. 1; AAA36315). FT {ECO:0000305}. FT CONFLICT 113 113 T -> P (in Ref. 6; ABQ95571). FT {ECO:0000305}. FT STRAND 3 10 {ECO:0000244|PDB:3DJH}. FT HELIX 12 14 {ECO:0000244|PDB:3DJH}. FT HELIX 19 31 {ECO:0000244|PDB:3DJH}. FT HELIX 35 37 {ECO:0000244|PDB:3DJH}. FT STRAND 39 43 {ECO:0000244|PDB:3DJH}. FT STRAND 47 50 {ECO:0000244|PDB:3DJH}. FT STRAND 58 66 {ECO:0000244|PDB:3DJH}. FT HELIX 70 88 {ECO:0000244|PDB:3DJH}. FT HELIX 92 94 {ECO:0000244|PDB:3DJH}. FT STRAND 95 101 {ECO:0000244|PDB:3DJH}. FT HELIX 104 106 {ECO:0000244|PDB:3DJH}. FT STRAND 107 109 {ECO:0000244|PDB:3DJH}. FT STRAND 112 114 {ECO:0000244|PDB:1GD0}. SQ SEQUENCE 115 AA; 12476 MW; 56D51107C05286B2 CRC64; MPMFIVNTNV PRASVPDGFL SELTQQLAQA TGKPPQYIAV HVVPDQLMAF GGSSEPCALC SLHSIGKIGG AQNRSYSKLL CGLLAERLRI SPDRVYINYY DMNAANVGWN NSTFA //