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Identification
HMDB Protein ID HMDBP00100
Secondary Accession Numbers
  • 5332
Name Macrophage migration inhibitory factor
Synonyms
  1. GIF
  2. Glycosylation-inhibiting factor
  3. L-dopachrome isomerase
  4. L-dopachrome tautomerase
  5. MIF
  6. Phenylpyruvate tautomerase
Gene Name MIF
Protein Type Enzyme
Biological Properties
General Function Involved in cell surface binding
Specific Function Pro-inflammatory cytokine. Involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti-inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity.
Pathways
  • Alkaptonuria
  • Disulfiram Action Pathway
  • Dopamine beta-hydroxylase deficiency
  • Hawkinsinuria
  • Monoamine oxidase-a deficiency (MAO-A)
  • Phenylalanine metabolism
  • Tyrosine Metabolism
  • Tyrosine metabolism
  • Tyrosinemia Type I
  • Tyrosinemia, transient, of the newborn
Reactions
Phenylpyruvic acid → Enol-phenylpyruvate details
L-Dopachrome → 5,6-Dihydroxyindole-2-carboxylic acid details
Phenylpyruvic acid → Enol-phenylpyruvate details
4-Hydroxyphenylpyruvic acid → 2-Hydroxy-3-(4-hydroxyphenyl)propenoic acid details
GO Classification
Biological Process
negative regulation of apoptotic process
positive regulation of fibroblast proliferation
cell proliferation
inflammatory response
positive regulation of ERK1 and ERK2 cascade
positive regulation of peptidyl-tyrosine phosphorylation
cell surface receptor signaling pathway
innate immune response
positive regulation of B cell proliferation
protein homotrimerization
negative regulation of cell aging
negative regulation of cell cycle arrest
negative regulation of DNA damage response, signal transduction by p53 class mediator
negative regulation of gene expression
positive regulation of cytokine secretion
positive regulation of peptidyl-serine phosphorylation
positive regulation of protein kinase A signaling cascade
regulation of macrophage activation
prostaglandin biosynthetic process
Cellular Component
cell surface
cytoplasm
extracellular region
extracellular space
Molecular Function
chemoattractant activity
dopachrome isomerase activity
cell surface binding
cytokine activity
phenylpyruvate tautomerase activity
Cellular Location
  1. Cytoplasm
  2. Secreted
Gene Properties
Chromosome Location 22
Locus 22q11.23
SNPs MIF
Gene Sequence
>348 bp
ATGCCGATGTTCATCGTAAACACCAACGTGCCCCGCGCCTCCGTGCCGGACGGGTTCCTC
TCCGAGCTCACCCAGCAGCTGGCGCAGGCCACCGGCAAGCCCCCCCAGTACATCGCGGTG
CACGTGGTCCCGGACCAGCTCATGGCCTTCGGCGGCTCCAGCGAGCCGTGCGCGCTCTGC
AGCCTGCACAGCATCGGCAAGATCGGCGGCGCGCAGAACCGCTCCTACAGCAAGCTGCTG
TGCGGCCTGCTGGCCGAGCGCCTGCGCATCAGCCCGGACAGGGTCTACATCAACTATTAC
GACATGAACGCGGCCAATGTGGGCTGGAACAACTCCACCTTCGCCTAA
Protein Properties
Number of Residues 115
Molecular Weight 12476.19
Theoretical pI 7.885
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>Macrophage migration inhibitory factor
MPMFIVNTNVPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMAFGGSSEPCALC
SLHSIGKIGGAQNRSYSKLLCGLLAERLRISPDRVYINYYDMNAANVGWNNSTFA
GenBank ID Protein 18699569
UniProtKB/Swiss-Prot ID P14174
UniProtKB/Swiss-Prot Entry Name MIF_HUMAN
PDB IDs
GenBank Gene ID AF469046
GeneCard ID MIF
GenAtlas ID MIF
HGNC ID HGNC:7097
References
General References
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  4. Hochstrasser DF, Frutiger S, Paquet N, Bairoch A, Ravier F, Pasquali C, Sanchez JC, Tissot JD, Bjellqvist B, Vargas R, et al.: Human liver protein map: a reference database established by microsequencing and gel comparison. Electrophoresis. 1992 Dec;13(12):992-1001. [PubMed:1286669 ]
  5. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40. doi: 10.1126/science.1175371. Epub 2009 Jul 16. [PubMed:19608861 ]
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  7. Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I: A genome annotation-driven approach to cloning the human ORFeome. Genome Biol. 2004;5(10):R84. Epub 2004 Sep 30. [PubMed:15461802 ]
  8. Weiser WY, Temple PA, Witek-Giannotti JS, Remold HG, Clark SC, David JR: Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7522-6. [PubMed:2552447 ]
  9. Mikayama T, Nakano T, Gomi H, Nakagawa Y, Liu YC, Sato M, Iwamatsu A, Ishii Y, Weiser WY, Ishizaka K: Molecular cloning and functional expression of a cDNA encoding glycosylation-inhibiting factor. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10056-60. [PubMed:8234256 ]
  10. Bernhagen J, Mitchell RA, Calandra T, Voelter W, Cerami A, Bucala R: Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry. 1994 Nov 29;33(47):14144-55. [PubMed:7947826 ]
  11. Paralkar V, Wistow G: Cloning the human gene for macrophage migration inhibitory factor (MIF). Genomics. 1994 Jan 1;19(1):48-51. [PubMed:8188240 ]
  12. Zeng FY, Weiser WY, Kratzin H, Stahl B, Karas M, Gabius HJ: The major binding protein of the interferon antagonist sarcolectin in human placenta is a macrophage migration inhibitory factor. Arch Biochem Biophys. 1993 May 15;303(1):74-80. [PubMed:7683862 ]
  13. Wistow GJ, Shaughnessy MP, Lee DC, Hodin J, Zelenka PS: A macrophage migration inhibitory factor is expressed in the differentiating cells of the eye lens. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1272-5. [PubMed:7679497 ]
  14. Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes FJ, Roger T, Calandra T, Kapurniotu A, Grell M, Finkelmeier D, Brunner H, Bernhagen J: Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature. 2000 Nov 9;408(6809):211-6. [PubMed:11089976 ]
  15. Donn RP, Shelley E, Ollier WE, Thomson W: A novel 5'-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2001 Aug;44(8):1782-5. [PubMed:11508429 ]
  16. Tan TH, Edgerton SA, Kumari R, McAlister MS, Roe SM, Nagl S, Pearl LH, Selkirk ME, Bianco AE, Totty NF, Engwerda C, Gray CA, Meyer DJ: Macrophage migration inhibitory factor of the parasitic nematode Trichinella spiralis. Biochem J. 2001 Jul 15;357(Pt 2):373-83. [PubMed:11439086 ]
  17. Shen L, Hu J, Lu H, Wu M, Qin W, Wan D, Li YY, Gu J: The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER. FEBS Lett. 2003 Apr 10;540(1-3):86-90. [PubMed:12681488 ]
  18. Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R: MIF signal transduction initiated by binding to CD74. J Exp Med. 2003 Jun 2;197(11):1467-76. [PubMed:12782713 ]
  19. Oddo M, Calandra T, Bucala R, Meylan PR: Macrophage migration inhibitory factor reduces the growth of virulent Mycobacterium tuberculosis in human macrophages. Infect Immun. 2005 Jun;73(6):3783-6. [PubMed:15908412 ]
  20. Emonts M, Sweep FC, Grebenchtchikov N, Geurts-Moespot A, Knaup M, Chanson AL, Erard V, Renner P, Hermans PW, Hazelzet JA, Calandra T: Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis. Clin Infect Dis. 2007 May 15;44(10):1321-8. Epub 2007 Apr 5. [PubMed:17443469 ]
  21. Merk M, Baugh J, Zierow S, Leng L, Pal U, Lee SJ, Ebert AD, Mizue Y, Trent JO, Mitchell R, Nickel W, Kavathas PB, Bernhagen J, Bucala R: The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor. J Immunol. 2009 Jun 1;182(11):6896-906. doi: 10.4049/jimmunol.0803710. [PubMed:19454686 ]
  22. Sugimoto H, Suzuki M, Nakagawa A, Tanaka I, Nishihira J: Crystal structure of macrophage migration inhibitory factor from human lymphocyte at 2.1 A resolution. FEBS Lett. 1996 Jul 1;389(2):145-8. [PubMed:8766818 ]
  23. Kato Y, Muto T, Tomura T, Tsumura H, Watarai H, Mikayama T, Ishizaka K, Kuroki R: The crystal structure of human glycosylation-inhibiting factor is a trimeric barrel with three 6-stranded beta-sheets. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3007-10. [PubMed:8610159 ]
  24. Sun HW, Bernhagen J, Bucala R, Lolis E: Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5191-6. [PubMed:8643551 ]
  25. Lubetsky JB, Swope M, Dealwis C, Blake P, Lolis E: Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in the phenylpyruvate tautomerase activity. Biochemistry. 1999 Jun 1;38(22):7346-54. [PubMed:10353846 ]
  26. Orita M, Yamamoto S, Katayama N, Aoki M, Takayama K, Yamagiwa Y, Seki N, Suzuki H, Kurihara H, Sakashita H, Takeuchi M, Fujita S, Yamada T, Tanaka A: Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography. J Med Chem. 2001 Feb 15;44(4):540-7. [PubMed:11170644 ]
  27. Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y: Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor. J Biol Chem. 2007 Aug 10;282(32):23089-95. Epub 2007 May 25. [PubMed:17526494 ]
  28. Crichlow GV, Lubetsky JB, Leng L, Bucala R, Lolis EJ: Structural and kinetic analyses of macrophage migration inhibitory factor active site interactions. Biochemistry. 2009 Jan 13;48(1):132-9. doi: 10.1021/bi8014423. [PubMed:19090677 ]