Macrophage migration inhibitory factor (MIF) is a homotrimeric pleiotropic proinflammatory cytokine and phenylpyruvate/D-dopachrome tautomerase secreted via a non-classical leaderless export pathway. In the extracellular space, MIF functions as the high-affinity agonistic ligand for the cell-surface receptor CD74 (the MHC class II invariant chain), recruiting the signaling co-receptor CD44 to activate Src-family tyrosine kinases and the sustained ERK1/2 MAP kinase cascade, and also acts as a non-cognate chemoattractant ligand for the chemokine receptors CXCR2 and CXCR4. Through receptor-mediated signaling and intracellular interactions with COPS5/JAB1 and TP53, MIF promotes leukocyte recruitment and activation, counter-regulates glucocorticoid immunosuppression, and suppresses p53-dependent apoptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001516 prostaglandin biosynthetic process | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | MODIFY | Summary: MIF stimulates prostaglandin E2 production and secretion via CD74-dependent signaling rather than catalyzing prostaglandin biosynthesis directly. Reason: PMID:12782713 demonstrates that extracellular MIF binding to CD74 induces ERK1/2 activation and downstream PGE2 secretion into the medium. MIF is an upstream signaling cytokine rather than an enzyme in the prostaglandin biosynthetic pathway, so this annotation should be refined to positive regulation of prostaglandin secretion (GO:0032308), which MIF already carries. Proposed replacements: positive regulation of prostaglandin secretion Supporting Evidence: PMID:12782713 MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. |
| GO:0001819 positive regulation of cytokine production | IDA PMID:19602265 Dual role of macrophage migration inhibitory factor (MIF) in... | KEEP AS NON CORE | Summary: Exogenous MIF stimulates autocrine cytokine secretion in breast cancer cells. Reason: PMID:19602265 shows that stimulation of MDA-MB-231 breast cancer cells with exogenous MIF induces a strong upregulation of cytokine secretion. This is a valid downstream cellular effect of MIF signaling. Supporting Evidence: PMID:19602265 Stimulation with exogenous MIF led to a dramatic upregulation of MIF secretion (50-fold) in MDA-MB-231 cells. |
| GO:0002020 protease binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse Mif reflecting interaction with the serine protease HTRA1. Reason: Supported by experimental evidence in PMID:28726057 showing that MIF binds and inhibits the serine protease HTRA1. Retained as a non-core binding interaction. |
| GO:0002906 negative regulation of mature B cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MIF promotes mature B cell survival downstream of CD74-CD44 receptor signaling. Reason: Valid downstream cellular outcome of MIF-CD74-CD44 survival signaling in B lymphocytes, transferred from mouse Mif. |
| GO:0004167 dopachrome isomerase activity | IDA PMID:17526494 Alternative chemical modifications reverse the binding orien... | ACCEPT | Summary: Homotrimeric MIF catalyzes the tautomerization/isomerization of dopachrome methyl esters in its interfacial active site. Reason: PMID:17526494 directly assays the dopachrome tautomerase/isomerase activity of recombinant human MIF and determines high-resolution crystal structures of inhibitors bound in the catalytic site formed between subunits of the homotrimer. Supporting Evidence: PMID:17526494 We studied the crystal structures of MIF.OXIM-based inhibitors and found two opposite orientations for binding to the active site that were dependent on the chemical structures of an R-group. One orientation was completely unexpected based on previous studies with hydroxyphenylpyruvate and (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1). PMID:21817065 D-DT was named for its ability to tautomerize the nonnaturally occurring, D -stereoisomer of dopachrome, which is a catalytic property shared with MIF. |
| GO:0004167 dopachrome isomerase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated EC/Rhea mapping for dopachrome isomerase activity. Reason: Consistent with the experimentally demonstrated dopachrome tautomerase/isomerase activity of human MIF (PMID:17526494). |
| GO:0005125 cytokine activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cytokine activity from the bilaterian MIF family ancestor PTN000237513. Reason: MIF is a prototypical proinflammatory cytokine that binds cell-surface CD74 to activate intracellular signaling cascades. Both experimental seeds (mouse Mif MGI:96982 and human MIF UniProtKB:P14174) are directly verified. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:96982 SUPPORTS TRANSFER Mouse Mif is experimentally characterized as a proinflammatory cytokine ligand for CD74. UniProtKB:P14174 SUPPORTS TRANSFER Human MIF is the target gene product itself and has direct experimental support (PMID:12782713) for cytokine activity. |
| GO:0005125 cytokine activity | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | ACCEPT | Summary: Direct experimental demonstration that MIF acts as an extracellular cytokine ligand that binds CD74 to activate ERK1/2 signaling and cellular responses. Reason: PMID:12782713 demonstrates that recombinant human MIF binds the extracellular domain of CD74 with nanomolar affinity (Kd ~ 9 nM) to initiate ERK1/2 MAPK activation, PGE2 production, and cell proliferation, establishing its core cytokine activity (an is_a descendant of GO:0048018 receptor ligand activity). Supporting Evidence: PMID:12782713 MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. |
| GO:0005125 cytokine activity | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology transfer of cytokine activity from mouse Mif. Reason: Consistent with the core cytokine activity of human MIF. |
| GO:0005126 cytokine receptor binding | IDA PMID:21817065 The D-dopachrome tautomerase (DDT) gene product is a cytokin... | MODIFY | Summary: MIF binds the cytokine receptor CD74 with nanomolar affinity to initiate intracellular signaling, which is more precisely captured as cytokine activity. Reason: PMID:21817065 measures high-affinity binding of MIF and DDT to the CD74 ectodomain and demonstrates downstream ERK1/2 activation. Because MIF binds CD74 as an agonistic signaling ligand rather than a non-signaling scaffold, the activity is more specifically represented by GO:0005125 (cytokine activity, a descendant of GO:0048018 receptor ligand activity), which MIF already carries. Proposed replacements: cytokine activity Supporting Evidence: PMID:21817065 Measurement of the equilibrium dissociation constants between human D-DT or MIF and sCD74 by surface plasmon resonance (BIAcore analysis) revealed a high-affinity binding interaction between D-DT and the MIF receptor ( K D of 5.42 × 10 −9 M) ( Fig. 3 B ), albeit 60% lower than for MIF ( K D = 1.40 × 10 −9 M). |
| GO:0005126 cytokine receptor binding | IPI PMID:17045821 CD44 is the signaling component of the macrophage migration ... | MODIFY | Summary: MIF binds CD74 (UniProtKB:P04233) to activate CD74-CD44 receptor complex signaling, which is more specifically captured by cytokine activity. Reason: PMID:17045821 shows that MIF binds CD74 and induces serine phosphorylation of CD74 and CD44 to activate Src and ERK1/2 signaling. Because MIF acts as the agonistic cytokine ligand for the CD74-CD44 receptor complex, GO:0005125 (cytokine activity) is the more informative molecular function term. Proposed replacements: cytokine activity Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. |
| GO:0005515 protein binding | IPI PMID:12681488 The apoptosis-associated protein BNIPL interacts with two ce... | REMOVE | Summary: Uninformative general protein binding annotation for interaction with BNIPL. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy and does not describe a specific molecular function. |
| GO:0005515 protein binding | IPI PMID:17526494 Alternative chemical modifications reverse the binding orien... | REMOVE | Summary: Uninformative general protein binding annotation for MIF self-association. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy; MIF self-association is already captured by GO:0042802 (identical protein binding) and GO:0070207 (protein homotrimerization). |
| GO:0005515 protein binding | IPI PMID:18677096 Macrophage migration inhibitory factor (MIF) interacts with ... | REMOVE | Summary: Uninformative general protein binding annotation for interaction with BCL2L11 (Bim). Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Uninformative general protein binding annotation from high-throughput yeast two-hybrid screen. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy. |
| GO:0005515 protein binding | IPI PMID:26280537 Secreted and O-GlcNAcylated MIF binds to the human EGF recep... | REMOVE | Summary: Uninformative general protein binding annotation for interaction with EGFR. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy. |
| GO:0005515 protein binding | IPI PMID:28726057 Macrophage migration inhibitory factor (MIF) modulates troph... | REMOVE | Summary: Uninformative general protein binding annotation for interaction with HTRA1. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy; protease interaction is already represented by GO:0002020 (protease binding). |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Uninformative general protein binding annotation from high-throughput interactome assay. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy. |
| GO:0005576 extracellular region | EXP PMID:15908412 Macrophage migration inhibitory factor reduces the growth of... | ACCEPT | Summary: MIF is secreted into the extracellular space by infected macrophages. Reason: MIF functions primarily as a secreted extracellular cytokine. |
| GO:0005576 extracellular region | EXP PMID:19454686 The Golgi-associated protein p115 mediates the secretion of ... | ACCEPT | Summary: MIF is secreted into the extracellular medium via a p115-dependent non-classical export pathway. Reason: PMID:19454686 demonstrates regulated secretion of MIF into cell supernatants by monocytes and macrophages. Supporting Evidence: PMID:19454686 MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. |
| GO:0005576 extracellular region | EXP PMID:2552447 Molecular cloning of a cDNA encoding a human macrophage migr... | ACCEPT | Summary: Cloning and expression of secreted human MIF in cell supernatants. Reason: Foundational study cloning human MIF and demonstrating its activity in extracellular supernatants. |
| GO:0005576 extracellular region | EXP PMID:8234256 Molecular cloning and functional expression of a cDNA encodi... | ACCEPT | Summary: Extracellular secretion of MIF/GIF protein. Reason: Confirms extracellular localization of secreted human MIF. |
| GO:0005576 extracellular region | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | ACCEPT | Summary: Proteomic detection of MIF in the extracellular matrix of human veins. Reason: Consistent with the core extracellular localization of secreted MIF. Supporting Evidence: PMID:27068509 Extracellular matrix proteins were enriched from venous tissues. The proteomics analysis revealed the presence of >150 extracellular matrix proteins, of which 48 had not been previously detected in venous tissue. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that MIF family members are active in the extracellular region. Reason: Both MIF and DDT are secreted cytokines active in the extracellular space. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1298381 SUPPORTS TRANSFER Mouse Ddt is a secreted MIF-family cytokine active in the extracellular region. MGI:MGI:96982 SUPPORTS TRANSFER Mouse Mif is a secreted cytokine active in the extracellular space. RGD:621163 SUPPORTS TRANSFER Rat Ddt is a secreted member of the MIF/DDT family. UniProtKB:P14174 SUPPORTS TRANSFER Human MIF is the target protein itself and is experimentally verified in the extracellular region. UniProtKB:P30046 SUPPORTS TRANSFER Human DDT is experimentally verified as a secreted cytokine in the extracellular region (PMID:21817065). |
| GO:0005576 extracellular region | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | ACCEPT | Summary: MIF acts in the extracellular space to bind the ectodomain of CD74. Reason: PMID:12782713 demonstrates extracellular MIF binding to the cell-surface ectodomain of CD74. Supporting Evidence: PMID:12782713 MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. |
| GO:0005576 extracellular region | IDA PMID:21817065 The D-dopachrome tautomerase (DDT) gene product is a cytokin... | ACCEPT | Summary: Circulating extracellular MIF and DDT measured in serum and cell supernatants. Reason: PMID:21817065 demonstrates extracellular secretion and circulating levels of MIF and DDT. Supporting Evidence: PMID:21817065 Measurement of the equilibrium dissociation constants between human D-DT or MIF and sCD74 by surface plasmon resonance (BIAcore analysis) revealed a high-affinity binding interaction between D-DT and the MIF receptor ( K D of 5.42 × 10 −9 M) ( Fig. 3 B ), albeit 60% lower than for MIF ( K D = 1.40 × 10 −9 M). |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation to extracellular region from UniProt subcellular location and mouse orthology. Reason: Consistent with the core extracellular localization of MIF. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5676133 | ACCEPT | Summary: Reactome assertion that extracellular MIF binds cell-surface CD74. Reason: Matches experimentally verified extracellular site of MIF ligand action. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | ACCEPT | Summary: Reactome assertion of MIF release into the extracellular space. Reason: Consistent with extracellular localization of secreted MIF. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | ACCEPT | Summary: Reactome assertion of MIF release from granules into the extracellular region. Reason: Consistent with extracellular localization of secreted MIF. |
| GO:0005737 cytoplasm | EXP PMID:11089976 Intracellular action of the cytokine MIF to modulate AP-1 ac... | KEEP AS NON CORE | Summary: MIF localizes to the cytoplasm where it interacts with JAB1/COPS5. Reason: PMID:11089976 demonstrates that MIF is present in the cytoplasm/cytosol where it binds JAB1. Retained as non-core relative to its primary extracellular signaling role. Supporting Evidence: PMID:11089976 MIF colocalizes with Jab1 in the cytosol, and both endogenous and exogenously added MIF following endocytosis bind Jab1. |
| GO:0005737 cytoplasm | EXP PMID:19454686 The Golgi-associated protein p115 mediates the secretion of ... | KEEP AS NON CORE | Summary: Preformed cytoplasmic pools of MIF interact with p115 prior to leaderless secretion. Reason: PMID:19454686 shows that MIF resides in preformed cytoplasmic pools and interacts with p115 in the cytoplasm before export. Supporting Evidence: PMID:19454686 MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. |
| GO:0005737 cytoplasm | IDA PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 i... | KEEP AS NON CORE | Summary: Immunofluorescence detection of MIF in the cytoplasm of human cartilage end plate chondrocytes. Reason: Reflects intracellular storage pools of MIF prior to secretion. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping to cytoplasm. Reason: Consistent with cytoplasmic pools of MIF prior to non-classical secretion. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Immunofluorescence detection of MIF in the cytosol. Reason: Consistent with preformed cytosolic MIF pools and cytosolic JAB1 interaction (PMID:11089976). |
| GO:0005886 plasma membrane | IDA PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 i... | KEEP AS NON CORE | Summary: Detection of MIF at the plasma membrane of chondrocytes expressing CD74. Reason: MIF lacks a transmembrane domain or lipid anchor; plasma membrane staining reflects receptor-bound MIF at the cell surface. |
| GO:0007166 cell surface receptor signaling pathway | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | MODIFY | Summary: PMID:12782713 specifically characterizes the macrophage migration inhibitory factor signaling pathway (GO:0035691) initiated by MIF binding to CD74. Reason: PMID:12782713 is the foundational paper demonstrating that extracellular MIF binds the cell-surface receptor CD74 (Kd ~ 9 nM) to initiate the macrophage migration inhibitory factor signaling pathway (GO:0035691), recruiting the co-receptor CD44 to activate Src and ERK1/2 MAP kinase signaling (PMID:17045821; PMID:21817065). In GOA, GO:0035691 (a descendant of GO:0007166) is annotated only to the receptor CD74, whereas MIF itself was annotated to the parent term GO:0007166 in 2003 before GO:0035691 was created; refining this annotation to GO:0035691 places the canonical cytokine ligand in its cognate signaling pathway. Proposed replacements: macrophage migration inhibitory factor signaling pathway Supporting Evidence: PMID:12782713 Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. PMID:17045821 These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction. PMID:21817065 We produced recombinant D-DT and demonstrate that it binds with high affinity to CD74, activates the ERK1/2 MAP kinase signaling cascade, and recapitulates many of the inflammatory functions of MIF, including modulation of macrophage migration and glucocorticoid-induced immunosuppression. |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:10562313 A proinflammatory cytokine inhibits p53 tumor suppressor act... | KEEP AS NON CORE | Summary: MIF promotes cell proliferation by bypassing p53-mediated growth arrest. Reason: PMID:10562313 demonstrates that MIF overcomes p53-mediated growth arrest and promotes fibroblast proliferation. Retained as a downstream cellular outcome. Supporting Evidence: PMID:10562313 To identify novel regulators of p53, we undertook two functional screens to isolate genes which bypassed either p53-mediated growth arrest or apoptosis. In both screens, we isolated cDNAs encoding macrophage migration inhibitory factor (MIF), a cytokine that was shown previously to exert both local and systemic proinflammatory activities. |
| GO:0009986 cell surface | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | ACCEPT | Summary: Extracellular MIF binds to CD74 on the surface of target cells. Reason: PMID:12782713 demonstrates by flow cytometry and confocal microscopy that MIF localizes to the cell surface via high-affinity binding to the CD74 ectodomain. Supporting Evidence: PMID:12782713 Using expression cloning and functional analysis, we report the identification of CD74, the cell surface form of the class II–associated invariant chain, as a cell surface binding protein for MIF. |
| GO:0010629 negative regulation of gene expression | IDA PMID:10562313 A proinflammatory cytokine inhibits p53 tumor suppressor act... | KEEP AS NON CORE | Summary: MIF suppresses p53-dependent transcriptional activation. Reason: PMID:10562313 shows that MIF inhibits p53 activity as a transcriptional activator; retained as a non-core downstream regulatory effect. Supporting Evidence: PMID:10562313 Treatment with MIF overcame p53 activity in three different biological assays, and suppressed its activity as a transcriptional activator. |
| GO:0010760 negative regulation of macrophage chemotaxis | IDA PMID:21817065 The D-dopachrome tautomerase (DDT) gene product is a cytokin... | KEEP AS NON CORE | Summary: MIF and DDT inhibit random and MCP-1-induced macrophage migration via CD74 signaling. Reason: PMID:21817065 demonstrates that MIF and DDT inhibit macrophage chemotaxis/migration in a CD74-dependent manner, which is a defining cellular phenotype downstream of MIF receptor signaling. |
| GO:0030336 negative regulation of cell migration | IMP PMID:22952837 Macrophage migration inhibitory factor inhibits the migratio... | KEEP AS NON CORE | Summary: MIF inhibits migration of cartilage end plate-derived stem cells via CD74. Reason: PMID:22952837 shows that recombinant human MIF inhibits cartilage end plate-derived stem cell migration in a dose-dependent manner and that the MIF antagonist ISO-1 restores migration. Supporting Evidence: PMID:22952837 Additionally, recombinant human MIF (r-MIF) inhibited the migration of CESCs in a dose-dependent manner. CESCs migration was restored when an antagonist of MIF, (S, R)-3(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), was added. |
| GO:0030890 positive regulation of B cell proliferation | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: MIF stimulates Raji B cell proliferation in a CD74-dependent manner. Reason: PMID:12782713 demonstrates MIF-induced proliferation of human Raji B cells blocked by anti-CD74 monoclonal antibodies; retained as a downstream cellular outcome of MIF-CD74 signaling. |
| GO:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse Mif reflecting positive regulation of TLR4/LPS signaling in macrophages. Reason: Downstream immunomodulatory consequence of MIF signaling in macrophages. |
| GO:0031982 vesicle | HDA PMID:19190083 Characterization of exosome-like vesicles released from huma... | KEEP AS NON CORE | Summary: High-throughput proteomic identification of MIF in exosome-like vesicles from human tracheobronchial epithelium. Reason: Consistent with non-classical vesicular/exosomal export of MIF. |
| GO:0032308 positive regulation of prostaglandin secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MIF stimulates prostaglandin E2 secretion downstream of CD74 and ERK1/2 signaling. Reason: Directly supported in human cells as well (PMID:12782713, PMID:24569872) as a downstream output of MIF-CD74 signaling. |
| GO:0032760 positive regulation of tumor necrosis factor production | IDA PMID:21817065 The D-dopachrome tautomerase (DDT) gene product is a cytokin... | KEEP AS NON CORE | Summary: MIF acts upstream of TNF-alpha production in macrophages and endotoxemia. Reason: Downstream proinflammatory cytokine cascade output of MIF-CD74 signaling (PMID:21817065). |
| GO:0033033 negative regulation of myeloid cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MIF inhibits macrophage/myeloid cell apoptosis via CD74-CD44 signaling and p53 suppression. Reason: Downstream survival outcome of MIF signaling in myeloid cells. |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: Reactome annotation of MIF in secretory granule lumen. Reason: Reflects vesicular storage pools involved in regulated MIF exocytosis. |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-8950732 | KEEP AS NON CORE | Summary: Reactome annotation of MIF in secretory granule lumen. Reason: Reflects vesicular storage pools involved in regulated MIF exocytosis. |
| GO:0042056 chemoattractant activity | IDA PMID:19602265 Dual role of macrophage migration inhibitory factor (MIF) in... | ACCEPT | Summary: Extracellular MIF acts as a chemoattractant that promotes cell migration and invasion via non-cognate activation of chemokine receptors CXCR2 and CXCR4. Reason: PMID:19602265 demonstrates that recombinant human MIF acts as a chemoattractant in Transwell invasion/migration assays and functions as a non-cognate chemokine-like ligand for CXCR2 and CXCR4. Supporting Evidence: PMID:19602265 Sharing an architectural 3D similarity with the atherogenic and angiogenic chemokine interleukin-8 (IL-8)/CXCL8, MIF was found to function as a non-cognate ligand of CXCR2 and as chemokine-like function (CLF) chemokine. Inflammatory leukocyte recruitment is dependent on MIF-CXCR2 and MIF-CXCR4 interactions [5]. |
| GO:0042327 positive regulation of phosphorylation | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | MODIFY | Summary: MIF-induced phosphorylation of ERK1 and ERK2 in PMID:12782713 is more specifically captured by positive regulation of ERK1 and ERK2 cascade (GO:0070374). Reason: PMID:12782713 specifically assays MIF-dependent phosphorylation and activation of ERK1/2 (MAPK3/MAPK1) downstream of CD74 binding, which is more precisely represented by GO:0070374 (positive regulation of ERK1 and ERK2 cascade), a term MIF already carries from the same study. Proposed replacements: positive regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:12782713 MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. |
| GO:0042802 identical protein binding | IPI PMID:20534506 Allosteric inhibition of macrophage migration inhibitory fac... | KEEP AS NON CORE | Summary: MIF self-associates to form a physiological homotrimer in crystal structures. Reason: MIF is an obligate homotrimer with three interfacial catalytic pockets; retained as a non-core structural self-interaction. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Binary self-interaction of human MIF in yeast two-hybrid interactome screening. Reason: Consistent with physiological MIF homotrimerization. |
| GO:0042802 identical protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Self-interaction of human MIF in binary interactome screening. Reason: Consistent with physiological MIF homotrimerization. |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Self-interaction of human MIF in HuRI binary interactome map. Reason: Consistent with physiological MIF homotrimerization. |
| GO:0043030 regulation of macrophage activation | NAS PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: MIF regulates monocyte/macrophage activation downstream of CD74 binding. Reason: Downstream immunological process regulated by MIF-CD74 signaling. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: MIF suppresses apoptosis in serum-deprived fibroblasts. Reason: PMID:12782713 assays MIF-mediated suppression of apoptosis in primary fibroblasts; retained as a downstream cellular survival outcome of MIF signaling. Supporting Evidence: PMID:12782713 MIF-mediated suppression of apoptosis was assessed in serum-deprived, primary fibroblasts by immunoassay of cytoplasmic histone-associated DNA fragments (Roche Biochemicals; references 10, 26). |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer of anti-apoptotic function from mouse Mif. Reason: Consistent with human experimental evidence (PMID:12782713, PMID:17045821). |
| GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | KEEP AS NON CORE | Summary: MIF signaling through the CD74-CD44 complex suppresses p53-mediated apoptosis. Reason: PMID:17045821 shows that CD74 and CD44 are required for MIF-mediated protection from p53-dependent apoptosis; retained as a downstream cellular outcome. Supporting Evidence: PMID:17045821 Studies of CD74, CD44, and CD74-CD44 transformants and corresponding mutant cells showed that CD74 and CD44 were necessary for MIF protection from apoptosis. |
| GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse Mif for negative regulation of p53-mediated DNA damage signaling. Reason: Consistent with human experimental evidence (PMID:10562313, PMID:17045821). |
| GO:0045089 positive regulation of innate immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MIF promotes innate immune responses as an upstream proinflammatory cytokine. Reason: Valid system-level immunological role of MIF transferred from mouse Mif. |
| GO:0048146 positive regulation of fibroblast proliferation | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: MIF stimulates proliferation of normal human lung fibroblasts via CD74. Reason: PMID:12782713 demonstrates that MIF stimulates mitogenesis in human lung fibroblasts and that anti-CD74 antibodies block this effect; retained as a downstream cellular response. |
| GO:0048146 positive regulation of fibroblast proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer of fibroblast proliferation regulation from mouse Mif. Reason: Consistent with human experimental evidence in PMID:12782713. |
| GO:0050178 phenylpyruvate tautomerase activity | EXP PMID:11439086 Macrophage migration inhibitory factor of the parasitic nema... | ACCEPT | Summary: Human MIF catalyzes the ketonization/tautomerization of phenylpyruvate and p-hydroxyphenylpyruvate. Reason: PMID:11439086 directly compares the catalytic efficiency of human MIF and Trichinella spiralis MIF in the ketonization of phenylpyruvate and p-hydroxyphenylpyruvate. Supporting Evidence: PMID:11439086 The catalytic specificity of recombinant TsMIF in the ketonization of phenylpyruvate (1.4x10(6) M(-1) x s(-1)) was comparable with that of human MIF, while that of p-hydroxyphenylpyruvate (9.1x10(4) M(-1) x s(-1)) was 71-fold lower. |
| GO:0050178 phenylpyruvate tautomerase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of phenylpyruvate tautomerase activity across the MIF/DDT family (PTHR11954). Reason: Both MIF and DDT conserve the N-terminal Pro-2 catalytic base and interfacial active site that catalyze phenylpyruvate tautomerization. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:96982 SUPPORTS TRANSFER Mouse Mif is experimentally verified to possess phenylpyruvate tautomerase activity. UniProtKB:P14174 SUPPORTS TRANSFER Human MIF is the target protein itself with direct experimental evidence for phenylpyruvate tautomerase activity. UniProtKB:P30046 SUPPORTS TRANSFER Human DDT (paralog) shares the conserved N-terminal Pro-2 tautomerase active site (PMID:21817065). |
| GO:0050178 phenylpyruvate tautomerase activity | IDA PMID:16285950 Macrophage migration inhibitory factor promotes intestinal t... | ACCEPT | Summary: Direct measurement of MIF phenylpyruvate tautomerase activity in human intestinal mucosa and colorectal adenomas. Reason: PMID:16285950 measures MIF tautomerase activity in human intestinal tissue and adenoma samples. Supporting Evidence: PMID:16285950 MIF messenger RNA, protein, and tautomerase activity were measured in normal intestinal mucosa and adenomas from patients with sporadic colorectal adenomas and in the adenomatous polyposis coli (Apc)Min/+ mouse model of intestinal tumorigenesis. |
| GO:0050178 phenylpyruvate tautomerase activity | IDA PMID:21817065 The D-dopachrome tautomerase (DDT) gene product is a cytokin... | ACCEPT | Summary: Direct assay of human MIF tautomerase activity catalyzed by the N-terminal Pro-2 residue. Reason: PMID:21817065 characterizes the conserved N-terminal proline-dependent tautomerase activity of human MIF and DDT. Supporting Evidence: PMID:21817065 The D-DT proteins share with MIF a canonical N-terminal proline (formed after posttranslational excision of the initiating methionine), which catalyzes substrate tautomerization ( 19 ), but they lack two of the three conserved cysteines (Cys 59 and Cys 80 ) that appear in all known mammalian MIF proteins. |
| GO:0050178 phenylpyruvate tautomerase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated EC/Rhea mapping for phenylpyruvate tautomerase activity (EC 5.3.2.1). Reason: Matches experimentally verified phenylpyruvate tautomerase activity of human MIF. |
| GO:0050918 positive chemotaxis | IEA GO_REF:0000108 | ACCEPT | Summary: Logical inference from GO:0042056 (chemoattractant activity). Reason: MIF directly promotes positive chemotaxis of leukocytes and tumor cells as a non-cognate ligand for CXCR2 and CXCR4 (PMID:19602265). |
| GO:0061081 positive regulation of myeloid leukocyte cytokine production involved in immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse Mif for stimulation of myeloid cytokine production. Reason: Downstream proinflammatory consequence of MIF receptor signaling in myeloid cells. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Proteomic identification of MIF in human urinary exosomes. Reason: High-throughput proteomic detection in extracellular exosomes; non-core localization. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Proteomic identification of MIF in human B-cell exosomes. Reason: High-throughput proteomic detection in extracellular exosomes; non-core localization. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Proteomic identification of MIF in prostatic secretion exosomes. Reason: High-throughput proteomic detection in extracellular exosomes; non-core localization. |
| GO:0070207 protein homotrimerization | IPI PMID:17526494 Alternative chemical modifications reverse the binding orien... | KEEP AS NON CORE | Summary: MIF assembles into a barrel-shaped homotrimer with three active sites at the subunit interfaces. Reason: PMID:17526494 confirms by X-ray crystallography that MIF exists as a homotrimer whose catalytic pockets lie at the interfaces between adjacent subunits. Supporting Evidence: PMID:17526494 We studied the crystal structures of MIF.OXIM-based inhibitors and found two opposite orientations for binding to the active site that were dependent on the chemical structures of an R-group. PMID:21817065 We considered it critical to work with native sequence proteins because of structure-function studies that have shown that modifications of the N or C termini interfere with trimer formation, the functional unit of MIF |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | ACCEPT | Summary: MIF binding to CD74 activates ERK1/2 MAP kinase phosphorylation. Reason: PMID:12782713 demonstrates that MIF binding to cell-surface CD74 initiates sustained phosphorylation and activation of the ERK1/2 MAP kinase cascade. Supporting Evidence: PMID:12782713 MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | ACCEPT | Summary: MIF activates ERK1 and ERK2 phosphorylation via the CD74-CD44 receptor complex and Src kinase. Reason: PMID:17045821 shows that MIF-induced ERK1/2 phosphorylation requires coexpression of CD74 and full-length CD44 as well as Src tyrosine kinase activity. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology transfer of ERK1/2 cascade activation from mouse Mif. Reason: Consistent with human experimental evidence (PMID:12782713, PMID:17045821). |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IGI PMID:21817065 The D-dopachrome tautomerase (DDT) gene product is a cytokin... | ACCEPT | Summary: MIF and its paralog DDT additively activate ERK1/2 phosphorylation through CD74-CD44. Reason: PMID:21817065 demonstrates that MIF and DDT both activate the CD74-CD44-ERK1/2 MAP kinase cascade. Supporting Evidence: PMID:21817065 Measurement of the equilibrium dissociation constants between human D-DT or MIF and sCD74 by surface plasmon resonance (BIAcore analysis) revealed a high-affinity binding interaction between D-DT and the MIF receptor ( K D of 5.42 × 10 −9 M) ( Fig. 3 B ), albeit 60% lower than for MIF ( K D = 1.40 × 10 −9 M). |
| GO:0080135 regulation of cellular response to stress | IEA GO_REF:0000117 | MODIFY | Summary: Broad automated ARBA prediction refined to MIF's experimentally characterized negative regulation of p53-mediated DNA damage stress signaling. Reason: GO:0080135 (regulation of cellular response to stress) is a broad automated ARBA term; the specific stress-response pathway regulated by MIF is negative regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043518, an is_a descendant of GO:0080135), which MIF already carries by IDA (PMID:17045821) and IEA (GO_REF:0000107). Proposed replacements: negative regulation of DNA damage response, signal transduction by p53 class mediator |
| GO:0090238 positive regulation of arachidonate secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MIF stimulates cPLA2-mediated arachidonate release downstream of ERK1/2 signaling. Reason: Valid downstream metabolic/inflammatory response to MIF-CD74-ERK1/2 activation. |
| GO:0141163 positive regulation of cAMP/PKA signal transduction | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | KEEP AS NON CORE | Summary: MIF binding to CD74-CD44 induces PKA-dependent serine phosphorylation of the receptor complex. Reason: PMID:17045821 demonstrates that MIF stimulation triggers PKA-mediated serine phosphorylation of CD74 and CD44 during receptor complex activation. |
| GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | KEEP AS NON CORE | Summary: MIF-CD74-CD44 signaling protects cells from p53-mediated intrinsic apoptosis. Reason: Downstream anti-apoptotic outcome of MIF-CD74-CD44 signal transduction (PMID:17045821). |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: Reactome annotation of MIF in neutrophil ficolin-1-rich granule lumen. Reason: Reflects granule storage prior to exocytosis in innate immune cells. |
| GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse Mif for induction of CXCL2/MIP-2 production. Reason: Downstream proinflammatory transcriptional output of MIF signaling. |
| GO:2000773 negative regulation of cellular senescence | IDA PMID:10562313 A proinflammatory cytokine inhibits p53 tumor suppressor act... | KEEP AS NON CORE | Summary: MIF bypasses p53-mediated cellular senescence and extends fibroblast lifespan. Reason: PMID:10562313 shows that MIF inhibits p53 activity and bypasses p53-mediated proliferative arrest/senescence in fibroblasts. |
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Download this section (compressed HTML)Q: How do the tautomerase catalytic pocket and the CD74-binding surface of MIF allosterically couple in vivo, and does an endogenous small-molecule tautomerase substrate physiological regulate MIF-CD74 signaling?
Q: What determines the partition of extracellular MIF signaling between the canonical CD74-CD44 complex and non-cognate CXCR2/CXCR4 heterocomplexes across distinct leukocyte subsets?
Experiment: Determine cryo-EM or crystal structures of the ternary MIF homotrimer bound to the CD74 ectodomain trimer and CD44 to resolve the exact stoichiometry and conformational coupling between the Pro-2 catalytic pocket and receptor activation.
Hypothesis: Binding of the MIF homotrimer to the CD74 trimer induces a conformational rearrangement in the membrane-proximal stalk of CD74 that exposes the CD44 interaction interface and triggers Src-family kinase recruitment.
Type: Cryo-EM and X-ray crystallography of the MIF-CD74-CD44 extracellular complex combined with site-directed mutagenesis.
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