CD74, the MHC class II-associated invariant chain (Ii), is a type II transmembrane glycoprotein with a short cytoplasmic N-terminal tail carrying dileucine endosomal sorting motifs, a single transmembrane segment and a large lumenal C-terminal region containing the CLIP segment and a trimerization domain. In the endoplasmic reticulum, Ii trimers nucleate the assembly of nine-chain complexes with MHC class II alpha-beta dimers: the CLIP segment occupies the peptide-binding groove, preventing premature peptide loading, while the cytoplasmic tail routes the complex through the Golgi to endosomal MHC class II compartments, where Ii is proteolytically degraded and CLIP is exchanged for antigenic peptide by HLA-DM. A minor fraction of CD74 escapes to the plasma membrane, where its lumenal domain is displayed extracellularly and serves as the receptor for the cytokine MIF; MIF signalling requires CD74 together with CD44 and can involve the chemokine receptors CXCR2 and CXCR4, activating ERK and NF-kB and promoting cell survival and inflammatory responses. CD74 is thus both an intracellular chaperone of antigen presentation and a cell-surface cytokine receptor, and it is also modified as a chondroitin sulfate proteoglycan.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-2130393 | ACCEPT | Summary: CD74 traffics with MHC class II through the Golgi. Reason: The Reactome MHC class II antigen presentation events place the invariant chain-MHC class II complex on Golgi membranes en route from the ER to endosomal compartments; this matches the established trafficking route. Supporting Evidence: PMID:1448172 First, it prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-2213243 | ACCEPT | Summary: CD74 traffics with MHC class II through the Golgi. Reason: The Reactome MHC class II antigen presentation events place the invariant chain-MHC class II complex on Golgi membranes en route from the ER to endosomal compartments; this matches the established trafficking route. Supporting Evidence: PMID:1448172 First, it prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0001516 prostaglandin biosynthetic process | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | MODIFY | Summary: MIF acting through CD74 induces prostaglandin E2 production. Reason: CD74 is not a prostaglandin-synthesizing enzyme; it transduces the MIF signal that raises COX2-dependent PGE2 output, which is the already-annotated regulatory term. Proposed replacements: positive regulation of prostaglandin biosynthetic process Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0001540 amyloid-beta binding | IPI PMID:19849849 CD74 interacts with APP and suppresses the production of Abe... | ACCEPT | Summary: CD74 interacts with APP and reduces amyloid-beta production. Reason: Direct interaction evidence with a named partner; the binding is informative and underlies the reported suppression of Abeta secretion. Supporting Evidence: PMID:19849849 we show that CD74, the invariant chain of class II major histocompatibility complex, interacts with APP and serves as a negative regulator of Abeta |
| GO:0001961 positive regulation of cytokine-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: CD74 is the MIF receptor and initiates MIF-triggered signalling. Reason: MIF binds CD74 and CD74 is required for MIF-induced responses; positive regulation of cytokine-mediated signalling is the process counterpart of its cytokine receptor activity. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 PMID:17045821 CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44 |
| GO:0001961 positive regulation of cytokine-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: CD74 is the MIF receptor and initiates MIF-triggered signalling. Reason: MIF binds CD74 and CD74 is required for MIF-induced responses; positive regulation of cytokine-mediated signalling is the process counterpart of its cytokine receptor activity. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 PMID:17045821 CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44 |
| GO:0001961 positive regulation of cytokine-mediated signaling pathway | IMP PMID:12782713 MIF signal transduction initiated by binding to CD74. | ACCEPT | Summary: CD74 is the MIF receptor and initiates MIF-triggered signalling. Reason: MIF binds CD74 and CD74 is required for MIF-induced responses; positive regulation of cytokine-mediated signalling is the process counterpart of its cytokine receptor activity. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 PMID:17045821 CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44 |
| GO:0002286 T cell activation involved in immune response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Inherited role in T cell activation during immune responses. Reason: Downstream of the antigen presentation function: CD74 enables loading of MHC class II with antigenic peptide, which activates CD4 T cells. Retained as a non-core process term. Supporting Evidence: PMID:1448172 allowing peptides derived from endocytosed proteins to bind to released class II molecules before their expression at the cell surface |
| GO:0002606 positive regulation of dendritic cell antigen processing and presentation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred positive regulation of dendritic cell antigen processing and presentation. Reason: Consistent with the chaperone role in class II maturation, though the human evidence is indirect; retained as non-core. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum, serves two functions important in antigen processing |
| GO:0002792 negative regulation of peptide secretion | IDA PMID:19849849 CD74 interacts with APP and suppresses the production of Abe... | KEEP AS NON CORE | Summary: CD74 overexpression reduces secretion of amyloid-beta peptide. Reason: A consequence of CD74 retaining APP in CD74-generated vacuoles rather than a dedicated secretion-control function; retained as non-core. Supporting Evidence: PMID:19849849 in HeLa cells, over expression of CD74 steers APP, but not Notch, to large vacuoles created by CD74 |
| GO:0002830 positive regulation of type 2 immune response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Inherited/ortholog-transferred positive regulation of type 2 immune response. Reason: An organism-level immune outcome downstream of MHC class II antigen presentation and MIF signalling; retained as non-core. Supporting Evidence: PMID:1448172 serves two functions important in antigen processing |
| GO:0002830 positive regulation of type 2 immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Inherited/ortholog-transferred positive regulation of type 2 immune response. Reason: An organism-level immune outcome downstream of MHC class II antigen presentation and MIF signalling; retained as non-core. Supporting Evidence: PMID:1448172 serves two functions important in antigen processing |
| GO:0002906 negative regulation of mature B cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred negative regulation of mature B cell apoptosis. Reason: Consistent with the documented pro-survival CD74-MIF signalling, but transferred from mouse; retained as non-core. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0004896 cytokine receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: CD74 is the cell-surface receptor for the cytokine MIF. Reason: CD74 alone mediates MIF binding in reconstituted cells, and MIF-induced signalling depends on it; this is a core molecular function of the surface pool. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0004896 cytokine receptor activity | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | ACCEPT | Summary: CD74 is the cell-surface receptor for the cytokine MIF. Reason: CD74 alone mediates MIF binding in reconstituted cells, and MIF-induced signalling depends on it; this is a core molecular function of the surface pool. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0004896 cytokine receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: CD74 is the cell-surface receptor for the cytokine MIF. Reason: CD74 alone mediates MIF binding in reconstituted cells, and MIF-induced signalling depends on it; this is a core molecular function of the surface pool. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0005515 protein binding | IPI PMID:17357109 70-kDa heat shock proteins: specific interactions with HLA-D... | REMOVE | Summary: Interaction of HLA-DR molecules and their peptide fragments with bacterial DnaK. Reason: Generic protein binding is uninformative, and the cited work concerns HSP70/DnaK interactions with HLA-DR rather than a defined CD74 molecular function. Removal does not assert the interaction is false. Supporting Evidence: PMID:17357109 we investigated the interaction of complete HLA-DR molecules with HSP70 and detected a specific HSP70:HLA-DR interaction |
| GO:0005515 protein binding | IPI PMID:17435771 MIF is a noncognate ligand of CXC chemokine receptors in inf... | MODIFY | Summary: CD74 forms complexes with the chemokine receptors CXCR2 and CXCR4 to signal in response to MIF. Reason: Generic protein binding is uninformative; the informative claim is that CD74 binds these signalling receptors, forming functional heteromeric MIF receptor complexes. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:19665027 We demonstrate that CD74/CXCR4 complexes formed when CD74 was expressed with CXCR4 in HEK293 cells PMID:17435771 MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2 |
| GO:0005515 protein binding | IPI PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | MODIFY | Summary: CD74 forms complexes with the chemokine receptors CXCR2 and CXCR4 to signal in response to MIF. Reason: Generic protein binding is uninformative; the informative claim is that CD74 binds these signalling receptors, forming functional heteromeric MIF receptor complexes. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:19665027 We demonstrate that CD74/CXCR4 complexes formed when CD74 was expressed with CXCR4 in HEK293 cells PMID:17435771 MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2 |
| GO:0005515 protein binding | IPI PMID:29190904 Measurements of heterotypic associations between cluster of ... | MODIFY | Summary: CD74 associates with CD44 at the cell surface. Reason: Generic protein binding is uninformative; CD44 is the signalling component of the MIF receptor complex, so binding to this signalling receptor is the informative term. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:29190904 we demonstrate clear heterotypic interaction between CD74 and CD44 PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | REMOVE | Summary: Interactions recovered in an interferon-stimulated-gene interaction proteomics network. Reason: Generic protein binding from a large-scale affinity-proteomics network, with no follow-up defining a CD74 function; uninformative. Supporting Evidence: PMID:30833792 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | REMOVE | Summary: Interactions recovered in an interferon-stimulated-gene interaction proteomics network. Reason: Generic protein binding from a large-scale affinity-proteomics network, with no follow-up defining a CD74 function; uninformative. Supporting Evidence: PMID:30833792 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape |
| GO:0005576 extracellular region | EXP PMID:25326458 Identification of chondroitin sulfate linkage region glycope... | KEEP AS NON CORE | Summary: CD74 is detected outside the cell, notably as a chondroitin sulfate-modified glycopeptide and in soluble form. Reason: CD74 carries a chondroitin sulfate chain on its lumenal/extracellular region and soluble CD74 is released; this extracellular pool is real but peripheral to the chaperone and receptor functions. Supporting Evidence: PMID:25326458 Identification of chondroitin sulfate linkage region glycopeptides reveals prohormones as a novel class of proteoglycans PMID:37453717 Mapping the Human Chondroitin Sulfate Glycoproteome |
| GO:0005576 extracellular region | EXP PMID:36213313 Mass spectrometric analysis of chondroitin sulfate-linked pe... | KEEP AS NON CORE | Summary: CD74 is detected outside the cell, notably as a chondroitin sulfate-modified glycopeptide and in soluble form. Reason: CD74 carries a chondroitin sulfate chain on its lumenal/extracellular region and soluble CD74 is released; this extracellular pool is real but peripheral to the chaperone and receptor functions. Supporting Evidence: PMID:25326458 Identification of chondroitin sulfate linkage region glycopeptides reveals prohormones as a novel class of proteoglycans PMID:37453717 Mapping the Human Chondroitin Sulfate Glycoproteome |
| GO:0005576 extracellular region | EXP PMID:37453717 Mapping the Human Chondroitin Sulfate Glycoproteome Reveals ... | KEEP AS NON CORE | Summary: CD74 is detected outside the cell, notably as a chondroitin sulfate-modified glycopeptide and in soluble form. Reason: CD74 carries a chondroitin sulfate chain on its lumenal/extracellular region and soluble CD74 is released; this extracellular pool is real but peripheral to the chaperone and receptor functions. Supporting Evidence: PMID:25326458 Identification of chondroitin sulfate linkage region glycopeptides reveals prohormones as a novel class of proteoglycans PMID:37453717 Mapping the Human Chondroitin Sulfate Glycoproteome |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: CD74 is detected outside the cell, notably as a chondroitin sulfate-modified glycopeptide and in soluble form. Reason: CD74 carries a chondroitin sulfate chain on its lumenal/extracellular region and soluble CD74 is released; this extracellular pool is real but peripheral to the chaperone and receptor functions. Supporting Evidence: PMID:25326458 Identification of chondroitin sulfate linkage region glycopeptides reveals prohormones as a novel class of proteoglycans PMID:37453717 Mapping the Human Chondroitin Sulfate Glycoproteome |
| GO:0005634 nucleus | IDA PMID:19423618 Increased CD74 expression in human atherosclerotic plaques: ... | KEEP AS NON CORE | Summary: CD74 signal is detected in the nucleus of vascular cells. Reason: Consistent with reports that the released CD74 intracellular domain translocates to the nucleus and contributes to transcriptional responses; retained as a non-core location. Supporting Evidence: PMID:19423618 Nuclear factor-kappaB (NF-kappaB) activation was assessed by southwestern histochemistry and electrophoretic mobility shift assay |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | TOO GENERAL | Summary: CD74 is detected in the cytoplasm. Reason: True but low-resolution: most of the cytoplasmic signal is CD74 on ER, Golgi and endosomal membranes, which are annotated specifically. Retained as non-core rather than treated as the informative location. Supporting Evidence: PMID:22952837 Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74 |
| GO:0005737 cytoplasm | IDA PMID:22952837 Macrophage migration inhibitory factor inhibits the migratio... | TOO GENERAL | Summary: CD74 is detected in the cytoplasm. Reason: True but low-resolution: most of the cytoplasmic signal is CD74 on ER, Golgi and endosomal membranes, which are annotated specifically. Retained as non-core rather than treated as the informative location. Supporting Evidence: PMID:22952837 Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74 |
| GO:0005737 cytoplasm | IDA PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 i... | TOO GENERAL | Summary: CD74 is detected in the cytoplasm. Reason: True but low-resolution: most of the cytoplasmic signal is CD74 on ER, Golgi and endosomal membranes, which are annotated specifically. Retained as non-core rather than treated as the informative location. Supporting Evidence: PMID:22952837 Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74 |
| GO:0005764 lysosome | IEA GO_REF:0000120 | MODIFY | Summary: CD74 reaches lysosomes, where it is degraded during MHC class II maturation. Reason: Correct but less specific than supported; CD74 is a membrane protein of the lysosomal membrane (annotated by several Reactome rows) rather than a soluble lysosomal protein. Proposed replacements: lysosomal membrane Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0005764 lysosome | ISS GO_REF:0000024 | MODIFY | Summary: CD74 reaches lysosomes, where it is degraded during MHC class II maturation. Reason: Correct but less specific than supported; CD74 is a membrane protein of the lysosomal membrane (annotated by several Reactome rows) rather than a soluble lysosomal protein. Proposed replacements: lysosomal membrane Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-2130336 | ACCEPT | Summary: CD74 is an integral membrane protein of endosomal/lysosomal MHC class II loading compartments. Reason: The dileucine motifs in its cytoplasmic tail direct the complex to acidic endosomal and lysosomal membranes, where Ii degradation and CLIP exchange occur. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-2130349 | ACCEPT | Summary: CD74 is an integral membrane protein of endosomal/lysosomal MHC class II loading compartments. Reason: The dileucine motifs in its cytoplasmic tail direct the complex to acidic endosomal and lysosomal membranes, where Ii degradation and CLIP exchange occur. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-2130504 | ACCEPT | Summary: CD74 is an integral membrane protein of endosomal/lysosomal MHC class II loading compartments. Reason: The dileucine motifs in its cytoplasmic tail direct the complex to acidic endosomal and lysosomal membranes, where Ii degradation and CLIP exchange occur. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-2213235 | ACCEPT | Summary: CD74 is an integral membrane protein of endosomal/lysosomal MHC class II loading compartments. Reason: The dileucine motifs in its cytoplasmic tail direct the complex to acidic endosomal and lysosomal membranes, where Ii degradation and CLIP exchange occur. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-2213236 | ACCEPT | Summary: CD74 is an integral membrane protein of endosomal/lysosomal MHC class II loading compartments. Reason: The dileucine motifs in its cytoplasmic tail direct the complex to acidic endosomal and lysosomal membranes, where Ii degradation and CLIP exchange occur. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-2213246 | ACCEPT | Summary: CD74 is an integral membrane protein of endosomal/lysosomal MHC class II loading compartments. Reason: The dileucine motifs in its cytoplasmic tail direct the complex to acidic endosomal and lysosomal membranes, where Ii degradation and CLIP exchange occur. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs |
| GO:0005768 endosome | IEA GO_REF:0000044 | ACCEPT | Summary: CD74 traffics through endosomes, including late endosomes and multivesicular bodies. Reason: The endosomal route is where CD74 is degraded and CLIP is exchanged; MHC class II compartments are late endosomal/multivesicular in character. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment PMID:20458337 Exosomes are first generated as the intraluminal vesicles (ILVs) of a specific type of multivesicular body |
| GO:0005770 late endosome | IEA GO_REF:0000120 | ACCEPT | Summary: CD74 traffics through endosomes, including late endosomes and multivesicular bodies. Reason: The endosomal route is where CD74 is degraded and CLIP is exchanged; MHC class II compartments are late endosomal/multivesicular in character. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment PMID:20458337 Exosomes are first generated as the intraluminal vesicles (ILVs) of a specific type of multivesicular body |
| GO:0005770 late endosome | ISS GO_REF:0000024 | ACCEPT | Summary: CD74 traffics through endosomes, including late endosomes and multivesicular bodies. Reason: The endosomal route is where CD74 is degraded and CLIP is exchanged; MHC class II compartments are late endosomal/multivesicular in character. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment PMID:20458337 Exosomes are first generated as the intraluminal vesicles (ILVs) of a specific type of multivesicular body |
| GO:0005771 multivesicular body | IEA GO_REF:0000107 | ACCEPT | Summary: CD74 traffics through endosomes, including late endosomes and multivesicular bodies. Reason: The endosomal route is where CD74 is degraded and CLIP is exchanged; MHC class II compartments are late endosomal/multivesicular in character. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment PMID:20458337 Exosomes are first generated as the intraluminal vesicles (ILVs) of a specific type of multivesicular body |
| GO:0005773 vacuole | IDA PMID:19849849 CD74 interacts with APP and suppresses the production of Abe... | KEEP AS NON CORE | Summary: Overexpressed CD74 generates large vacuoles in HeLa cells and localizes to them. Reason: An overexpression phenotype rather than the physiological compartment; retained as non-core. Supporting Evidence: PMID:19849849 over expression of CD74 steers APP, but not Notch, to large vacuoles created by CD74 |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: CD74 assembles with MHC class II in the endoplasmic reticulum. Reason: The invariant chain associates with class II alpha-beta dimers in the ER, which is the first step of its chaperone function; it is an integral ER membrane protein at that stage. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: CD74 assembles with MHC class II in the endoplasmic reticulum. Reason: The invariant chain associates with class II alpha-beta dimers in the ER, which is the first step of its chaperone function; it is an integral ER membrane protein at that stage. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | ACCEPT | Summary: CD74 transits the Golgi apparatus with MHC class II. Reason: Part of the established ER-Golgi-endosome route of the class II/Ii complex, supported by imaging and by the Reactome trafficking events. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000120 | ACCEPT | Summary: CD74 transits the Golgi apparatus with MHC class II. Reason: Part of the established ER-Golgi-endosome route of the class II/Ii complex, supported by imaging and by the Reactome trafficking events. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0005886 plasma membrane | IDA PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0005886 plasma membrane | IDA PMID:22952837 Macrophage migration inhibitory factor inhibits the migratio... | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0005886 plasma membrane | IDA PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 i... | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2130500 | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2130640 | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2130725 | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5676133 | ACCEPT | Summary: A minor pool of CD74 reaches the plasma membrane, where it functions as the MIF receptor. Reason: Surface CD74 was detected directly in several human cell types and is required for MIF binding and signalling; most CD74 is intracellular, but this surface pool carries the receptor function and makes CD74 an antibody target. Supporting Evidence: PMID:19665027 Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface PMID:17045821 CD74 alone mediated MIF binding |
| GO:0006457 protein folding | IEA GO_REF:0000108 | ACCEPT | Summary: CD74 acts as a chaperone during MHC class II folding and assembly. Reason: The mapping follows from its protein folding chaperone activity, which is directly supported by the structural and assembly work on Ii/CLIP and class II. Supporting Evidence: PMID:7477400 Previous data indicate that this complex is an intermediate in class II histocompatibility maturation, occurring between invariant chain-DR3 and antigenic peptide-DR3 complexes |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000002 | ACCEPT | Summary: The CD74 cytoplasmic tail routes the MHC class II complex from the ER to endosomes. Reason: This targeting activity is the second classical function of the invariant chain and is directly supported. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0006886 intracellular protein transport | ISS GO_REF:0000024 | ACCEPT | Summary: The CD74 cytoplasmic tail routes the MHC class II complex from the ER to endosomes. Reason: This targeting activity is the second classical function of the invariant chain and is directly supported. Supporting Evidence: PMID:1448172 it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0006955 immune response | IEA GO_REF:0000002 | MODIFY | Summary: InterPro mapping of the invariant chain to immune response. Reason: True but uninformative; the specific process is antigen processing and presentation, already annotated by IBA and InterPro. Proposed replacements: antigen processing and presentation Supporting Evidence: PMID:1448172 serves two functions important in antigen processing |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred localization to the external side of the plasma membrane. Reason: Correct in principle for the type II topology (the lumenal C-terminal region faces outward at the surface), but the human surface pool is small and is already captured by the plasma membrane and cell surface rows. Supporting Evidence: PMID:19665027 showed CD74/CXCR4 complexes at the cell surface |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: CD74 is detectable on the cell surface of monocytes, tumour and stem cells. Reason: Antibody labelling of intact cells and surface MIF-binding assays establish that the lumenal domain is exposed extracellularly; this is the basis of CD74-directed antibodies. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:22952837 MIF and its receptor, CD74, are involved in regulating the migration of human mesenchymal stem cells (MSCs) |
| GO:0009986 cell surface | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | ACCEPT | Summary: CD74 is detectable on the cell surface of monocytes, tumour and stem cells. Reason: Antibody labelling of intact cells and surface MIF-binding assays establish that the lumenal domain is exposed extracellularly; this is the basis of CD74-directed antibodies. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:22952837 MIF and its receptor, CD74, are involved in regulating the migration of human mesenchymal stem cells (MSCs) |
| GO:0009986 cell surface | IDA PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | ACCEPT | Summary: CD74 is detectable on the cell surface of monocytes, tumour and stem cells. Reason: Antibody labelling of intact cells and surface MIF-binding assays establish that the lumenal domain is exposed extracellularly; this is the basis of CD74-directed antibodies. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:22952837 MIF and its receptor, CD74, are involved in regulating the migration of human mesenchymal stem cells (MSCs) |
| GO:0009986 cell surface | IDA PMID:22952837 Macrophage migration inhibitory factor inhibits the migratio... | ACCEPT | Summary: CD74 is detectable on the cell surface of monocytes, tumour and stem cells. Reason: Antibody labelling of intact cells and surface MIF-binding assays establish that the lumenal domain is exposed extracellularly; this is the basis of CD74-directed antibodies. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:22952837 MIF and its receptor, CD74, are involved in regulating the migration of human mesenchymal stem cells (MSCs) |
| GO:0010628 positive regulation of gene expression | IMP PMID:19423618 Increased CD74 expression in human atherosclerotic plaques: ... | KEEP AS NON CORE | Summary: CD74 engagement increases expression of inflammatory genes in vascular cells. Reason: A transcriptional consequence of MIF-CD74 signalling rather than a direct activity; retained as non-core. Supporting Evidence: PMID:19423618 Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-2130731 | ACCEPT | Summary: CD74 is present in ER-to-Golgi transport vesicles with MHC class II. Reason: Expected station on the annotated secretory route of the class II/Ii complex, as modelled in Reactome. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-2213243 | ACCEPT | Summary: CD74 is present in ER-to-Golgi transport vesicles with MHC class II. Reason: Expected station on the annotated secretory route of the class II/Ii complex, as modelled in Reactome. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: CD74 is an integral membrane protein. Reason: Membrane is true but uninformative; the specific membranes (ER, Golgi, endosome/lysosome, plasma membrane) are annotated. Supporting Evidence: file:human/CD74/CD74-uniprot.txt Cell membrane {ECO:0000305}; Single-pass type II membrane protein {ECO:0000305}. Endoplasmic reticulum membrane. Golgi apparatus, trans-Golgi network. Endosome. Lysosome. |
| GO:0016020 membrane | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | MODIFY | Summary: CD74 is an integral membrane protein. Reason: Membrane is true but uninformative; the specific membranes (ER, Golgi, endosome/lysosome, plasma membrane) are annotated. Supporting Evidence: file:human/CD74/CD74-uniprot.txt Cell membrane {ECO:0000305}; Single-pass type II membrane protein {ECO:0000305}. Endoplasmic reticulum membrane. Golgi apparatus, trans-Golgi network. Endosome. Lysosome. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: CD74 is an integral membrane protein. Reason: Membrane is true but uninformative; the specific membranes (ER, Golgi, endosome/lysosome, plasma membrane) are annotated. Supporting Evidence: file:human/CD74/CD74-uniprot.txt Cell membrane {ECO:0000305}; Single-pass type II membrane protein {ECO:0000305}. Endoplasmic reticulum membrane. Golgi apparatus, trans-Golgi network. Endosome. Lysosome. |
| GO:0016064 immunoglobulin mediated immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred role in immunoglobulin-mediated immune response. Reason: Downstream of CD4 T-cell help enabled by MHC class II presentation; retained as non-core. Supporting Evidence: PMID:1448172 serves two functions important in antigen processing |
| GO:0019882 antigen processing and presentation | IBA GO_REF:0000033 | ACCEPT | Summary: CD74 is required for normal MHC class II antigen processing and presentation. Reason: The chaperone and targeting functions of the invariant chain are the core of its biology, supported by structural and cell-biological work and conserved across vertebrates. Supporting Evidence: PMID:1448172 serves two functions important in antigen processing PMID:7477400 The structure shows that the CLIP fragment binds to DR3 in a way almost identical to that in which antigenic peptides bind class II histocompatibility glycoproteins |
| GO:0019882 antigen processing and presentation | IEA GO_REF:0000002 | ACCEPT | Summary: CD74 is required for normal MHC class II antigen processing and presentation. Reason: The chaperone and targeting functions of the invariant chain are the core of its biology, supported by structural and cell-biological work and conserved across vertebrates. Supporting Evidence: PMID:1448172 serves two functions important in antigen processing PMID:7477400 The structure shows that the CLIP fragment binds to DR3 in a way almost identical to that in which antigenic peptides bind class II histocompatibility glycoproteins |
| GO:0019883 antigen processing and presentation of endogenous antigen | NAS PMID:10981873 Expression of MHC class II-associated invariant chain (Ii;CD... | KEEP AS NON CORE | Summary: Statement that CD74 participates in antigen presentation in thymic epithelium. Reason: The cited paper is an expression survey of thymic neoplasms; the class II pathway it describes is already captured more directly by the main antigen-presentation annotations. Supporting Evidence: PMID:10981873 In these cells, MHC class II-associated invariant chain (CD74) is involved in antigen presentation during T-cell selection |
| GO:0019955 cytokine binding | IEA GO_REF:0000107 | ACCEPT | Summary: CD74 binds MIF, including the MIF orthologue secreted by hookworms. Reason: Direct binding evidence; cytokine binding is the molecular basis of CD74's receptor function. Supporting Evidence: PMID:17567581 a secreted hookworm Macrophage Migration Inhibitory Factor (MIF) that interacts with the human MIF receptor CD74 PMID:17045821 CD74 alone mediated MIF binding |
| GO:0019955 cytokine binding | IPI PMID:17567581 Structural and functional characterization of a secreted hoo... | ACCEPT | Summary: CD74 binds MIF, including the MIF orthologue secreted by hookworms. Reason: Direct binding evidence; cytokine binding is the molecular basis of CD74's receptor function. Supporting Evidence: PMID:17567581 a secreted hookworm Macrophage Migration Inhibitory Factor (MIF) that interacts with the human MIF receptor CD74 PMID:17045821 CD74 alone mediated MIF binding |
| GO:0023026 MHC class II protein complex binding | IDA PMID:1448172 HLA-DR molecules from an antigen-processing mutant cell line... | ACCEPT | Summary: CD74 binds MHC class II complexes, and CLIP-containing Ii fragments remain associated with HLA-DR in processing mutants. Reason: Direct biochemical evidence of the Ii-class II association that defines the chaperone function. Supporting Evidence: PMID:1448172 HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides |
| GO:0030336 negative regulation of cell migration | IMP PMID:20198449 Activation of CD74 inhibits migration of human mesenchymal s... | KEEP AS NON CORE | Summary: CD74 activation by MIF or an agonist antibody reduces migration of mesenchymal and cartilage end plate stem cells. Reason: A cell-type-specific signalling outcome of MIF-CD74 engagement; retained as non-core. Supporting Evidence: PMID:20198449 CD74 activation inhibits in a dose-dependent PMID:22952837 Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74 |
| GO:0030336 negative regulation of cell migration | IMP PMID:22952837 Macrophage migration inhibitory factor inhibits the migratio... | KEEP AS NON CORE | Summary: CD74 activation by MIF or an agonist antibody reduces migration of mesenchymal and cartilage end plate stem cells. Reason: A cell-type-specific signalling outcome of MIF-CD74 engagement; retained as non-core. Supporting Evidence: PMID:20198449 CD74 activation inhibits in a dose-dependent PMID:22952837 Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74 |
| GO:0030658 transport vesicle membrane | TAS Reactome:R-HSA-2130378 | ACCEPT | Summary: CD74 is present in transport and endocytic (including clathrin-coated) vesicle membranes. Reason: These are stations of the annotated class II/Ii trafficking itinerary, including internalization of surface-delivered complexes, as modelled in Reactome. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0030658 transport vesicle membrane | TAS Reactome:R-HSA-2130500 | ACCEPT | Summary: CD74 is present in transport and endocytic (including clathrin-coated) vesicle membranes. Reason: These are stations of the annotated class II/Ii trafficking itinerary, including internalization of surface-delivered complexes, as modelled in Reactome. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0030666 endocytic vesicle membrane | TAS Reactome:R-HSA-2130486 | ACCEPT | Summary: CD74 is present in transport and endocytic (including clathrin-coated) vesicle membranes. Reason: These are stations of the annotated class II/Ii trafficking itinerary, including internalization of surface-delivered complexes, as modelled in Reactome. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0030666 endocytic vesicle membrane | TAS Reactome:R-HSA-2213235 | ACCEPT | Summary: CD74 is present in transport and endocytic (including clathrin-coated) vesicle membranes. Reason: These are stations of the annotated class II/Ii trafficking itinerary, including internalization of surface-delivered complexes, as modelled in Reactome. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-2130486 | ACCEPT | Summary: CD74 is present in transport and endocytic (including clathrin-coated) vesicle membranes. Reason: These are stations of the annotated class II/Ii trafficking itinerary, including internalization of surface-delivered complexes, as modelled in Reactome. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-2130725 | ACCEPT | Summary: CD74 is present in transport and endocytic (including clathrin-coated) vesicle membranes. Reason: These are stations of the annotated class II/Ii trafficking itinerary, including internalization of surface-delivered complexes, as modelled in Reactome. Supporting Evidence: PMID:1448172 targets the class II-invariant chain complex to an acidic endosomal compartment |
| GO:0030890 positive regulation of B cell proliferation | IMP PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: MIF signalling through CD74 promotes B cell proliferation. Reason: Downstream cellular outcome of the receptor function; retained as non-core. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0031394 positive regulation of prostaglandin biosynthetic process | IMP PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 i... | ACCEPT | Summary: CD74 mediates MIF-induced prostaglandin production in cartilage end plate cells. Reason: Loss/blockade of CD74 reduces the MIF-driven inflammatory output, supporting this regulatory role. Supporting Evidence: PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 in cartilage end plates with Modic type 1 changes on MRI |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-2130378 | ACCEPT | Summary: CD74 is present in trans-Golgi network membranes during class II trafficking. Reason: Expected and Reactome-modelled station on the route from the ER to the endosomal loading compartment. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-2130393 | ACCEPT | Summary: CD74 is present in trans-Golgi network membranes during class II trafficking. Reason: Expected and Reactome-modelled station on the route from the ER to the endosomal loading compartment. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-2130619 | ACCEPT | Summary: CD74 is present in trans-Golgi network membranes during class II trafficking. Reason: Expected and Reactome-modelled station on the route from the ER to the endosomal loading compartment. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-2130641 | ACCEPT | Summary: CD74 is present in trans-Golgi network membranes during class II trafficking. Reason: Expected and Reactome-modelled station on the route from the ER to the endosomal loading compartment. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-2213236 | ACCEPT | Summary: CD74 is present in trans-Golgi network membranes during class II trafficking. Reason: Expected and Reactome-modelled station on the route from the ER to the endosomal loading compartment. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-8951498 | ACCEPT | Summary: CD74 is present in trans-Golgi network membranes during class II trafficking. Reason: Expected and Reactome-modelled station on the route from the ER to the endosomal loading compartment. Supporting Evidence: PMID:1448172 prevents class II molecules from binding peptides in the early stages of intracellular transport |
| GO:0032722 positive regulation of chemokine production | IMP PMID:19423618 Increased CD74 expression in human atherosclerotic plaques: ... | KEEP AS NON CORE | Summary: CD74 contributes to chemokine production by vascular cells. Reason: Downstream inflammatory output of MIF-CD74 signalling; retained as non-core. Supporting Evidence: PMID:19423618 contribution to inflammatory responses in vascular cells |
| GO:0032755 positive regulation of interleukin-6 production | IMP PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 i... | KEEP AS NON CORE | Summary: MIF acting through CD74 increases IL-6 and IL-8 production. Reason: Downstream cytokine outputs of the receptor function; retained as non-core. Supporting Evidence: PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 |
| GO:0032757 positive regulation of interleukin-8 production | IMP PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 i... | KEEP AS NON CORE | Summary: MIF acting through CD74 increases IL-6 and IL-8 production. Reason: Downstream cytokine outputs of the receptor function; retained as non-core. Supporting Evidence: PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 |
| GO:0032991 protein-containing complex | IDA PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | MODIFY | Summary: CD74 is part of protein complexes at the cell surface. Reason: True but uninformative; the specific assembly supported here is the MIF receptor complex with CXCR4/CXCR2 and CD44. Proposed replacements: macrophage migration inhibitory factor receptor complex Supporting Evidence: PMID:19665027 endogenous CD74/CXCR4 complexes were isolated by co-immunoprecipitation from monocytes |
| GO:0034341 response to type II interferon | IDA PMID:32855215 MHC class II transactivator CIITA induces cell resistance to... | KEEP AS NON CORE | Summary: CD74 expression is induced by interferon-gamma through CIITA-driven MHC class II transcription. Reason: An expression response shared with the whole class II locus rather than a CD74-specific activity; retained as non-core. Supporting Evidence: PMID:32855215 MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses |
| GO:0034341 response to type II interferon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CD74 expression is induced by interferon-gamma through CIITA-driven MHC class II transcription. Reason: An expression response shared with the whole class II locus rather than a CD74-specific activity; retained as non-core. Supporting Evidence: PMID:32855215 MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses |
| GO:0035691 macrophage migration inhibitory factor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: CD74 is the receptor that initiates MIF signalling. Reason: The pathway term matches the directly demonstrated receptor function. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0035692 macrophage migration inhibitory factor receptor complex | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | ACCEPT | Summary: CD74 is a component of the MIF receptor complex together with CD44. Reason: Reconstitution experiments show CD74 binds MIF while full-length CD44 supplies the signalling function, defining a two-component receptor. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:0035692 macrophage migration inhibitory factor receptor complex | IEA GO_REF:0000107 | ACCEPT | Summary: CD74 is a component of the MIF receptor complex together with CD44. Reason: Reconstitution experiments show CD74 binds MIF while full-length CD44 supplies the signalling function, defining a two-component receptor. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:0035693 NOS2-CD74 complex | IEA GO_REF:0000107 | UNDECIDED | Summary: Ortholog-transferred membership in a NOS2-CD74 complex. Reason: Transferred from mouse; no human evidence for this complex was available in the cached material, and the source experiments could not be assessed. |
| GO:0035718 macrophage migration inhibitory factor binding | IBA GO_REF:0000033 | ACCEPT | Summary: CD74 binds MIF directly. Reason: Direct binding shown in reconstituted CD74-expressing cells and conserved across the family; this is the core molecular function of surface CD74. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:17567581 interacts with the human MIF receptor CD74 |
| GO:0035718 macrophage migration inhibitory factor binding | IEA GO_REF:0000002 | ACCEPT | Summary: CD74 binds MIF directly. Reason: Direct binding shown in reconstituted CD74-expressing cells and conserved across the family; this is the core molecular function of surface CD74. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:17567581 interacts with the human MIF receptor CD74 |
| GO:0035718 macrophage migration inhibitory factor binding | IPI PMID:17045821 CD44 is the signaling component of the macrophage migration ... | ACCEPT | Summary: CD74 binds MIF directly. Reason: Direct binding shown in reconstituted CD74-expressing cells and conserved across the family; this is the core molecular function of surface CD74. Supporting Evidence: PMID:17045821 CD74 alone mediated MIF binding PMID:17567581 interacts with the human MIF receptor CD74 |
| GO:0042289 MHC class II protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: CD74 binds MHC class II alpha-beta dimers. Reason: The Ii-class II association in the ER is the defining interaction of the invariant chain, supported directly and conserved across vertebrates. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0042289 MHC class II protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: CD74 binds MHC class II alpha-beta dimers. Reason: The Ii-class II association in the ER is the defining interaction of the invariant chain, supported directly and conserved across vertebrates. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0042289 MHC class II protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: CD74 binds MHC class II alpha-beta dimers. Reason: The Ii-class II association in the ER is the defining interaction of the invariant chain, supported directly and conserved across vertebrates. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0042289 MHC class II protein binding | NAS PMID:10981873 Expression of MHC class II-associated invariant chain (Ii;CD... | ACCEPT | Summary: CD74 binds MHC class II alpha-beta dimers. Reason: The Ii-class II association in the ER is the defining interaction of the invariant chain, supported directly and conserved across vertebrates. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0042609 CD4 receptor binding | IPI PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | UNDECIDED | Summary: CD4 receptor binding inferred from a study of CD4 ligation on monocytes. Reason: The cited work is about antibody ligation of CD4 on monocytes driving macrophage differentiation; a direct CD74-CD4 interaction is not established by the cached abstract, so the claim cannot be adjudicated here. Supporting Evidence: PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection |
| GO:0042613 MHC class II protein complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CD74 is a transient component of the nine-chain class II/Ii complex. Reason: CD74 is part of the immature class II complex but is removed before the mature peptide-loaded MHC class II protein complex is displayed, so membership is stage-restricted; retained as non-core. Supporting Evidence: PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs, allowing peptides derived from endocytosed proteins to bind to released class II molecules |
| GO:0042613 MHC class II protein complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CD74 is a transient component of the nine-chain class II/Ii complex. Reason: CD74 is part of the immature class II complex but is removed before the mature peptide-loaded MHC class II protein complex is displayed, so membership is stage-restricted; retained as non-core. Supporting Evidence: PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs, allowing peptides derived from endocytosed proteins to bind to released class II molecules |
| GO:0042658 MHC class II protein binding, via antigen binding groove | IDA PMID:7477400 The structure of an intermediate in class II MHC maturation:... | ACCEPT | Summary: The CLIP segment of CD74 occupies the MHC class II peptide-binding groove. Reason: The crystal structure of CLIP bound to HLA-DR3 directly shows binding through the antigen-binding groove. Supporting Evidence: PMID:7477400 The structure shows that the CLIP fragment binds to DR3 in a way almost identical to that in which antigenic peptides bind class II histocompatibility glycoproteins |
| GO:0042802 identical protein binding | TAS PMID:12782713 MIF signal transduction initiated by binding to CD74. | ACCEPT | Summary: CD74 self-associates into trimers. Reason: Trimerization of the invariant chain nucleates assembly of the nine-chain class II/Ii complex, consistent with the annotated trimerization domain. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0043030 regulation of macrophage activation | NAS PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: CD74 mediates MIF effects on macrophage activation. Reason: Downstream immunological outcome of the receptor function; retained as non-core. Supporting Evidence: PMID:12782713 MIF is an upstream activator of monocytes/macrophages |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: MIF-CD74 signalling is pro-survival. Reason: A downstream signalling outcome, mediated through ERK and NF-kB rather than by CD74 acting on the apoptotic machinery; retained as non-core. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | KEEP AS NON CORE | Summary: Engagement of surface complexes containing CD74 activates NF-kB in monocytes. Reason: Downstream signalling output; retained as non-core. Supporting Evidence: PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage differentiation |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-2213246 | KEEP AS NON CORE | Summary: Proteolytic fragments of CD74 appear in the lysosomal lumen during its degradation. Reason: Reflects Ii degradation rather than a functional residence of the intact protein; retained as non-core. Supporting Evidence: PMID:1448172 Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs |
| GO:0043410 positive regulation of MAPK cascade | IEA GO_REF:0000117 | MODIFY | Summary: ARBA mapping to positive regulation of MAPK cascade. Reason: Correct but less specific than supported; the experimentally demonstrated output is activation of the ERK1/ERK2 cascade, which the gene already carries. Proposed replacements: positive regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:17045821 MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44 |
| GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: MIF signalling through CD74 suppresses p53-dependent responses. Reason: A documented downstream consequence of MIF-CD74-CD44 signalling rather than a direct activity of CD74 on p53; retained as non-core. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| 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 signalling through CD74 suppresses p53-dependent responses. Reason: A documented downstream consequence of MIF-CD74-CD44 signalling rather than a direct activity of CD74 on p53; retained as non-core. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MIF signalling through CD74 suppresses p53-dependent responses. Reason: A documented downstream consequence of MIF-CD74-CD44 signalling rather than a direct activity of CD74 on p53; retained as non-core. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:0044183 protein folding chaperone | IDA PMID:7477400 The structure of an intermediate in class II MHC maturation:... | ACCEPT | Summary: CD74 acts as a dedicated chaperone for MHC class II maturation. Reason: The CLIP-DR3 structure and the maturation intermediate it represents establish that CD74 occupies and protects the groove until HLA-DM catalyses peptide exchange. Supporting Evidence: PMID:7477400 Previous data indicate that this complex is an intermediate in class II histocompatibility maturation, occurring between invariant chain-DR3 and antigenic peptide-DR3 complexes |
| GO:0045058 T cell selection | NAS PMID:10981873 Expression of MHC class II-associated invariant chain (Ii;CD... | KEEP AS NON CORE | Summary: CD74 contributes to T cell selection in the thymus through class II presentation. Reason: An organism-level developmental outcome of the antigen presentation function; retained as non-core. Supporting Evidence: PMID:10981873 MHC class II-associated invariant chain (CD74) is involved in antigen presentation during T-cell selection |
| GO:0045657 positive regulation of monocyte differentiation | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | KEEP AS NON CORE | Summary: Ligation of surface complexes containing CD74 promotes monocyte-to-macrophage differentiation. Reason: Downstream cellular outcome; retained as non-core. Supporting Evidence: PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection |
| GO:0048146 positive regulation of fibroblast proliferation | IMP PMID:12782713 MIF signal transduction initiated by binding to CD74. | KEEP AS NON CORE | Summary: MIF acting through CD74 promotes fibroblast proliferation. Reason: Downstream proliferative output of the receptor function; retained as non-core. Supporting Evidence: PMID:12782713 MIF signal transduction initiated by binding to CD74 |
| GO:0050998 nitric-oxide synthase binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Ortholog-transferred nitric-oxide synthase binding. Reason: Transferred from mouse along with the NOS2-CD74 complex annotation; no human evidence was available and the source experiments could not be assessed. |
| GO:0060907 positive regulation of macrophage cytokine production | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CD74 mediates MIF-induced cytokine production by macrophages. Reason: Downstream output of the MIF receptor function, supported in human cells for IL-6 and IL-8; retained as non-core. Supporting Evidence: PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 |
| GO:0060907 positive regulation of macrophage cytokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CD74 mediates MIF-induced cytokine production by macrophages. Reason: Downstream output of the MIF receptor function, supported in human cells for IL-6 and IL-8; retained as non-core. Supporting Evidence: PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 |
| GO:0060907 positive regulation of macrophage cytokine production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CD74 mediates MIF-induced cytokine production by macrophages. Reason: Downstream output of the MIF receptor function, supported in human cells for IL-6 and IL-8; retained as non-core. Supporting Evidence: PMID:24569872 Migration inhibitory factor enhances inflammation via CD74 |
| GO:0065003 protein-containing complex assembly | ISS GO_REF:0000024 | ACCEPT | Summary: CD74 nucleates assembly of the nine-chain MHC class II/invariant chain complex. Reason: Trimeric Ii binding three class II dimers is the assembly step that its chaperone function performs. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: CD74 is detected in B-cell exosomes. Reason: Expected from its residence in multivesicular MHC class II compartments whose intraluminal vesicles are released; peripheral to its functions. Supporting Evidence: PMID:20458337 MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis |
| GO:0070206 protein trimerization | IEA GO_REF:0000002 | ACCEPT | Summary: CD74 trimerizes through its lumenal trimerization domain. Reason: Domain-based mapping that matches the established trimeric architecture of the invariant chain and its role in complex assembly. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IBA GO_REF:0000033 | ACCEPT | Summary: MIF binding to CD74 activates the ERK1/ERK2 cascade. Reason: Directly demonstrated in reconstituted cells and in primary systems; this is the principal signalling output of the receptor function. Supporting Evidence: PMID:17045821 MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44 |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:17045821 CD44 is the signaling component of the macrophage migration ... | ACCEPT | Summary: MIF binding to CD74 activates the ERK1/ERK2 cascade. Reason: Directly demonstrated in reconstituted cells and in primary systems; this is the principal signalling output of the receptor function. Supporting Evidence: PMID:17045821 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: MIF binding to CD74 activates the ERK1/ERK2 cascade. Reason: Directly demonstrated in reconstituted cells and in primary systems; this is the principal signalling output of the receptor function. Supporting Evidence: PMID:17045821 MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44 |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:12782713 MIF signal transduction initiated by binding to CD74. | ACCEPT | Summary: MIF binding to CD74 activates the ERK1/ERK2 cascade. Reason: Directly demonstrated in reconstituted cells and in primary systems; this is the principal signalling output of the receptor function. Supporting Evidence: PMID:17045821 MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44 |
| GO:0090023 positive regulation of neutrophil chemotaxis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred positive regulation of neutrophil chemotaxis. Reason: Consistent with MIF-CD74-CXCR2 mediated leukocyte recruitment, though transferred from mouse; retained as non-core. Supporting Evidence: PMID:17435771 MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment |
| GO:0090023 positive regulation of neutrophil chemotaxis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred positive regulation of neutrophil chemotaxis. Reason: Consistent with MIF-CD74-CXCR2 mediated leukocyte recruitment, though transferred from mouse; retained as non-core. Supporting Evidence: PMID:17435771 MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-2130478 | ACCEPT | Summary: The lumenal domain of CD74 faces the ER lumen, consistent with its type II topology. Reason: CD74 is a type II membrane protein: its C-terminal CLIP-containing region lies in the ER lumen, where it engages the class II groove. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-2130731 | ACCEPT | Summary: The lumenal domain of CD74 faces the ER lumen, consistent with its type II topology. Reason: CD74 is a type II membrane protein: its C-terminal CLIP-containing region lies in the ER lumen, where it engages the class II groove. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-2213241 | ACCEPT | Summary: The lumenal domain of CD74 faces the ER lumen, consistent with its type II topology. Reason: CD74 is a type II membrane protein: its C-terminal CLIP-containing region lies in the ER lumen, where it engages the class II groove. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-8951500 | ACCEPT | Summary: The lumenal domain of CD74 faces the ER lumen, consistent with its type II topology. Reason: CD74 is a type II membrane protein: its C-terminal CLIP-containing region lies in the ER lumen, where it engages the class II groove. Supporting Evidence: PMID:1448172 The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum |
| GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: MIF-CD74 signalling suppresses p53-dependent apoptosis after DNA damage. Reason: Downstream survival output of the receptor function rather than a direct activity on the apoptotic machinery; retained as non-core. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MIF-CD74 signalling suppresses p53-dependent apoptosis after DNA damage. Reason: Downstream survival output of the receptor function rather than a direct activity on the apoptotic machinery; retained as non-core. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator | IMP PMID:17045821 CD44 is the signaling component of the macrophage migration ... | KEEP AS NON CORE | Summary: MIF-CD74 signalling suppresses p53-dependent apoptosis after DNA damage. Reason: Downstream survival output of the receptor function rather than a direct activity on the apoptotic machinery; retained as non-core. Supporting Evidence: PMID:17045821 CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex |
| GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred positive regulation of CXCL2 production. Reason: A chemokine output of MIF-CD74 signalling transferred from mouse; retained as non-core. Supporting Evidence: PMID:19423618 contribution to inflammatory responses in vascular cells |
| GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred positive regulation of CXCL2 production. Reason: A chemokine output of MIF-CD74 signalling transferred from mouse; retained as non-core. Supporting Evidence: PMID:19423618 contribution to inflammatory responses in vascular cells |
| GO:2000448 positive regulation of macrophage migration inhibitory factor signaling pathway | IMP PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | ACCEPT | Summary: CD74 complexes with CXCR4 amplify MIF signalling. Reason: Endogenous CD74/CXCR4 complexes in monocytes and antibody blockade of either component establish that CD74 positively regulates the MIF pathway. Supporting Evidence: PMID:19665027 MIF-stimulated CD74-dependent AKT activation was blocked by anti-CXCR4 and anti-CD74 a |
Loading supporting content…
Download this section (compressed HTML)Q: What proportion of total CD74 reaches the plasma membrane in different cell types, and what controls escape from ER retention and endosomal routing?
Q: Does surface CD74 signal as an autonomous receptor, or always as part of heteromeric complexes with CD44, CXCR2 or CXCR4?
Experiment: Reconstitute CD74 in cells lacking CD44, CXCR2 and CXCR4, measure MIF binding and each downstream output (ERK, AKT, NF-kB), and restore partners individually.
Hypothesis: Surface CD74 requires a partner transmembrane receptor for every signalling output, and alone is only a binding subunit.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)