id: MODULE:mif_signaling title: MIF signaling pathway module description: >- Macrophage migration inhibitory factor (MIF) and its paralog D-dopachrome tautomerase (DDT, also called MIF-2) are secreted homotrimeric cytokines that bind the cell-surface receptor CD74 (the MHC class II invariant chain) in complex with the signaling co-receptor CD44 on responding immune and parenchymal cells, initiating SRC-family kinase and ERK1/2 MAP kinase signaling cascades that regulate leukocyte activation, inflammatory cytokine production and cell survival. status: DRAFT scope: ABSTRACT evidence: - source_id: GO:0035691 title: macrophage migration inhibitory factor signaling pathway statement: The module is grounded in the GO biological process term for the macrophage migration inhibitory factor signaling pathway. - source_id: PMID:12782713 title: MIF signal transduction initiated by binding to CD74. statement: Identifies cell-surface CD74 as the high-affinity receptor for MIF required for MIF-induced ERK1/2 activation, PGE2 production and cell proliferation. supporting_text: >- 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. - source_id: PMID:17045821 title: CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. statement: Shows that CD74 forms a signaling receptor complex with CD44, which is required for MIF-induced SRC and ERK1/2 activation and protection from apoptosis. supporting_text: >- CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. - source_id: PMID:21817065 title: The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). statement: Demonstrates that D-dopachrome tautomerase (DDT / MIF-2) is a second MIF-family cytokine ligand that binds CD74 with high affinity and activates ERK1/2 signaling in a CD74- and CD44-dependent manner. supporting_text: >- We show that recombinant D-DT protein binds CD74 with high affinity, leading to activation of ERK1/2 MAP kinase and downstream proinflammatory pathways. - source_id: file:interpro/panther/PTHR11954/PTHR11954-review.yaml statement: PANTHER family review for PTHR11954 (D-DOPACHROME DECARBOXYLASE), covering the MIF and DDT subfamilies and PAINT node PTN000237513. - source_id: file:genes/human/MIF/MIF-ai-review.yaml statement: Gene review for human MIF (UniProtKB:P14174). notes: >- Boundary. The module has two steps: a secreted MIF-family cytokine ligand (MIF or DDT) and the cell-surface macrophage migration inhibitory factor receptor complex (GO:0035692) on the responding cell. The receptor step is modelled as a complex because neither subunit is a functional receptor alone: CD74 binds MIF but cannot signal by itself, and CD44, whose intracytoplasmic domain is required for MIF-induced Src-dependent ERK1/2 activation, is the signaling unit (PMID:17045821). The non-cognate chemokine receptors CXCR2, CXCR4 and ACKR3 (which MIF also engages), and intracellular effectors (SRC-family kinases, ERK1/2, AMPK, JAB1/CSN5) are not modelled as parts. The representative members (human MIF, DDT, CD74 and CD44; mouse Mif, Ddt, Cd74 and Cd44) are examples, not a species scope. Taxon scope. The module is scoped to Euteleostomi (NCBITaxon:117571), the clade in which all required parts exist: the CD74 receptor node PTN002679661 in PTHR14093:SF17 is placed at taxon:117571 and is seeded by human, mouse and zebrafish CD74; the CD44 node PTN002566805 in PTHR10225, which carries GO:0035692 and GO:0004896, is also placed at taxon:117571; and the CD44 subfamily PTHR10225:SF6 has a zebrafish member (cd44a, UniProtKB:E7F6T0, per its UniProt PANTHER cross-reference). The MIF ligand family itself is older: its cytokine-activity node PTN000237513 in PTHR11954 is placed at Bilateria (taxon:33213) and the family root PTN000237510 at Eukaryota (taxon:2759). MIF homologues outside the vertebrates (for example in nematodes, which lack CD74) therefore do not instantiate this module; what receptor, if any, they signal through is outside its scope. Ligand function term. The ligand step uses GO:0005125 cytokine activity, a child of GO:0048018 receptor ligand activity, following the GO-CAM signaling receptor guideline that a ligand enables receptor ligand activity or a child. PAINT node PTN000237513 in PTHR11954 and IBA/IEA annotations on human MIF assert GO:0005125 cytokine activity, while experimental annotations from PMID:17045821 and PMID:21817065 on human MIF and DDT use GO:0005126 cytokine receptor binding (refined via MODIFY to GO:0005125 in genes/human/MIF/MIF-ai-review.yaml). Members of PTHR11954 also possess an ancestral phenylpyruvate tautomerase / D-dopachrome decarboxylase catalytic site around N-terminal Pro-2 (PTN000237510, GO:0050178 phenylpyruvate tautomerase activity), which overlaps the CD74-binding surface (PMID:17526494, PMID:21817065); that enzymatic activity is documented in interpro/panther/PTHR11954/PTHR11954-review.yaml and genes/human/MIF/MIF-ai-review.yaml. Receptor complex and function terms. The receptor step is a PROTEIN_COMPLEX participant grounded to GO:0035692 macrophage migration inhibitory factor receptor complex, with two active units. CD74 is the MIF-binding unit (GO:0035718 macrophage migration inhibitory factor binding), grounded to subfamily PANTHER:PTHR14093:SF17 rather than the parent PANTHER:PTHR14093 (which also includes the thyroglobulin subfamily PTHR14093:SF19); PAINT node PTN002679661 propagates GO:0035718 and GO:0004896 cytokine receptor activity. CD44 is the signaling unit, grounded to PANTHER:PTHR10225:SF6 (CD44 ANTIGEN); GOA records it as contributes_to GO:0004896 (IDA, PMID:17045821; IBA via PTN002566805) and part_of GO:0035692. The complex as a whole enables GO:0004896 cytokine receptor activity. Human CD74 and CD44 do not yet have gene reviews in this repository; the naked mole-rat Cd44 review (genes/HETGA/Cd44) assesses GO:0035692 and is cited on the receptor-complex step. Annotation state (GOA GAFs). As recorded in projects/LIGANDS_IN_SIGNALING/results/triage.json (human :371-381, mouse :2668-2678, rat :5387-5397), only the receptor CD74 (CD74 in human, mCD74/iso:Long in mouse, Cd74 in rat) is annotated to GO:0035691 macrophage migration inhibitory factor signaling pathway in GOA, whereas neither ligand (MIF or DDT) carries GO:0035691: human MIF (UniProtKB:P14174, genes/human/MIF/MIF-goa.tsv) carries the parent term GO:0007166 cell surface receptor signaling pathway by IDA from PMID:12782713 and GO:0070374 positive regulation of ERK1 and ERK2 cascade, while human DDT (UniProtKB:P30046) carries GO:0005126 cytokine receptor binding (IDA) and GO:0070374 (IGI with UniProtKB:P14174) from PMID:21817065. The human MIF gene review refines GO:0007166 (IDA, PMID:12782713) via MODIFY to GO:0035691, and the PTHR11954 family review recommends adding GO:0035691 at PTN000237513. module: id: mif_signaling label: MIF signaling pathway module_type: SIGNALING_PATHWAY description: >- Secreted MIF or DDT (MIF-2) homotrimers bind the cell-surface receptor CD74 (in complex with the co-receptor CD44) on a responding cell to initiate intracellular signaling. concepts: - preferred_term: macrophage migration inhibitory factor signaling pathway term: id: GO:0035691 label: macrophage migration inhibitory factor signaling pathway context: taxa: - preferred_term: Euteleostomi term: id: NCBITaxon:117571 label: Euteleostomi parts: - order: 1 role: secreted ligand node: id: mif_ligand label: MIF-family cytokine ligand module_type: SIGNALING_PATHWAY description: Secreted homotrimeric MIF or DDT (MIF-2) cytokine released by immune, endocrine or parenchymal cells via a non-classical export pathway. annotons: - id: mif_ddt_ligand_family label: MIF/DDT cytokine ligand participant: selector_type: FAMILY family: preferred_term: MIF / D-dopachrome tautomerase (DDT) cytokines term: id: PANTHER:PTHR11954 label: D-DOPACHROME DECARBOXYLASE description: >- Covers the metazoan MIF and DDT (MIF-2) subfamilies (PTHR11954:SF6 MIF and PTHR11954:SF22 DDT in vertebrates) descended from PAINT clade node PTN000237513, as reviewed in interpro/panther/PTHR11954/PTHR11954-review.yaml. representative_members: - preferred_term: MIF term: id: UniProtKB:P14174 label: Macrophage migration inhibitory factor - preferred_term: DDT term: id: UniProtKB:P30046 label: D-dopachrome decarboxylase - preferred_term: Mif term: id: UniProtKB:P34884 label: Macrophage migration inhibitory factor - preferred_term: Ddt term: id: UniProtKB:O35215 label: D-dopachrome decarboxylase ancestral_nodes: - preferred_term: PAINT node PTN000237513 (Bilateria MIF/DDT cytokine activity) term: id: PANTHER:PTN000237513 label: PTN000237513 description: >- Local PAINT IBD node in PTHR11954 (taxon:33213 Bilateria) seeded by human MIF (UniProtKB:P14174) and mouse Mif (MGI:MGI:96982), propagating F:GO:0005125 cytokine activity across the bilaterian MIF/DDT clade. evidence: - source_id: GO_REF:0000033 statement: IBD propagation of GO:0005125 cytokine activity from PAINT node PTN000237513 in PTHR11954. - preferred_term: PAINT node PTN000237510 (Eukaryota root extracellular localization) term: id: PANTHER:PTN000237510 label: PTN000237510 description: >- Root PAINT IBD node in PTHR11954 (taxon:2759 Eukaryota) seeded by human MIF (UniProtKB:P14174), human DDT (UniProtKB:P30046), mouse Mif (MGI:MGI:96982), mouse Ddt (MGI:MGI:1298381) and rat Ddt (RGD:621163), propagating C:GO:0005576 extracellular region and F:GO:0050178 phenylpyruvate tautomerase activity. evidence: - source_id: GO_REF:0000033 statement: IBD propagation of GO:0005576 extracellular region from PAINT node PTN000237510 in PTHR11954. function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity processes: - preferred_term: macrophage migration inhibitory factor signaling pathway term: id: GO:0035691 label: macrophage migration inhibitory factor signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Secreted homotrimeric cytokine ligand (MIF or DDT/MIF-2) that binds the extracellular domain of CD74 to initiate MIF pathway signaling. evidence: - source_id: PMID:12782713 title: MIF signal transduction initiated by binding to CD74. statement: MIF binds the extracellular domain of CD74 with nanomolar affinity and activates ERK1/2 signaling. supporting_text: >- A recombinant, soluble form of CD74 binds MIF with a dissociation constant of approximately 9 x 10-9 Kd, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal-regulated kinase activation in defined cell systems. - source_id: PMID:21817065 title: The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). statement: DDT (MIF-2) also binds the CD74 ectodomain with high affinity and activates ERK1/2 phosphorylation in a CD74/CD44-dependent manner. supporting_text: >- D-DT–induced ERK1/2 phosphorylation was strictly dependent on the expression of both CD74 and CD44, as previously reported for MIF - order: 2 role: receptor complex node: id: mif_receptor_complex label: CD74-CD44 MIF receptor complex module_type: SIGNALING_PATHWAY description: Cell-surface macrophage migration inhibitory factor receptor complex (GO:0035692), in which the type II transmembrane protein CD74 (MHC class II invariant chain) binds extracellular MIF or DDT and the transmembrane co-receptor CD44 supplies the signal-transducing cytoplasmic domain needed for SRC-family kinase and ERK1/2 activation. annotons: - id: mif_receptor_complex_annoton label: CD74-CD44 MIF receptor complex participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: macrophage migration inhibitory factor receptor complex term: id: GO:0035692 label: macrophage migration inhibitory factor receptor complex active_units: - id: cd74_mif_binding_unit label: CD74 role: MIF/DDT-binding unit; binds the ligand through its extracellular domain but cannot signal alone participant: selector_type: FAMILY family: preferred_term: CD74 (MHC class II invariant chain / MIF receptor) term: id: PANTHER:PTHR14093:SF17 label: HLA CLASS II HISTOCOMPATIBILITY ANTIGEN GAMMA CHAIN description: >- Subfamily PTHR14093:SF17 of PANTHER:PTHR14093 (HLA CLASS II GAMMA CHAIN); the parent family also includes the thyroglobulin subfamily PTHR14093:SF19, which shares only the type-1 thyroglobulin repeat. representative_members: - preferred_term: CD74 term: id: UniProtKB:P04233 label: HLA class II histocompatibility antigen gamma chain - preferred_term: Cd74 term: id: UniProtKB:P04441 label: H-2 class II histocompatibility antigen gamma chain ancestral_nodes: - preferred_term: PAINT node PTN002679661 (CD74 MIF binding and cytokine receptor activity) term: id: PANTHER:PTN002679661 label: PTN002679661 description: >- Local PAINT IBD node in PTHR14093 (taxon:117571 Euteleostomi) seeded by human CD74 (UniProtKB:P04233), mouse Cd74 (MGI:MGI:96534) and zebrafish cd74a (ZFIN:ZDB-GENE-000901-1), propagating 13 terms including F:GO:0035718 macrophage migration inhibitory factor binding and F:GO:0004896 cytokine receptor activity. evidence: - source_id: GO_REF:0000033 statement: IBD propagation of GO:0035718 macrophage migration inhibitory factor binding from PAINT node PTN002679661 in PTHR14093. function: preferred_term: macrophage migration inhibitory factor binding term: id: GO:0035718 label: macrophage migration inhibitory factor binding evidence: - source_id: PMID:12782713 title: MIF signal transduction initiated by binding to CD74. statement: MIF binds the extracellular domain of cell-surface CD74, and CD74 is required for MIF-induced ERK1/2 activation. supporting_text: >- 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. - source_id: PMID:17045821 title: CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. statement: CD74 alone is sufficient for MIF binding. supporting_text: CD74 alone mediated MIF binding - id: cd44_signaling_unit label: CD44 role: signal-transducing unit; its intracytoplasmic domain is required for MIF-induced Src-dependent ERK1/2 activation participant: selector_type: FAMILY family: preferred_term: CD44 term: id: PANTHER:PTHR10225:SF6 label: CD44 ANTIGEN description: >- CD44 subfamily of PANTHER:PTHR10225 (hyaluronan receptor family). CD44 is also the principal hyaluronan receptor; only its role as the signaling subunit of the MIF receptor complex is in scope here. representative_members: - preferred_term: CD44 term: id: UniProtKB:P16070 label: CD44 antigen - preferred_term: Cd44 term: id: UniProtKB:P15379 label: CD44 antigen ancestral_nodes: - preferred_term: PAINT node PTN002566805 (CD44 MIF receptor complex) term: id: PANTHER:PTN002566805 label: PTN002566805 description: >- PAINT IBD node in PTHR10225 (taxon:117571 Euteleostomi) seeded by mouse Cd44 (MGI:MGI:88338) and human CD44 (UniProtKB:P16070), propagating C:GO:0035692 macrophage migration inhibitory factor receptor complex, F:GO:0004896 cytokine receptor activity (contributes_to in GOA) and GO:0070374 positive regulation of ERK1 and ERK2 cascade, among six terms. evidence: - source_id: GO_REF:0000033 statement: IBD propagation of GO:0035692 and GO:0004896 from PAINT node PTN002566805 in PTHR10225. function: preferred_term: cytokine receptor activity term: id: GO:0004896 label: cytokine receptor activity notes: GOA records CD44 as contributes_to GO:0004896 (IDA, PMID:17045821; IBA via PTN002566805), i.e. it supplies part of the receptor activity of the complex rather than binding MIF itself. evidence: - source_id: PMID:17045821 title: CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. statement: MIF-induced ERK1/2 phosphorylation requires full-length CD44 in addition to CD74, and CD44 is an integral member of the CD74 receptor complex. supporting_text: >- CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. function: preferred_term: cytokine receptor activity term: id: GO:0004896 label: cytokine receptor activity processes: - preferred_term: macrophage migration inhibitory factor signaling pathway term: id: GO:0035691 label: macrophage migration inhibitory factor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Cell-surface receptor complex in which CD74 binds MIF or DDT and CD44 transduces the signal to Src-family kinases and the ERK1/2 cascade. Neither subunit alone is a functional MIF receptor. evidence: - source_id: GO:0035692 title: macrophage migration inhibitory factor receptor complex statement: The GO definition of the MIF receptor complex states that it comprises the CD74 and CD44 cell surface proteins, which is the composition modelled in this step. - source_id: file:HETGA/Cd44/Cd44-ai-review.yaml title: Naked mole-rat Cd44 gene review statement: The existing Cd44 ortholog review assesses the MIF receptor complex term and notes that its GO definition names both CD44 and CD74, which corroborates modelling the receptor step as a CD74-CD44 complex. supporting_text: >- The GO definition of this complex names CD44 and CD74 explicitly - source_id: PMID:17045821 title: CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. statement: CD74 and CD44 together form the MIF receptor complex that signals to ERK1/2 and protects cells from apoptosis. supporting_text: >- These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction. connections: - source: mif_ligand target: mif_receptor_complex connection_type: POSITIVELY_REGULATES description: Binding of extracellular MIF or DDT (MIF-2) activates the CD74-CD44 receptor complex.