MIF signaling pathway module

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.

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.