MIF signal transduction initiated by binding to CD74 Journal Article
| Authors: | Leng, L.; Metz, C. N.; Fang, Y.; Xu, J.; Donnelly, S.; Baugh, J.; Delohery, T.; Chen, Y.; Mitchell, R. A.; Bucala, R. |
| Article Title: | MIF signal transduction initiated by binding to CD74 |
| Abstract: | Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 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. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation. |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; protein domain; cell proliferation; animals; mice; mice, knockout; apoptosis; gene expression; map kinase signaling system; protein binding; protein interaction; enzyme activation; cloning, molecular; cytokine; prostaglandin e2; recombinant proteins; membrane protein; ligand; mitogen activated protein kinase 1; cytokine production; target cell; receptor; immunity; protein folding; monocytes; protein structure; antigen binding; histocompatibility antigens class ii; x ray crystallography; mitogen-activated protein kinases; surface plasmon resonance; cell activation; immunocompetent cell; dissociation constant; map kinase; mitogen-activated protein kinase 1; mitogen-activated protein kinase 3; macrophage migration inhibition factor; cd74 antigen; invariant chain; antigens, differentiation, b-lymphocyte; membrane receptor; humans; human; priority journal; article; macrophage migration inhibitory factor; cd70 antigen; macrophage migration-inhibitory factors |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 197 |
| Issue: | 11 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2003-06-02 |
| Start Page: | 1467 |
| End Page: | 1476 |
| Language: | English |
| DOI: | 10.1084/jem.20030286 |
| PUBMED: | 12782713 |
| PROVIDER: | scopus |
| PMCID: | PMC2193907 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
