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MIF Signal Transduction Initiated by Binding to CD74

MIF Signal Transduction Initiated by Binding to CD74 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 PGE 2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10 −9 K d , 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. cytokine invariant chain macrophage migration inhibitory factor MAP kinase receptor Footnotes ↵ * Abbreviations used in this paper: Alexa-MIF, Alexa-488–modified MIF; ERK, extracellular signal–regulated kinase; MIF, macrophage migration inhibitory factor; sCD74, soluble CD74. Submitted: 21 February 2003 Accepted: 27 March 2003 Revision received 21 February 2003 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

MIF Signal Transduction Initiated by Binding to CD74

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References (64)

Publisher
Rockefeller University Press
Copyright
© 2003 Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.20030286
pmid
12782713
Publisher site
See Article on Publisher Site

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 PGE 2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10 −9 K d , 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. cytokine invariant chain macrophage migration inhibitory factor MAP kinase receptor Footnotes ↵ * Abbreviations used in this paper: Alexa-MIF, Alexa-488–modified MIF; ERK, extracellular signal–regulated kinase; MIF, macrophage migration inhibitory factor; sCD74, soluble CD74. Submitted: 21 February 2003 Accepted: 27 March 2003 Revision received 21 February 2003

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Jun 2, 2003

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