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 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.

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…In accord with previous studies demonstrating an attenuating effect of sCD74 on MIF‐triggered signaling,28, 37 we identified sCD74 as an inhibitor of MIF‐mediated AKT activation. MIF‐induced phosphorylation of AKT has previously been demonstrated to depend on CXCR4 and CD74 57, 68.…”

“…Cardioprotection by MIF is mediated through its intrinsic antioxidant capacity and by signaling through its cognate receptor CD74, a type II transmembrane glycoprotein and the surface form of class II invariant chain 25, 26, 27, 28, 29, 30, 31. In fact, The MIF/CD74/AMPK (adenosine monophosphate kinase) signaling pathway has repeatedly been demonstrated to play a pivotal protective role in acute myocardial ischemia/reperfusion injury 31, 32, 33.…”

MIF loss impairs Myc-induced lymphomagenesis

“…10,11 However, based on the recently observed correlation of MIF expression levels and tumor aggressiveness it was proposed that MIF might also serve as a link between inflammation and cancer. [12][13][14][15][16][17] Within the hematopoietic system, MIF is expressed by several cell types, including B-lymphoid, 51 T-lymphoid, 52 myeloid, 53,54 and erythroid progenitor cells (OP, unpublished). Here, we provide direct evidence for MIF's involvement in malignant processes in vivo.…”

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

“…MIF promotes cell proliferation and blockade of MIF by antibodies or genetic deletion leads to reduced cellular proliferation and inhibition of tumor growth and angiogenesis (Takahashi et al, 1998;Chesney et al, 1999;Hudson et al, 1999;Shimizu et al, 1999;Mitchell and Bucala, 2000;Bando et al, 2002;Amin et al, 2003;Nishihira et al, 2003). These effects may involve MIF-mediated regulation of CD74-dependent ERK mitogen-activated protein kinase (MAPK) signaling and activation of cytosolic phospholipase A2 (cPLA2) (Mitchell et al, 1999;Leng et al, 2003;Lue et al, 2006), modulation of activities of the tumor-associated protein c-Jun activation domain-binding protein-1 (JAB1) and signaling through the COP9 signalosome (CSN) (Kleemann et al, 2000;Burger-Kentischer et al, 2005). JAB1 is CSN5 of the CSN and functions as coactivator of activator protein-1 (AP-1)-driven gene expression and participates in CSN-mediated activation of SCF-E3 ligase-dependent proteasomal degradation of cell cycle regulators such as p27 or p53 (Chamovitz and Segal, 2001; Bech-Otschir et al, 2002; Wolf et al, 2003).…”