A functional heteromeric MIF receptor formed by CD74 and CXCR4

MIF is a chemokine-like inflammatory mediator that triggers leukocyte recruitment by binding to CXCR2 and CXCR4. MIF also interacts with CD74/invariant chain, a single-pass membrane-receptor. We identified complexes between CD74 and CXCR2 with a role in leukocyte recruitment. It is unknown whether CD74 also binds to CXCR4. We demonstrate that CD74/ CXCR4 complexes formed when CD74 was expressed with CXCR4 in HEK293 cells. Expression of CD74-variants lacking an ER-retention signal showed CD74/ CXCR4 complexes at the cell surface. Importantly, endogenous CD74/ CXCR4 complexes were isolated by co-immunoprecipitation from monocytes. Finally, MIF-stimulated CD74-dependent AKT activation was blocked by anti-CXCR4 and anti-CD74 antibodies and AMD3100, whereas CXCL12-stimulated AKT activation was not reduced by anti-CD74. Thus, CD74 forms functional complexes with CXCR4 that mediate MIF-specific signaling. Structured summary: MINT-7234512, MINT-7234528: CD74 (uniprotkb: P04233) physically interacts (MI: 0915) with CXCR4 ( uniprotkb: P61073) by anti tag coimmunoprecipitation (MI: 0007) MINT-7234542: CD74 ( uniprotkb: P04233) and CXCR4 (uniprotkb: P61073) physically interact ( MI: 0915) by anti bait coimmunoprecipitation ( MI: 0006) MINT-7234499: CXCR4 ( uniprotkb: P61073) and CD74 ( uniprotkb: P04233) colocalize ( MI: 0403) by fluorescence microscopy ( MI: 0416) (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.