A functional heteromeric MIF receptor formed by CD74 and CXCR4

FEBS Lett. 2009 Sep 3;583(17):2749-57. doi: 10.1016/j.febslet.2009.07.058. Epub 2009 Aug 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Cell Line
  • Enzyme Activation
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Macrophage Migration-Inhibitory Factors / immunology*
  • Monocytes / cytology
  • Monocytes / immunology
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / immunology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Receptors, Immunologic / chemistry
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology


  • Antigens, Differentiation, B-Lymphocyte
  • Histocompatibility Antigens Class II
  • Macrophage Migration-Inhibitory Factors
  • Multiprotein Complexes
  • Receptors, CXCR4
  • Receptors, Immunologic
  • Recombinant Fusion Proteins
  • invariant chain
  • macrophage migration inhibitory factor receptor
  • Proto-Oncogene Proteins c-akt