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.
Schwartz
Verena
V
Department of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany.
Lue
Hongqi
H
Kraemer
Sandra
S
Korbiel
Joanna
J
Krohn
Regina
R
Ohl
Kim
K
Bucala
Richard
R
Weber
Christian
C
Bernhagen
Jürgen
J
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D046912:Multiprotein Complexes / Q000737:chemistry / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D046912:Multiprotein Complexes; D019718:Receptors, CXCR4; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C045084:invariant chain; C033184:macrophage migration inhibitory factor receptor; D051057:Proto-Oncogene Proteins c-akt