Abstract
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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / metabolism*
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Cell Line
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Enzyme Activation
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / metabolism*
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Humans
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Macrophage Migration-Inhibitory Factors / immunology*
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Monocytes / cytology
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Monocytes / immunology
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / immunology*
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / metabolism
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Receptors, Immunologic / chemistry
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / immunology
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
Substances
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Antigens, Differentiation, B-Lymphocyte
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Histocompatibility Antigens Class II
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Macrophage Migration-Inhibitory Factors
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Multiprotein Complexes
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Receptors, CXCR4
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Receptors, Immunologic
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Recombinant Fusion Proteins
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invariant chain
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macrophage migration inhibitory factor receptor
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Proto-Oncogene Proteins c-akt