Abstract
The signals regulating the survival of mature splenic B cells have become a major focus in recent studies of B cell immunology. Durable B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. In this study, we describe a novel biological mechanism involved in mature B cell homeostasis, the hepatocyte growth factor/scatter factor (HGF)/c-Met pathway. We demonstrate that c-Met activation by HGF leads to a survival cascade, whereas its blockade results in induction of mature B cell death. Our results emphasize a unique and critical function for c-Met signaling in the previously described macrophage migration inhibitory factor/CD74-induced survival pathway. Macrophage migration inhibitory factor recruits c-Met to the CD74/CD44 complex and thereby enables the induction of a signaling cascade within the cell. This signal results in HGF secretion, which stimulates the survival of the mature B cell population in an autocrine manner. Thus, the CD74-HGF/c-Met axis defines a novel physiologic survival pathway in mature B cells, resulting in the control of the humoral immune response.
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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Apoptosis / drug effects
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B-Lymphocytes / cytology
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B-Lymphocytes / metabolism*
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Blotting, Western
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Cell Membrane / metabolism
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Cell Survival / drug effects
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Cells, Cultured
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Flow Cytometry
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Hepatocyte Growth Factor / genetics
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Hepatocyte Growth Factor / metabolism*
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Hepatocyte Growth Factor / pharmacology
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / metabolism*
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism
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Macrophage Migration-Inhibitory Factors / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Protein Binding
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
Substances
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Antigens, Differentiation, B-Lymphocyte
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Histocompatibility Antigens Class II
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Hyaluronan Receptors
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Macrophage Migration-Inhibitory Factors
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invariant chain
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met