Journal
JOURNAL OF IMMUNOLOGY
Volume 188, Issue 1, Pages 259-269Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1101468
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Funding
- Israel Science Foundation [1973/08]
- Israel Cancer Association
- National Institutes of Health [AR049610, AR050498, AI042310]
- Alliance for Lupus Research
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Lasting B cell persistence depends on survival signals that are transduced by cell surface receptors. In this study, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase zeta (RPTP zeta). We demonstrate that MK initiates a signaling cascade leading to B cell survival by binding to RPTP zeta. In mice lacking PTPRZ, the proportion and number of the mature B cell population are reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74-induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and chronic lymphocytic leukemia cells. Our results indicate that MK and RPTPz are important regulators of the B cell repertoire. These findings could pave the way toward understanding the mechanisms shaping B cell survival and suggest novel therapeutic strategies based on the blockade of the MK/RPTP zeta-dependent survival pathway. The Journal of Immunology, 2012, 188: 259-269.
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