TY - JOUR
T1 - The cytokine midkine and its receptor RPTPζ regulate b cell survival in a pathway induced by CD74
AU - Cohen, Sivan
AU - Shoshana, Or Yam
AU - Zelman-Toister, Einat
AU - Maharshak, Nitsan
AU - Binsky-Ehrenreich, Inbal
AU - Gordin, Maya
AU - Hazan-Halevy, Inbal
AU - Herishanu, Yair
AU - Shvidel, Lev
AU - Haran, Michal
AU - Leng, Lin
AU - Bucala, Richard
AU - Harroch, Sheila
AU - Shachar, Idit
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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 ζ (RPTPζ). We demonstrate that MK initiates a signaling cascade leading to B cell survival by binding to RPTPζ. 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 RPTPζ 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/RPTPζ-dependent survival pathway.
AB - 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 ζ (RPTPζ). We demonstrate that MK initiates a signaling cascade leading to B cell survival by binding to RPTPζ. 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 RPTPζ 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/RPTPζ-dependent survival pathway.
UR - http://www.scopus.com/inward/record.url?scp=84855382403&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1101468
DO - 10.4049/jimmunol.1101468
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C2 - 22140262
AN - SCOPUS:84855382403
SN - 0022-1767
VL - 188
SP - 259
EP - 269
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -