The cytokine midkine and its receptor RPTPζ regulate b cell survival in a pathway induced by CD74

Sivan Cohen, Or Yam Shoshana, Einat Zelman-Toister, Nitsan Maharshak, Inbal Binsky-Ehrenreich, Maya Gordin, Inbal Hazan-Halevy, Yair Herishanu, Lev Shvidel, Michal Haran, Lin Leng, Richard Bucala, Sheila Harroch, Idit Shachar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)259-269
Number of pages11
JournalJournal of Immunology
Issue number1
StatePublished - 1 Jan 2012
Externally publishedYes


FundersFunder number
National Institute of Allergy and Infectious DiseasesR56AI042310


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