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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 \u03b6 (RPTP\u03b6). We demonstrate that MK initiates a signaling cascade leading to B cell survival by binding to RPTP\u03b6. 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 RPTP\u03b6 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\u03b6-dependent survival pathway.<\/jats:p>","DOI":"10.4049\/jimmunol.1101468","type":"journal-article","created":{"date-parts":[[2011,12,3]],"date-time":"2011-12-03T15:23:45Z","timestamp":1322925825000},"page":"259-269","source":"Crossref","is-referenced-by-count":69,"title":["The Cytokine Midkine and Its Receptor RPTP\u03b6 Regulate B Cell Survival in a Pathway Induced by CD74"],"prefix":"10.1093","volume":"188","author":[{"given":"Sivan","family":"Cohen","sequence":"first","affiliation":[{"name":"Department of Immunology, Weizmann Institute of Science , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Or-yam","family":"Shoshana","sequence":"additional","affiliation":[{"name":"Department of Immunology, Weizmann Institute of Science , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einat","family":"Zelman-Toister","sequence":"additional","affiliation":[{"name":"Department of Immunology, Weizmann Institute of Science , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitsan","family":"Maharshak","sequence":"additional","affiliation":[{"name":"Department of Immunology, Weizmann Institute of Science , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inbal","family":"Binsky-Ehrenreich","sequence":"additional","affiliation":[{"name":"Department of Immunology, Weizmann Institute of Science , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Gordin","sequence":"additional","affiliation":[{"name":"Department of Immunology, Weizmann Institute of Science , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inbal","family":"Hazan-Halevy","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tel Aviv Sourasky Medical Center , Tel Aviv 64239 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Herishanu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tel Aviv Sourasky Medical Center , Tel Aviv 64239 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lev","family":"Shvidel","sequence":"additional","affiliation":[{"name":"Hematology Institute, Kaplan Medical Center , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Haran","sequence":"additional","affiliation":[{"name":"Hematology Institute, Kaplan Medical Center , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Leng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yale University School of Medicine , New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Bucala","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yale University School of Medicine , New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Harroch","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Institut Pasteur , 75724 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idit","family":"Shachar","sequence":"additional","affiliation":[{"name":"Department of Immunology, Weizmann Institute of Science , Rehovot 76100 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,1,1]]},"reference":[{"key":"2025032409423615800_r1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/j.1600-065X.2010.00944.x","article-title":"B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor","volume":"237","author":"Mackay","year":"2010","journal-title":"Immunol. 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