title: The cytokine midkine and its receptor RPTPζ regulate B cell survival in a pathway induced by CD74.
abstract: 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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
authors.forename: Sivan
authors.initials: S
authors.lastname: Cohen
authors.forename: Or-yam
authors.initials: OY
authors.lastname: Shoshana
authors.forename: Einat
authors.initials: E
authors.lastname: Zelman-Toister
authors.forename: Nitsan
authors.initials: N
authors.lastname: Maharshak
authors.forename: Inbal
authors.initials: I
authors.lastname: Binsky-Ehrenreich
authors.forename: Maya
authors.initials: M
authors.lastname: Gordin
authors.forename: Inbal
authors.initials: I
authors.lastname: Hazan-Halevy
authors.forename: Yair
authors.initials: Y
authors.lastname: Herishanu
authors.forename: Lev
authors.initials: L
authors.lastname: Shvidel
authors.forename: Michal
authors.initials: M
authors.lastname: Haran
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Sheila
authors.initials: S
authors.lastname: Harroch
authors.forename: Idit
authors.initials: I
authors.lastname: Shachar
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000078792:Midkine; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D017978:Receptors, Growth Factor; C045084:invariant chain; C408049:midkine receptors; D000078792:Midkine; D019859:Proto-Oncogene Proteins c-met; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2