Search tips
Search criteria

Results 1-9 (9)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
author:("shahar, idi")
1.  Midkine as a regulator of B cell survival in health and disease 
British Journal of Pharmacology  2014;171(4):888-895.
In healthy individuals, the pool of peripheral lymphocytes is constant in size. The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, survival and proliferation. Survival factors have been shown to play a critical role in maintaining the correct size of lymphocyte populations. Midkine, a heparin-binding cytokine was recently shown to be involved in cell proliferation, differentiation and apoptosis in various cell types including normal and malignant B cells. This review focuses on the role of midkine in the regulation of peripheral B cell survival in health and disease.
Linked Articles
This article is part of a themed section on Midkine. To view the other articles in this section visit
PMCID: PMC3925027  PMID: 24111754
BCR; BAFF; MIF; CD74; invariant chain; B cells; survival
2.  CD84 is a survival receptor for CLL cells 
Oncogene  2013;33(8):1006-1016.
Chronic lymphocytic leukemia (CLL) is a malignancy of mature lymphocytes that is manifest by the progressive accumulation of transformed cells, mostly due to their decreased apoptosis. CD84 belongs to the Signaling Lymphocyte Activating Molecule (SLAM) family of immunoreceptors and has an as yet unknown function in normal B cells and CLL lymphocytes. We show that CD84 is over-expressed in CLL cells. Activation of cell surface CD84 initiates a signaling cascade, which enhances cell survival. Both immunoneutralization or blockade of CD84 induce cell death in vitro and in vivo. Thus, overexpression of CD84 from an early stage may be critical for the survival of CLL. These findings suggest novel therapeutic strategies based on the blockade of a CD84 dependent survival pathway.
PMCID: PMC3796123  PMID: 23435417
3.  The Cytokine Midkine and its Receptor RPTPζ Regulate B Cell Survival in a Pathway Induced by CD741 
Lasting B-cell persistence depends on survival signals that are transduced by cell surface receptors. Here, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia (CLL) cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase zeta (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 is 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 CLL cells. Our results indicate that MK and RPTPζ are important regulators of the B cell repertoire. These findings could pave the way towards understanding the mechanisms shaping B cell survival, and suggest novel therapeutic strategies based on the blockade of the midkine/RPTPζ-dependent survival pathway.
PMCID: PMC3244541  PMID: 22140262
4.  TAp63 Regulates VLA-4 Expression and Chronic Lymphocytic Leukemia Cell Migration to the Bone Marrow in a CD74-Dependent Manner 
The hallmark of chronic lymphocytic leukemia (CLL) is the relentless accumulation of mature lymphocytes, mostly due to their decreased apoptosis. CD74 was recently shown to serve as a survival receptor on CLL cells. In this study, we show that stimulation of CD74 with its natural ligand, migration inhibitory factor, initiates a signaling cascade that results in upregulation of TAp63, which directly regulates CLL survival. In addition, TAp63 expression elevates the expression of the integrin VLA-4, particularly during the advanced stage of the disease. Blocking of CD74, TAp63, or VLA-4 inhibits the in vivo homing of CLL cells to the bone marrow (BM). Thus, CD74 and its target genes TAp63 and VLA-4 facilitate migration of CLL cells back to the BM, where they interact with the supportive BM environment that rescues them from apoptosis. These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival.
PMCID: PMC3129539  PMID: 20357260
5.  Mad3 Negatively Regulates B Cell Differentiation in the Spleen by Inducing Id2 Expression 
Molecular Biology of the Cell  2010;21(11):1864-1871.
Id2 is a negative regulator of B cell differentiation. Its expression was found to depend on Myc–Max–Mad transcriptional complexes. Here, we show that Mad3 expression levels that are elevated in immature B cells are actively involved in inducing Id2 expression by binding to its promoter, resulting in its augmented expression.
Immature B cells migrate to the spleen where they differentiate into mature cells. This final maturation step is crucial to enable B cells to become responsive to antigens and to participate in the immune response. Previously, we showed that Id2 acts as a negative regulator of the differentiation of immature B cells occurring in the spleen. Id2 expression has been found to depend on Myc–Max–Mad transcriptional complexes in mammary epithelial cells. Nearly all studies to date have shown that Mad proteins inhibit proliferation, presumably by antagonizing the function of Myc proteins. In the current study, we followed the Mad family members during peripheral B cell differentiation. We show that Mad3 actively regulates B cell differentiation. Our results demonstrate that high expression levels of Mad3 in immature B cells induce Id2 expression, which inhibits transcription of genes essential for B cell differentiation. During their differentiation to mature cells, B cells reduce their Mad3 expression, enabling the maturation process to occur.
PMCID: PMC2877644  PMID: 20375148
6.  CD74 is a survival receptor on colon epithelial cells 
AIM: To investigate the expression and function of CD74 in normal murine colon epithelial cells (CEC) and colon carcinoma cells.
METHODS: Expression of CD74 mRNA and protein were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and fluorescence-activated cell sorter (FACS). The effect of migration inhibitory factor (MIF) on the survival of normal CEC from C57BL/6, NOD/SCID, and CD74 deficient mice both in vitro and in vivo, and on the CT26 carcinoma cell line was analyzed by (quantitative) qRT-PCR, RT-PCR, Western blotting and FACS.
RESULTS: CD74 was found to be expressed on normal CEC. Stimulation of CD74 by MIF induced a signaling cascade leading to up-regulation of Bcl-2 expression, resulting in a significant increased survival of CEC. CD74 was also expressed on the CT26 colon carcinoma cell line and its stimulation by MIF resulted in enhanced cell survival, up-regulation of Akt phosphorylation and Bcl-2 expression.
CONCLUSION: CD74 is expressed on CEC and colon carcinoma cells and serves as a survival receptor in these cells. These results may have implications on colorectal cancer research.
PMCID: PMC2900717  PMID: 20614481
CD74; Migration inhibitory factor; Colon epithelial cells
7.  CD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family 
Molecular Biology of the Cell  2005;16(11):5061-5069.
Quite a few regulatory proteins, including transcription factors, are normally maintained in a dormant state to be activated after internal or environmental cues. Recently, a novel strategy, requiring proteolytic cleavage, was described for the mobilization of dormant transcription factors. These transcription factors are initially synthesized in an inactive form, whereas “nesting” in integral membrane precursor proteins. After a cleavage event, these new active factors are released from the membrane and can migrate into the nucleus to drive regulated gene transcription. This mechanism, regulated intramembrane proteolysis (RIP), controls diverse biological processes in prokaryotes and eukaryotes in response to a variety of signals. The MHC class II chaperone, CD74 (invariant chain, Ii), was previously shown to function as a signaling molecule in several pathways. Recently, we demonstrated that after intramembranal cleavage, the CD74 cytosolic fragment (CD74-ICD) is released and induces activation of transcription mediated by the NF-κB p65/RelA homodimer and the B-cell-enriched coactivator, TAFII105. Here, we add CD74 to the growing family of RIP-processed proteins. Our studies show that CD74 ectodomain must be processed in the endocytic compartments to allow its intramembrane cleavage that liberates CD74 intracellular domain (CD74-ICD). We demonstrate that CD74-ICD translocates to the nucleus and induces the activation of the p65 member of NF-κB in this compartment.
PMCID: PMC1266406  PMID: 16107560
8.  Autocrine Secretion of Interferon γ Negatively Regulates Homing of Immature B Cells 
The Journal of Experimental Medicine  2000;192(9):1381-1388.
The mechanism by which immature B cells are sequestered from encountering foreign antigens present in lymph nodes or sites of inflammation, before their final maturation in the spleen, has not been elucidated. We show here that immature B cells fail to home to the lymph nodes. These cells can actively exclude themselves from antigen-enriched sites by downregulating their integrin-mediated adhesion to the extracellular matrix protein, fibronectin. This inhibition is mediated by interferon γ secretion. Perturbation of interferon γ activity in vivo leads to the homing of immature B cells to the lymph nodes. This is the first example of autocrine regulation of immune cell migration to sites of foreign antigen presentation.
PMCID: PMC2193359  PMID: 11067886
lymph nodes; adhesion; migration; interferon γ; invariant chain−/− mice
9.  Invariant Chain Controls H2-M Proteolysis in Mouse Splenocytes and Dendritic Cells 
The Journal of Experimental Medicine  2000;191(6):1057-1062.
The association of invariant (Ii) chain with major histocompatibility complex (MHC) class II dimers is required for proper antigen presentation to T cells by antigen-presenting cells. Mice lacking Ii chain have severe abnormalities in class II transport, T cell selection, and B cell maturation. We demonstrate here that H2-M, which is required for efficient class II antigenic peptide loading, is unexpectedly downregulated in splenocytes and mature dendritic cells (DCs) from Ii−/− mice. Downregulation reflects an increased rate of degradation in Ii−/− cells. Degradation apparently occurs within lysosomes, as it is prevented by cysteine protease inhibitors such as E64, but not by the proteasome inhibitor lactacystin. Thus, Ii chain may act as a lysosomal protease inhibitor in B cells and DCs, with its deletion contributing indirectly to the loss of H2-M.
PMCID: PMC2193111  PMID: 10727467
invariant chain; H2-M; DM; cathepsin; dendritic cell

Results 1-9 (9)