Impaired cell adhesion, apoptosis, and signaling in WASP gene-disrupted Nalm-6 pre-B cells and recovery of cell adhesion using a transducible form of WASp

2012 ◽  
Vol 95 (3) ◽  
pp. 299-310 ◽  
Author(s):  
Rikiya Sato ◽  
Susumu Iiizumi ◽  
Eun-Sung Kim ◽  
Fumiko Honda ◽  
Sang-Kyou Lee ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
B Cells ◽  
Wasp Gene

scholarly journals Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

1997 ◽  
Vol 185 (12) ◽  
pp. 2121-2131 ◽  
Author(s):  
Robbert van der Voort ◽  
Taher E.I. Taher ◽  
Robert M.J. Keehnen ◽  
Lia Smit ◽  
Martijn Groenink ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Germinal Center ◽  
Scatter Factor ◽  
Hepatocyte Growth

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

Regulation of epithelial and lymphocyte cell adhesion by adenosine deaminase–CD26 interaction

2002 ◽  
Vol 361 (2) ◽  
pp. 203-209 ◽  
Author(s):  
Silvia GINÉS ◽  
Marta MARIÑO ◽  
Josefa MALLOL ◽  
Enric I. CANELA ◽  
Chikao MORIMOTO ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Surface ◽  
Adenosine Deaminase ◽  
Cell To Cell Adhesion ◽  
Lymphocyte Cell

The extra-enzymic function of cell-surface adenosine deaminase (ADA), an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes, B cells and T cells, has lately been the subject of numerous studies. Cell-surface ADA is able to transduce co-stimulatory signals in T cells via its interaction with CD26, an integral membrane protein that acts as ADA-binding protein. The aim of the present study was to explore whether ADA—CD26 interaction plays a role in the adhesion of lymphocyte cells to human epithelial cells. To meet this aim, different lymphocyte cell lines (Jurkat and CEM T) expressing endogenous, or overexpressing human, CD26 protein were tested in adhesion assays to monolayers of colon adenocarcinoma human epithelial cells, Caco-2, which express high levels of cell-surface ADA. Interestingly, the adhesion of Jurkat and CEM T cells to a monolayer of Caco-2 cells was greatly dependent on CD26. An increase by 50% in the cell-to-cell adhesion was found in cells containing higher levels of CD26. Incubation with an anti-CD26 antibody raised against the ADA-binding site or with exogenous ADA resulted in a significant reduction (50–70%) of T-cell adhesion to monolayers of epithelial cells. The role of ADA—CD26 interaction in the lymphocyte—epithelial cell adhesion appears to be mediated by CD26 molecules that are not interacting with endogenous ADA (ADA-free CD26), since SKW6.4 (B cells) that express more cell-surface ADA showed lower adhesion than T cells. Adhesion stimulated by CD26 and ADA is mediated by T cell lymphocyte function-associated antigen. A role for ADA—CD26 interaction in cell-to-cell adhesion was confirmed further in integrin activation assays. FACS analysis revealed a higher expression of activated integrins on T cell lines in the presence of increasing amounts of exogenous ADA. Taken together, these results suggest that the ADA—CD26 interaction on the cell surface has a role in lymphocyte—epithelial cell adhesion.

TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemia

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4703-4712 ◽  
Author(s):  
Jennifer L. Costantini ◽  
Samuel M. S. Cheung ◽  
Sen Hou ◽  
Hongzhao Li ◽  
Sam K. Kung ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Types ◽  
Potential Interaction ◽  
Cytoskeletal Proteins ◽  
Lymphocytic Leukemia ◽  
Pleckstrin Homology Domain ◽  
Ph Domain

Abstract Tandem pleckstrin homology domain proteins (TAPPs) are recruited to the plasma membrane via binding to phosphoinositides produced by phosphoinositide 3-kinases (PI3Ks). Whereas PI3Ks are critical for B-cell activation, the functions of TAPP proteins in B cells are unknown. We have identified 40 potential interaction partners of TAPP2 in B cells, including proteins involved in cytoskeletal rearrangement, signal transduction and endocytic trafficking. The association of TAPP2 with the cytoskeletal proteins utrophin and syntrophin was confirmed by Western blotting. We found that TAPP2, syntrophin, and utrophin are coexpressed in normal human B cells and B-chronic lymphocytic leukemia (B-CLL) cells. TAPP2 and syntrophin expression in B-CLL was variable from patient to patient, with significantly higher expression in the more aggressive disease subset identified by zeta-chain–associated protein kinase of 70 kDa (ZAP70) expression and unmutated immunoglobulin heavy chain (IgH) genes. We examined whether TAPP can regulate cell adhesion, a known function of utrophin/syntrophin in other cell types. Expression of membrane-targeted TAPP2 enhanced B-cell adhesion to fibronectin and laminin, whereas PH domain–mutant TAPP2 inhibited adhesion. siRNA knockdown of TAPP2 or utrophin, or treatment with PI3K inhibitors, significantly inhibited adhesion. These findings identify TAPP2 as a novel link between PI3K signaling and the cytoskeleton with potential relevance for leukemia progression.

scholarly journals Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth

2018 ◽  
Vol 92 (9) ◽  
Author(s):  
Xiaohui Mo ◽  
Fang Wei ◽  
Yin Tong ◽  
Ling Ding ◽  
Qing Zhu ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Cell Adhesion ◽  
B Cells ◽  
B Cell ◽  
Cancer Progression ◽  
Epstein Barr Virus ◽  
Lactate Production ◽  
Barr Virus ◽  
Viral Microrna ◽  
Epstein Barr

ABSTRACT High plasma lactate is associated with poor prognosis of many malignancies, but its role in virally mediated cancer progression and underlying molecular mechanisms are unclear. Epstein-Barr virus (EBV), the first human oncogenic virus, causes several cancers, including B-cell lymphoma. Here, we report that lactate dehydrogenase A (LDH-A) expression and lactate production are elevated in EBV-immortalized B lymphoblastic cells, and lactic acid (LA; acidic lactate) at low concentration triggers EBV-infected B-cell adhesion, morphological changes, and proliferation in vitro and in vivo . Moreover, LA-induced responses of EBV-infected B cells uniquely occurs in viral latency type III, and it is dramatically associated with the inhibition of global viral microRNAs, particularly the miR-BHRF1 cluster, and the high expression of SMAD3 , JUN , and COL1A genes. The introduction of miR-BHRF1-1 blocks the LA-induced effects of EBV-infected B cells. Thus, this may be a novel mechanism to explain EBV-immortalized B lymphoblastic cell malignancy in an LA microenvironment. IMPORTANCE The tumor microenvironment is complicated, and lactate, which is created by cell metabolism, contributes to an acidic microenvironment that facilitates cancer progression. However, how LA operates in virus-associated cancers is unclear. Thus, we studied how EBV (the first tumor virus identified in humans; it is associated with many cancers) upregulates the expression of LDH-A and lactate production in B lymphoma cells. Elevated LA induces adhesion and the growth of EBV-infected B cells by inhibiting viral microRNA transcription. Thus, we offer a novel understanding of how EBV utilizes an acidic microenvironment to promote cancer development.

Platelets selectively enhance lymphocyte adhesion on subendothelial matrix under arterial flow conditions

2012 ◽  
Vol 108 (08) ◽  
pp. 328-337 ◽  
Author(s):  
Maria Ersoy ◽  
Paul Hjemdahl ◽  
Naphtali Savion ◽  
David Varon ◽  
Galia Spectre ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
B Cells ◽  
Nk Cells ◽  
Platelet Activation ◽  
Platelet Adhesion ◽  
Nk Cell ◽  
Lymphocyte Adhesion ◽  
Subendothelial Matrix ◽  
Coated Surface ◽  
Coated Surfaces

SummaryPlatelet adhesion at sites of cardiovascular injury may facilitate leukocyte deposition. We asked if and how platelets enhance lymphocyte adhesion on different subendothelial matrix protein (SEMP)-coated surface at arterial shear stress. Hirudinised whole blood was subjected to an arterial shear rate (500 s−1) in a Cone and Plate(let) analyser (CPA) for 5 minutes using plates coated with bovine serum albumin (BSA), collagen, fibrinogen, von Willebrand factor (vWF), or fibronectin. Platelet and lymphocyte adhesion were monitored by CPA and flow cytometry. Exposure of blood to collagen, fibrinogen, and vWF-coated surfaces induced platelet activation. The most marked effect was seen with collagen-coating, which markedly enhanced the adhesion of all lymphocyte subpopulations compared to BSA-coating. Fibrinogen-coating supported both T and NK cell adhesion, while vWF-coated surface only enhanced NK cell deposition. In contrast, fibronectin enhanced neither platelet activation nor lymphocyte adhesion. Moreover, platelets preferentially facilitated adhesion of large CD4+ and CD8+ T cells and NK cells, and of small B cells. Enhanced cell adhesion of larger lymphocytes was associated with elevated platelet conjugation and higher lymphocyte expression of PSGL-1, Mac-1, and CD40L. The enhancement of lymphocyte adhesion was totally platelet-dependent, and was abolished in platelet-depleted blood. Moreover, blockade of the platelet adhesion molecules P-selectin, GPIIb/IIIa, and CD40L attenuated platelet-dependent lymphocyte deposition. In conclusion, platelets support lymphocyte adhesion on SEMP-coated surfaces under arterial shear. The enhancement is selective for large T and NK cells and small B cells.

scholarly journals cDNA cloning of the B cell membrane protein CD22: a mediator of B-B cell interactions.

1991 ◽  
Vol 173 (1) ◽  
pp. 137-146 ◽  
Author(s):  
G L Wilson ◽  
C H Fox ◽  
A S Fauci ◽  
J H Kehrl
Keyword(s):  
Amino Acids ◽  
Cell Adhesion ◽  
B Cells ◽  
Cell Membrane ◽  
Membrane Protein ◽  
B Cell ◽  
Cell Adhesion Molecule ◽  
Northern Blot Analysis ◽  
B Lymphocyte ◽  
Cell Membrane Protein

We have cloned a full-length cDNA for the B cell membrane protein CD22, which is referred to as B lymphocyte cell adhesion molecule (BL-CAM). Using subtractive hybridization techniques, several B lymphocyte-specific cDNAs were isolated. Northern blot analysis with one of the clones, clone 66, revealed expression in normal activated B cells and a variety of B cell lines, but not in normal activated T cells, T cell lines, Hela cells, or several tissues, including brain and placenta. One major transcript of approximately 3.3 kb was found in B cells although several smaller transcripts were also present in low amounts (approximately 2.6, 2.3, and 1.6 kb). Sequence analysis of a full-length cDNA clone revealed an open reading frame of 2,541 bases coding for a predicted protein of 847 amino acids with a molecular mass of 95 kD. The BL-CAM cDNA is nearly identical to a recently isolated cDNA clone for CD22, with the exception of an additional 531 bases in the coding region of BL-CAM. BL-CAM has a predicted transmembrane spanning region and a 140-amino acid intracytoplasmic domain. Search of the National Biological Research Foundation protein database revealed that this protein is a member of the immunoglobulin super family and that it had significant homology with three homotypic cell adhesion proteins: carcinoembryonic antigen (29% identity over 460 amino acids), myelin-associated glycoprotein (27% identity over 425 amino acids), and neural cell adhesion molecule (21.5% over 274 amino acids). Northern blot analysis revealed low-level BL-CAM mRNA expression in unactivated tonsillar B cells, which was rapidly increased after B cell activation with Staphylococcus aureus Cowan strain 1 and phorbol myristate acetate, but not by various cytokines, including interleukin 4 (IL-4), IL-6, and gamma interferon. In situ hybridization with an antisense BL-CAM RNA probe revealed expression in B cell-rich areas in tonsil and lymph node, although the most striking hybridization was in the germinal centers. COS cells transfected with a BL-CAM expression vector were immunofluorescently stained positively with two different CD22 antibodies, each of which recognizes a different epitope. Additionally, both normal tonsil B cells and a B cell line were found to adhere to COS transfected with BL-CAM in the sense but not the antisense direction.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Stimulation of tyrosine phosphorylation after ligation of beta7 and beta1 integrins on human B cells

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1855-1861
Author(s):  
SN Manie ◽  
A Astier ◽  
D Wang ◽  
JS Phifer ◽  
J Chen ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
B Cells ◽  
Tyrosine Phosphorylation ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Multiple Substrates ◽  
Phosphorylated Proteins ◽  
Intracellular Signals ◽  
Cell Adhesion Molecule 1 ◽  
Alpha4 Beta7

B lymphocytes express several members of the integrin family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. In addition to beta1 integrins, predominantly alpha4 beta1, mature B cells also express alpha4 beta7, which is a receptor for vascular cell adhesion molecule-1 and fibronectin, and is also involved in the homing of B cells to mucosal sites through binding to a third ligand, mucosal address in cell adhesion molecule-1. Here we describe that crosslinking of alpha4 beta7 integrins on B cell lines and normal tonsillar B cells, induces tyrosine phosphorylation of multiple substrates of 105–130 kD, indicating that beta7 integrin plays a role as signaling molecule in B cells. This pattern of phosphorylated proteins was very similar to that induced following ligation of alpha4 beta1. Interestingly, ligation of alpha5 beta1 or alpha6 beta1 also stimulated the 105–125 kD group of phosphorylated proteins, whereas ligation of beta2 integrins did not. The focal adhesion tyrosine kinase p125FAK was identified as one of these substrates. Beta1 or beta7 mediated tyrosine phosphorylations were markedly decreased when the microfilament assembly was inhibited by cytochalasin B. These results suggest that intracellular signals initiated by different integrins in B cells may converge, to similar cytoskeleton-dependent tyrosine phosphorylated proteins.

scholarly journals Differential attachment of human neoplastic B cells to purified extracellular matrix molecules

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1586-1594 ◽  
Author(s):  
D Segat ◽  
C Pucillo ◽  
G Marotta ◽  
R Perris ◽  
A Colombatti
Keyword(s):  
Extracellular Matrix ◽  
Cell Adhesion ◽  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Philadelphia Chromosome ◽  
Maturation State ◽  
Neoplastic Lymphocytes

Recirculation of normal and neoplastic lymphocytes occurs via binding to the endothelial luminar surface, followed by extravasation and the subsequent interaction of the cells with components of the underlying basement membrane and stromal extracellular matrix (ECM). To identify matrix constituents that could be involved in the tissue dissemination of neoplastic B cells, we have examined the ability of three lymphoma B- cell lines and one Philadelphia chromosome (Ph1)-positive cell line established from the lymphoid transformation of a chronic myeloid leukemia (CML) to adhere to a range of purified ECM molecules. Immunophenotyping with a panel of markers suggested that the lines derived from cells that had undergone transformation at distinct stages of B-cell maturation. The four cell lines displayed a differential ability to adhere to the ECM molecules tested. BV-173, Ci-1, and Sc-1 cells attached to various degrees to fibronectin (FN). Ri-1, Ci-1, and Sc-1 cells attached to human laminin (LN) variants, whereas only Ci-1 and Sc-1 cells showed some affinity for collagen (Col) type VI. All four cell lines interacted with fibrillar Col I, but only BV-173 and Ri- 1 cells attached to fibrillar Col III. The subendothelial Col VIII only was active as a substratum for BV-173 cells. In all cases, cells bound to fibrillar collagens when they were assembled into polymeric fibrils, and were incapable of adhering to monomeric and denatured collagen. In contrast to cell adhesion to FN and LN, which showed a plateau at high substrate concentrations, adhesion to fibrillar Col I reached a peak at intermediary concentrations and decreased thereafter, suggesting that cells respond to a definite macromolecular arrangement of collagenous fibrils. Adhesion to individual ECM molecules was not directly correlated with the apparent maturation state of the cells, nor with the relative density of known ECM receptors. Taken together, these results suggest that interaction of neoplastic B cells with selected matrix components may influence their dispersion throughout tissues. We further suggest that the use of quantitative cell adhesion assays in vitro may provide means of defining the behavioral traits of neoplastic B cells in vivo.

The Scaffolding Protein NEDD9 Regulates Chronic Lymphocytic Leukemia Cell Migration Via the CXCR4 - CXCL12 Axis and Promotes Disease Progression

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-2
Author(s):  
Lisa Rusyn ◽  
Sebastian Reinartz ◽  
Anastasia Nikiforov ◽  
Nelly Mikhael ◽  
Christian Pallasch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Adhesion ◽  
B Cells ◽  
Peripheral Blood ◽  
Treatment Strategies ◽  
Scaffold Protein ◽  
Lower Proportion ◽  
Dramatic Reduction

Despite the undeniable vast improvement in CLL treatment strategies, resistance to novel compounds such as ibrutinib and venetoclax already emerged and posed a challenge in many aggressive cases. The fundamental role of the homing process in CLL progression and presumably relapse prompted us to analyze the impact of a crucial regulator of chemokine response, migration and lymphocyte homing - namely NEDD9 - on CLL pathogenesis. The scaffold protein NEDD9 is frequently upregulated and hyperphosphorylated in different cancer entities, with its deregulation being associated with poor clinical outcome and therapy resistance. In B cells, activation of integrin- and the B cell receptor signaling pathways leads to hyperphosphorylation of NEDD9, predominantly by Src family kinases, promoting cell adhesion, migration and chemotaxis. To elucidate the functional relevance of NEDD9 in CLL pathogenesis in vivo,Eµ-TCL1 transgenic mice were crossbred with Nedd9 deficient mice. CLL burden was monitored in the peripheral blood of Nedd9-proficient (TCL1tg/wt Nedd9wt/wt)versus Nedd9-deficient (TCL1tg/wt Nedd9-/-) mice every two months over a year, revealing a significantly lower proportion of CLL per total B cells (CLL/B cells) in the peripheral blood in TCL1tg/wt Nedd9-/- mice at four and six months of age. CLL onset was clearly delayed in TCL1tg/wt Nedd9-/- mice in comparison to TCL1tg/wt Nedd9wt/wt mice. The infiltration of CLL cells into the spleen and bone marrow was significantly reduced in TCL1tg/wt Nedd9-/- mice at three and ten months, accompanied by significantly longer overall survival of the TCL1tg/wt Nedd9-/- group. Particularly, this eminent role of Nedd9 in CLL pathogenesis could be largely attributed to Nedd9 expression in B cells. Using a conditional Nedd9 knockout mouse exclusively in B cells (TCL1tg/wt CD19Cretg/wt Nedd9flfl (TCN)), we observed a highly similar phenotype of TCN mice to the TCL1tg/wt Nedd9-/- mice, including significantly delayed CLL onset, lower proportion of CLL per total B cells (CLL/B cells) in the peripheral blood, and reduced hepatosplenomegaly in TCN mice compared to the control TCL1tg/wt CD19Crewt/wt Nedd9flfl (TN) mice. In summary, our mouse data suggest that Nedd9 deficiency significantly delayed CLL onset and progression, particularly in the early stages of CLL. Moreover, Nedd9 deficiency significantly decreased the accumulation of CLL cells both in typical leukemic homing organs such as spleen and bone marrow as well as in the peripheral blood in two independent mouse models and significantly prolonged survival of the TCL1tg/wt Nedd9-/- mice. The strongly reduced capacity of Nedd9-deficient CLL cells to migrate and home to the lymphoid niche prompted us to investigate the underlying mechanistic signaling pathway upon Nedd9 loss. For this purpose, we examined surface expression levels of prominent cell trafficking mediators on Nedd9-proficient and -deficient CLL cells, and found a consistently reduced level of CXCR4 on the surface of TCL1tg/wt Nedd9-/-cells. In the transwell assay, CLL cells isolated from TCL1tg/wt Nedd9-/- mice showed a dramatic reduction in migration towards CXCL12 compared to their wild type counter parts. In line with the results of the murine CLL cells, NEDD9-depleted MEC1 cells (shNedd9) also showed decreased CXCR4 levels and dramatic reduction in migration towards CXCL12 compared to the control cell line (shNT). Collectively, we provide the first direct evidence that genetic targeting of Nedd9 in vivo impairs CLL cell adhesion, migration and chemotaxis, resulting in decreased CLL cell infiltration into secondary lymphoid organs and the bone marrow. These observations could serve as basis for the development of new treatment strategies, targeting a scaffold protein to impair the homing process of CLL cells, a prerequisite for their survival and expansion within the microenvironment of protective niches. Disclosures No relevant conflicts of interest to declare.

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