The Experts below are selected from a list of 121248 Experts worldwide ranked by ideXlab platform
Joan E. Wither - One of the best experts on this subject based on the ideXlab platform.
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Interferon-α induces altered transitional B Cell Signaling and function in Systemic Lupus Erythematosus.
Journal of autoimmunity, 2015Co-Authors: Nan-hua Chang, Julie J. Kim, Carolina Landolt-marticorena, Paul R. Fortin, Dafna D. Gladman, Murray B. Urowitz, Joan E. WitherAbstract:Previous studies suggest that the B Cells of patients with Systemic Lupus Erythematosus (SLE) are hyper-responsive to BCR crosslinking; however, it has Been unclear whether this is the result of altered B Cell Signaling or differences in various B Cell suBpopulations in SLE patients as compared to healthy controls. Here we have developed a novel Phosflow technique that permits examination of Cell Signaling in distinct B Cell suBpopulations stratified Based upon developmental stage and Cell surface IgM levels, which we use to show that the naive B Cells of SLE patients are hyper-responsive to IgM receptor crosslinking, resulting in increased SYK phosphorylation. We further demonstrate that this hyper-responsiveness is most marked in the transitional B Cell suBset and that it is associated with altered function, resulting in decreased apoptosis and increased proliferation of these Cells. Examination of repeated samples from the same patients revealed that the hyper-responsiveness fluctuated over time, suggesting that it may Be mediated By pro-inflammatory factors rather than genetic variations Between patients. In support of this concept, incuBation of healthy control B Cells with IFN-α or SLE plasma induced the hyper-responsive phenotype, which was Blocked By anti-IFN-α antiBody. Furthermore, no oBvious correlation was seen Between genetic variants that are proposed to alter BCR Signaling and the increased SYK phosphorylation. The findings suggest that pro-inflammatory factors, in particular Type I IFNs, modulate B Cell function in SLE in a way that could contriBute to the Breach of tolerance in this condition.
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The B-Cell transmemBrane protein CD72 Binds to and is an in vivo suBstrate of the protein tyrosine phosphatase SHP-1
Current biology : CB, 1998Co-Authors: Monica J. S. Nadler, Tony Pawson, Laurie A. Brennan, Gerald D. Gish, John F. Timms, Noemi Fusaki, Jenny Jongstra-bilen, Nobuhiko Tada, Joan E. WitherAbstract:ABstract Background: Signals from the B-Cell antigen receptor (BCR) help to determine B-Cell fate, directing either proliferation, differentiation, or growth arrest/apoptosis. The protein tyrosine phosphatase SHP-1 is known to regulate the strength of BCR Signaling. Although the B-Cell co-receptor CD22 Binds SHP-1, B Cells in CD22-deficient mice are much less severely affected than those in SHP-1-deficient mice, suggesting that SHP-1 may also regulate B-Cell Signaling By affecting other Signaling molecules. Moreover, direct suBstrates of SHP-1 have not Been identified in any B-Cell Signaling pathway. Results: We identified the B-Cell transmemBrane protein CD72 as a new SHP-1 Binding protein and as an in vivo suBstrate of SHP-1 in B Cells. We also defined the Binding sites for SHP-1 and the adaptor protein GrB2 on CD72. Tyrosine phosphorylation of CD72 correlated strongly with BCR-induced growth arrest/apoptosis in B-Cell lines and in primary B Cells. Preligation of CD72 attenuated BCR-induced growth arrest/death signals in immature and mature B Cells or B-Cell lines, whereas preligation of CD22 enhanced BCR-induced growth arrest/apoptosis. Conclusions: We have identified CD72 as the first clear in vivo suBstrate of SHP-1 in B Cells. Our results suggest that tyrosine-phosphorylated CD72 may transmit signals for BCR-induced apoptosis. By dephosphorylating CD72, SHP-1 may have a positive role in B-Cell Signaling. These results have potentially important implications for the involvement of CD72 and SHP-1 in B-Cell development and autoimmunity.
Anne B. Satterthwaite - One of the best experts on this subject based on the ideXlab platform.
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Bruton's tyrosine kinase, a component of B Cell Signaling pathways, has multiple roles in the pathogenesis of lupus
Frontiers in immunology, 2018Co-Authors: Anne B. SatterthwaiteAbstract:Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized By the loss of adaptive immune tolerance to nucleic acid containing antigens. The resulting autoantiBodies form immune complexes that promote inflammation and tissue damage. Defining the signals that drive pathogenic autoantiBody production is an important step in the development of more targeted therapeutic approaches for lupus, which is currently treated primarily with non-specific immunosuppression. Here, we review the contriBution of Bruton’s tyrosine kinase (Btk), a component of B and myeloid Cell Signaling pathways, to disease in murine lupus models. Both gain- and loss-of-function genetic studies have revealed that Btk plays multiple roles in the production of autoantiBodies. These include promoting the activation, plasma Cell differentiation, and class switching of autoreactive B Cells. Small molecule inhiBitors of Btk are effective at reducing autoantiBody levels, B Cell activation, and kidney damage in several lupus models. These studies suggest that Btk may promote end organ damage Both By facilitating the production of autoantiBodies and By mediating the inflammatory response of myeloid Cells to these immune complexes. While Btk has not Been associated with SLE in GWAS studies, SLE B Cells display Signaling defects in components Both upstream and downstream of Btk consistent with enhanced activation of Btk Signaling pathways. Taken together, these oBservations indicate that limiting Btk activity is critical for maintaining B Cell tolerance and preventing the development of autoimmune disease. Btk inhiBitors, generally well-tolerated and approved to treat B Cell malignancy, may thus Be a useful therapeutic approach for SLE.
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Constitutive memBrane association potentiates activation of Bruton tyrosine kinase
Oncogene, 1997Co-Authors: David J. Rawlings, Owen N. Witte, Hyunsun Park, Roberta M Kato, Anne B. SatterthwaiteAbstract:Mutations in the nonreceptor tyrosine kinase Btk result in the B Cell immunodeficiencies X-linked agammagloBulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Genetic and Biochemical evidence implicates Btk as a key component of several B Cell Signaling pathways. Activation of Btk By a point mutation (E41K) within the PH domain (Btk*) results in fiBroBlast transformation and is correlated with increased memBrane localization of Btk. When wild type Btk is activated By coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the memBrane fraction. To determine whether memBrane association is sufficient to activate Btk, we targeted Btk to the plasma memBrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive memBrane association greatly enhanced the aBility of Btk to transform Rat2 fiBroBlasts in the presence of high levels of Src activity. All memBrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required memBrane localization, Btk kinase activity, transphosphorylation By Src family kinases, and an intact SH2 domain But not the PH or SH3 domains. These data suggest that memBrane localization is a critical early step in Btk activation.
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Lessons from human genetic variants in the study of B-Cell differentiation
Current opinion in immunology, 1996Co-Authors: Anne B. Satterthwaite, Owen N. WitteAbstract:Several human B-Cell immunodeficiencies result from mutations in signal transducing molecules. The past year has seen significant advances in our understanding of how these molecules are integrated into B Cell Signaling pathways. The phenotypes of mice deficient in several of these genes have revealed species-specific differences in the requirements for early B Cell development.
Katherine A. Siminovitch - One of the best experts on this subject based on the ideXlab platform.
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Regulation of B Cell signal transduction By SH2-containing protein–tyrosine phosphatases
Seminars in immunology, 1998Co-Authors: Katherine A. Siminovitch, Benjamin G. NeelAbstract:ABstract Tyrosyl phosphorylation plays a key role in B lymphocyte Signaling. The mechanisms By which protein tyrosine kinases (PTKs) regulate Signaling pathways in B Cells have Been investigated extensively. More recently, attention has turned to the protein–tyrosine phosphatases (PTPs), particularly those containing SH2 domains. SHP-1 has Been shown to Be a critical regulator of antigen receptor Signaling, acting, at least in part, via inhiBitory co-receptors containing SHP-1 Binding sites. These studies have Been aided consideraBly By the analysis of mice carrying naturally-arising mutations in the SHP-1 gene as well as mice Bearing targeted mutations in other components of B Cell Signaling pathways. The function of SHP-2 in B Cells is less clear, although studies in other Cell systems suggests that it may play a signal-enhancing role.
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The motheaten mutation rescues B Cell Signaling and development in CD45-deficient mice.
The Journal of experimental medicine, 1997Co-Authors: Giovanni Pani, Katherine A. Siminovitch, Christopher J. PaigeAbstract:The cytosolic SHP-1 and transmemBrane CD45 protein tyrosine phosphatases (PTP) play critical roles in regulating signal transduction via the B Cell antigen receptor (BCR). These PTPs differ, however, in their effects on BCR function. For example, BCR-mediated mitogenesis is essentially aBlated in mice lacking CD45 (CD45(-)), But is enhanced in SHP-1-deficient motheaten (me) and viaBle motheaten (mev) mice. To determine whether these PTPs act independently or coordinately in modulating the physiologic outcome of BCR engagement, we assessed B Cell development and Signaling in CD45-deficient mev (CD45-/SHP-1-) mice. Here we report that the CD45-/SHP-1-) Cells undergo appropriate induction of protein kinase activity, mitogen-activated protein kinase activation, and proliferative responses after BCR aggregation. However, BCR-elicited increases in the tyrosine phosphorylation of several SHP-1-associated phosphoproteins, including CD19, were suBstantially enhanced in CD45-/SHP-1-, compared to wild-type and CD45- Cells. In addition, we oBserved that the patterns of Cell surface expression of mu, delta, and CD5, which distinguish the PTP-deficient from normal mice, are largely restored to normal levels in the douBle mutant animals. These findings indicate a critical role for the Balance of SHP-1 and CD45 activities in determining the outcome of BCR stimulation and suggest that these PTPs act in a coordinate fashion to couple antigen receptor engagement to B Cell activation and maturation.
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Identification of the tyrosine phosphatase PTP1C as a B Cell antigen receptor-associated protein involved in the regulation of B Cell Signaling.
The Journal of experimental medicine, 1995Co-Authors: Giovanni Pani, John C. Cambier, Maya Kozlowski, Gordon B. Mills, Katherine A. SiminovitchAbstract:Recent data implicating loss of PTP1C tyrosine phosphatase activity in the genesis of the multiple hemopoietic Cell defects found in systemic autoimmune/immunodeficient motheaten (me) and viaBle motheaten (mev) mice suggest that PTP1C plays an important role in modulating intraCellular Signaling events regulating Cell activation and differentiation. To Begin elucidating the role for this cytosolic phosphatase in lymphoid Cell signal transduction, we have examined early Signaling events and mitogenic responses induced By B Cell antigen receptor (BCR) ligation in me and mev splenic B Cells and in CD5+ CH12 lymphoma Cells, which represent the lymphoid population amplified in motheaten mice. Despite their lack of functional PTP1C, me and mev B Cells proliferated normally in response to LPS. However, compared with wild-type B Cells, Cells from the mutant mice were hyperresponsive to normally suBmitogenic concentrations of F(aB')2 anti-Ig antiBody, and they exhiBited reduced susceptiBility to the inhiBitory effects of Fc gamma IIRB cross-linking on BCR-induced proliferation. Additional studies of unstimulated CH12 and wild-type splenic B Cells revealed the constitutive association of PTP1C with the resting BCR complex, as evidenced By coprecipitation of PTP1C protein and phosphatase activity with BCR components and the depletion of BCR-associated tyrosine phosphatase activity By anti-PTP1C antiBodies. These results suggest a role for PTP1C in regulating the tyrosine phosphorylation state of the resting BCR complex components, a hypothesis supported By the oBservation that PTP1C specifically induces dephosphorylation of a 35-kD BCR-associated protein likely representing Ig-alpha. In contrast, whereas memBrane Ig cross-linking was associated with an increase in the tyrosine phosphorylation of PTP1C and an approximately 140-kD coprecipitated protein, PTP1C was no longer detected in the BCR complex after receptor engagement, suggesting that PTP1C dissociates from the activated receptor complex. Together these results suggest a critical role for PTP1C in modulating BCR Signaling capacity, and they indicate that the PTP1C influence on B Cell Signaling is likely to Be realized in Both resting and activated Cells.
Chandra Mohan - One of the best experts on this subject based on the ideXlab platform.
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Altered B-Cell Signaling in lupus.
Autoimmunity Reviews, 2009Co-Authors: Kui Liu, Chandra MohanAbstract:Systemic lupus erythematosus (SLE) is an autoimmune disease of complex etiology primarily characterized By the presence of high titers of autoantiBodies targeting many nuclear as well as cytoplasmic antigens, with resultant end-organ damage. ABerrant Signaling events have Been documented in various lymphocyte populations, and they have constituted attractive targets for therapeutic intervention. Murine models of lupus (conventional or engineered) have yielded interesting snapshots of the Signaling status of lupus lymphocytes, and many of these alterations in Cell Signaling oBserved in murine models of lupus have also Been documented in patient samples. Analyses of B-Cell Signaling in various murine lupus models have not only provided an in-depth perspective of the Signaling status and possiBly the underlying mechanisms leading to enhanced survival of autoimmune B Cells, But have also presented us with potential strategies for treating lupus.
Wenxia Song - One of the best experts on this subject based on the ideXlab platform.
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wasp family proteins regulate the moBility of the B Cell receptor during Signaling activation
Nature Communications, 2020Co-Authors: Wenxia Song, Ivan Reysuarez, Brittany A Wheatley, Peter K Koo, Anshuman Bhanja, Zhou Shu, S G J Mochrie, Hari ShroffAbstract:Regulation of memBrane receptor moBility tunes Cellular response to external signals, such as in Binding of B Cell receptors (BCR) to antigen, which initiates Signaling. However, whether BCR Signaling is regulated By BCR moBility, and what factors mediate this regulation, are not well understood. Here we use single molecule imaging to examine BCR movement during Signaling activation and a novel machine learning method to classify BCR trajectories into distinct diffusive states. InhiBition of actin dynamics downstream of the actin nucleating factors, Arp2/3 and formin, decreases BCR moBility. Constitutive loss or acute inhiBition of the Arp2/3 regulator, N-WASP, which is associated with enhanced Signaling, increases the proportion of BCR trajectories with lower diffusivity. Furthermore, loss of N-WASP reduces the diffusivity of CD19, a stimulatory co-receptor, But not that of FcγRIIB, an inhiBitory co-receptor. Our results implicate a dynamic actin network in fine-tuning receptor moBility and receptor-ligand interactions for modulating B Cell Signaling.
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n wasp regulates the moBility of the B Cell receptor and co receptors during Signaling activation
bioRxiv, 2019Co-Authors: Wenxia Song, Ivan Reysuarez, Brittany A Wheatley, Peter K Koo, Zhou Shu, S G J Mochrie, Hari Shroff, Arpita UpadhyayaAbstract:ABstract Regulation of memBrane receptor moBility is important in tuning the Cell’s response to external signals. This is particularly relevant in the context of immune receptor Signaling. The Binding of B Cell receptors (BCR) to antigen induces B Cell receptor activation. While actin dynamics and BCR Signaling are known to Be linked, the role of actin dynamics in modulating receptor moBility is not well understood. Here, we use single molecule imaging to examine BCR movement during Signaling activation and examine the role of actin dynamics on BCR moBility. We use a novel machine learning Based method to classify BCR trajectories into distinct diffusive states and show that the actin regulatory protein N-WASP regulates receptor moBility. Constitutive loss or acute inhiBition of N-WASP, which is associated with enhanced Signaling, leads to a predominance of BCR trajectories with lower diffusivity and is correlated with a decrease in actin dynamics. Furthermore, loss of N-WASP reduces diffusivity of CD19, a stimulatory co-receptor of the BCR But not that of unstimulated FcγRIIB, an inhiBitory co-receptor. The effect of N-WASP is mirrored By inhiBition of the Arp2/3 complex and formins. Our results implicate the dynamic actin network in fine-tuning receptor moBility and receptor-ligand interactions, thereBy modulating B Cell Signaling.
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SuBCellular topography modulates actin dynamics and Signaling in B-Cells.
Molecular biology of the cell, 2018Co-Authors: Christina Ketchum, Xiaoyu Sun, Alexandra Suberi, John T. Fourkas, Wenxia Song, Arpita UpadhyayaAbstract:B-Cell Signaling activation is most effectively triggered By the Binding of B-Cell receptors (BCRs) to memBrane-Bound antigens. In vivo, B-Cells encounter antigen on antigen-presenting Cells (APC), which possess complex surfaces with convoluted topographies, a fluid memBrane and deformaBle Cell Bodies. However, whether and how the physical properties of antigen presentation affect B-Cell activation is not well understood. Here we use nanotopographic surfaces that allow systematic variation of geometric parameters to show that surface features on a suBCellular scale influence B-Cell Signaling and actin dynamics. Parallel nanoridges with spacings of 3 microns or greater induce actin intensity oscillations on the ventral Cell surface. Nanotopography-induced actin dynamics requires BCR Signaling, actin polymerization, and myosin contractility. The topography of the stimulatory surface also modulates the distriBution of BCR clusters in activated B-Cells. Finally, B-Cells stimulated on nanopatterned surfaces exhiBit intraCellular calcium oscillations with frequencies that depend on topography. Our results point to the importance of physical aspects of ligand presentation, in particular, nanotopography for B-Cell activation and antigen gathering.
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Ligand MoBility Regulates B Cell Receptor Clustering and Signaling Activation
Biophysical journal, 2014Co-Authors: Christina Ketchum, Wenxia Song, Heather Miller, Arpita UpadhyayaAbstract:Antigen Binding to the B Cell receptor (BCR) induces receptor clustering, Cell spreading, and the formation of Signaling microclusters, triggering B Cell activation. Although the Biochemical pathways governing early B Cell Signaling have Been well studied, the role of the physical properties of antigens, such as antigen moBility, has not Been fully examined. We study the interaction of B Cells with BCR ligands coated on glass or tethered to planar lipid Bilayer surfaces to investigate the differences in B Cell response to immoBile and moBile ligands. Using high-resolution total internal reflection fluorescence (TIRF) microscopy of live Cells, we followed the movement and spatial organization of BCR clusters and the associated Signaling. Although ligands on either surface were aBle to cross-link BCRs and induce clustering, B Cells interacting with moBile ligands displayed greater Signaling than those interacting with immoBile ligands. Quantitative analysis revealed that moBile ligands enaBled BCR clusters to move farther and merge more efficiently than immoBile ligands. These differences in physical reorganization of receptor clusters were associated with differences in actin remodeling. PerturBation experiments revealed that a dynamic actin cytoskeleton actively reorganized receptor clusters. These results suggest that ligand moBility is an important parameter for regulating B Cell Signaling.
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n wasp is essential for the negative regulation of B Cell receptor Signaling
PLOS Biology, 2013Co-Authors: Chaohong Liu, Wenxia Song, Arpita Upadhyaya, Xiaoming Bai, Shruti Sharma, Carin I M Dahlberg, Lisa S Westerberg, Scott B Snapper, Xiaodong ZhaoAbstract:Negative regulation of receptor Signaling is essential for controlling Cell activation and differentiation. In B-lymphocytes, the down-regulation of B-Cell antigen receptor (BCR) Signaling is critical for suppressing the activation of self-reactive B Cells; however, the mechanism underlying the negative regulation of Signaling remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we demonstrate that neuronal Wiskott–Aldrich syndrome protein (N-WASP), which is coexpressed with WASP in all immune Cells, is a critical negative regulator of B-Cell Signaling. B-Cell–specific N-WASP gene deletion causes enhanced and prolonged BCR Signaling and elevated levels of autoantiBodies in the mouse serum. The increased Signaling in N-WASP knockout B Cells is concurrent with increased accumulation of F-actin at the B-Cell surface, enhanced B-Cell spreading on the antigen-presenting memBrane, delayed B-Cell contraction, inhiBition in the merger of Signaling active BCR microclusters into Signaling inactive central clusters, and a Blockage of BCR internalization. Upon BCR activation, WASP is activated first, followed By N-WASP in mouse and human primary B Cells. The activation of N-WASP is suppressed By Bruton's tyrosine kinase-induced WASP activation, and is restored By the activation of SH2 domain-containing inositol 5-phosphatase that inhiBits WASP activation. Our results reveal a new mechanism for the negative regulation of BCR Signaling and Broadly suggest an actin-mediated mechanism for Signaling down-regulation.
