Lyn Tyrosine KinaseAccentuating the Positive and the Negative

Xu, Yuekang; Harder, Kenneth W.; Huntington, Nicholas D.; Hibbs, Margaret L.; Tarlinton, David M.

doi:10.1016/s1074-7613(04)00381-4

Cited by 165 publications

(241 citation statements)

References 6 publications

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“…To demonstrate the therapeutic effects of HDACi in a different model of autoimmunity, we tested for efficacy in mice with a loss of function mutation in Lyn, a Src kinase family member and downstream regulator of BCR signalling 40 that also accumulate high levels of pathogenic autoantibodies [41][42][43] . In this model, panobinostat caused a dramatic reduction in autoantibody levels ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

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Histone deacetylase inhibitors (HDACi) are approved for treating certain haematological malignancies, however, recent evidence also illustrates they are modulators of the immune system. In experimental models, HDACi are particularly potent against malignancies originating from the B-lymphocyte lineage. Here we examine the ability of this class of compounds to modify both protective and autoimmune antibody responses. In vitro, HDACi affect B-cell proliferation, survival and differentiation in an HDAC-class-dependent manner. Strikingly, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduces autoreactive plasma-cell numbers, autoantibodies and nephritis, while other immune parameters remain largely unaffected. Immunized control mice treated with panobinostat or the clinically approved HDACi vorinostat have significantly impaired primary antibody responses, but these treatments surprisingly spare circulating memory B cells. These studies indicate that panobinostat is a potential therapy for B-cell-driven autoimmune conditions and HDACi do not induce major long-term detrimental effects on B-cell memory.

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Section: Resultsmentioning

confidence: 99%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

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“…A similar model could be envisioned for CaMKIIγ, and CKLiK plus CaMKIIγ may be part of a complex signaling network that regulates both neutrophil differentiation and function. Precedence for this model is provided by two other regulators of hematopoiesis: the Src family kinase Lyn can positively and negatively regulate cytokine signaling in B-cells and in myeloid lineages, and concentrations of PU.1 determine whether it cooperates with or antagonizes the function of C/EBPα to regulate neutrophil maturation [42][43][44].…”

Section: Discussionmentioning

confidence: 99%

A cascade of Ca2+/calmodulin-dependent protein kinases regulates the differentiation and functional activation of murine neutrophils

Gaines

Lamoureux

Marisetty

et al. 2008

Experimental Hematology

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Objective-The function of neutrophils as primary mediators of innate immunity depends on the activity of granule proteins and critical components of the NADPH oxidase complex. Expression of their cognate genes is regulated during neutrophil differentiation by a complex network of intracellular signaling pathways. In this study we have investigated the role of two members of the calcium/calmodulin-dependent protein kinase (CaMK) signaling cascade, CaMKI-like kinase (CKLiK) and CaMKKα, in regulating neutrophil differentiation and functional activation.Materials and Methods-Mouse myeloid cell lines were used to examine the expression of a CaMK cascade in developing neutrophils and to examine the effects of constitutive activation versus inhibition of CaMKs on neutrophil maturation.Results-Expression of CaMKKα was shown to increase during neutrophil differentiation in multiple cell lines, whereas expression of CKLiK increased as multipotent progenitors committed to promyelocytes but then decreased as cells differentiated into mature neutrophils. Expression of constitutively active CKLiKs did not affect morphologic maturation, but caused dramatic decreases in both respiratory burst responses and chemotaxis. This loss of neutrophil function was accompanied by reduced secondary granule and gp91 phox gene expression. The CaMK inhibitor KN93 attenuated cytokine-stimulated proliferative responses in promyelocytic cell lines, and inhibited the respiratory burst. Similar data were observed with the CaMKKα inhibitor, STO-609.Conclusions-Overactivation of a cascade of CaMKs inhibits neutrophil maturation, suggesting that these kinases play an antagonistic role during neutrophil differentiation, but at least one CaMK is required for myeloid cell expansion and functional activation.

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“…Once phosphorylated, the CD79a/b ITAM domains recruit the protein tyrosine kinase Syk, which is subsequently phosphorylated by Lyn and mediates critical downstream signaling pathways, leading to proliferation and differentiation of B cells (24,25). B cells were stimulated and the ability of BTLA to regulate Syk tyrosine phosphorylation was assessed by immunoprecipitation followed by Western blot analysis.…”

Section: Btla Is a Negative Regulator Of Syk Blnk And Plc␥2mentioning

confidence: 99%

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

Vendel¹,

Calemine-Fenaux²,

Izrael-Tomasevic³

et al. 2009

The Journal of Immunology

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B and T lymphocyte attenuator (BTLA) functions as a negative regulator of T cell activation and proliferation. Although the role of BTLA in regulating T cell responses has been characterized, a thorough investigation into the precise molecular mechanisms involved in BTLA-mediated lymphocyte attenuation and, more specifically, its role in regulating B cell activation has not been presented. In this study, we have begun to elucidate the biochemical mechanisms by which BTLA functions to inhibit B cell activation. We describe the cell surface expression of BTLA on various human B cell subsets and confirm its ability to attenuate B cell proliferation upon associating with its known ligand, herpesvirus entry mediator (HVEM). BTLA associates with the BCR and, upon binding to HVEM, recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 and reduces activation of signaling molecules downstream of the BCR. This is exemplified by a quantifiable decrease in tyrosine phosphorylation of the protein tyrosine kinase Syk, as measured by absolute quantification mass spectrometry. T he B and T lymphocyte attenuator (BTLA) 2 is an Ig superfamily coinhibitory receptor with structural and functional similarities to programmed cell death 1 (PD-1) and CTLA-4 (1-3). However, unlike PD-1 and CTLA-4, which bind members of the B7 Ig superfamily receptors, the established ligand for BTLA is the TNFR family member herpesvirus entry mediator (HVEM) (TNFRSF14) (3-5). HVEM binding leads to tyrosine phosphorylation of the cytoplasmic tail of BTLA, which contains a proposed Grb2/Grb2-related adaptor protein (Grap) docking site and two ITIMs (5-11). Biochemical analysis has revealed that phosphorylation at multiple tyrosines within the cytoplasmic tail of BTLA is necessary and required for efficient recruitment of protein tyrosine phosphatases and BTLA-mediated attenuation of T cell effector response and cell proliferation (5,8,10,11).The role of BTLA appears to be limited to lymphocyte activation as shown in BTLA-deficient mice, which present normal lymphoid organ development and near wild-type lymphocyte numbers. However, these mice display hyperproliferative T and B cell responses to TCR-and BCR-mediated activation, respectively (9, 11). Furthermore, loss of BTLA function leads to increased susceptibility to experimental autoimmune encephalomyelitis and MHC-mismatched allograft rejection, supporting the role of BTLA in modulating T cell activation and effector responses (11,12).Surface expression analysis of BTLA indicates that it is expressed on a wide number of lymphocytes in mice. It is most highly expressed on B cells, followed by CD4 ϩ T cells, and lower expression on CD8 ϩ T cells, macrophages, dendritic cells, and NK cells (9, 13). During murine B cell development, BTLA expression first appears in pre-B cells and shows increased expression through B cell maturation, with the highest expression on mature B cells (9). In this study, we show a detailed cell surface expression profile of BTLA during human B cell deve...

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Lyn Tyrosine KinaseAccentuating the Positive and the Negative

Cited by 165 publications

References 6 publications

Manipulation of B-cell responses with histone deacetylase inhibitors

Manipulation of B-cell responses with histone deacetylase inhibitors

A cascade of Ca2+/calmodulin-dependent protein kinases regulates the differentiation and functional activation of murine neutrophils

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

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