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Search results for: Syk

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#33670716   2021/02/18 To Up

Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions.

Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter. Bioinformatic analyses allowed for unveiling the main differences in signaling pathways, network topology and signal propagation from SYK to its potential effectors. In breast cancer cells, the SYK target-enriched signaling pathways included intercellular adhesion and Hippo signaling components that are often linked to tumor suppression. In Burkitt lymphoma cells, the SYK target-enriched signaling pathways included molecules that could play a role in SYK pro-oncogenic function in B-cell lymphomas. Several protein interactions were profoundly rewired in the breast cancer network compared with the Burkitt lymphoma network. These data demonstrate that proteomic profiling combined with mathematical network modeling allows untangling complex pathway interplays and revealing difficult to discern interactions among the SYK pathways that positively and negatively affect tumor formation and progression.
Marion Buffard, Aurélien Naldi, Gilles Freiss, Marcel Deckert, Ovidiu Radulescu, Peter J Coopman, Romain M Larive

2681 related Products with: Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions.

5 G50 ug 25 mg500IU

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#33657162   2021/03/03 To Up

Long-term platelet priming after glycoprotein VI stimulation in comparison to Protease-Activating Receptor (PAR) stimulation.

Platelets can respond to multiple antagonists and agonists, implying that their activation state is a consequence of past exposure to these substances. While platelets are often considered as one-time responsive cells, they likely can respond to sequential application of inhibitors and stimuli. We hypothesized that the ability of platelets to sequentially respond depends on the time and type of repeated agonist application. The present proof-of-concept data show that iloprost (cAMP elevation), tirofiban (integrin αIIbβ3 blocker) and Syk kinase inhibition subacutely modulated platelet aggregation, i.e. halted this process even when applied after agonist. In comparison to thrombin-activated receptor (PAR) stimulation, glycoprotein VI (GPVI) stimulation was less sensitive to time-dependent blockage of aggregation, with Syk inhibition as an exception. Furthermore, cytosolic Ca2+ measurements indicated that, when compared to PAR, prior GPVI stimulation induced a more persistent, priming activation state of platelets that influenced the response to a next agent. Overall, these data point to an unexpected priming memory of activated platelets in subacutely responding to another inhibitor or stimulus, with a higher versatility and faster offset after PAR stimulation than after GPVI stimulation.
Jinmi Zou, Jiayu Wu, Mark Roest, Johan W M Heemskerk

1643 related Products with: Long-term platelet priming after glycoprotein VI stimulation in comparison to Protease-Activating Receptor (PAR) stimulation.

50 ug100 ug1,000 IU100 μg96tests100 ug50 IU100 μg100 ug10 IU100 ug100

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#33645216   2021/03/01 To Up

Sialylated Lipooligosaccharide Contributes to Penetration of Porcine Respiratory Epithelial Barrier.

Pathogens utilize various mechanisms to escape host immunological surveillance, break down different tissue barriers, and cause infection. Sialylation is an important surface modification of bacterial outer membrane components, especially the lipooligosaccharide of Gram-negative bacteria. It is widely involved in multiple microbe-host interactions, such as bacterial virulence regulation, host recognition, and immune evasion. There are some sialylation modifications on the lipooligosaccharide structure of () virulent strains. However, the role of lipooligosaccharide sialylation modification in the process of infection and penetration of the porcine respiratory epithelial barrier is still unclear. In this study, we investigated the role and mechanism of -mediated lipooligosaccharide sialylation in invasion of the host respiratory epithelial barrier. Specifically, -mediated lipooligosaccharide sialylation and sialylated-lipooligosaccharide interacted with Siglec1 on porcine alveolar macrophages 3D4/21 and triggered the subsequent generation of TGFβ1 through Siglec1/Dap12/Syk/p38 signaling cascade. TGFβ1 decreased the tracheal epithelial tight junctions and the expression of extracellular adhesion molecule fibronectin, thus assisting invasion and entry to the respiratory epithelial barrier. Characterizing the potential effects and mechanisms of lipooligosaccharide sialylation-mediated TGFβ1 production would further expand our current knowledge on the pathogenesis of which will contribute to better prevention and control of infection in piglets.
Huan Wang, Wenbin Wei, Qi Cao, Manman Xu, Qichao Chen, Yujin Lv, Chen Tan, Menghong Dai, Xiaojuan Xu, Huanchun Chen, Xiangru Wang

2169 related Products with: Sialylated Lipooligosaccharide Contributes to Penetration of Porcine Respiratory Epithelial Barrier.

500.1 mg1 module0.1 mg10 mg lyophilized1 module96 wells (1 kit)500 1KG1 kit(96 Wells)100

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#33643306   2021/02/12 To Up

Human IgA-Expressing Bone Marrow Plasma Cells Characteristically Upregulate Programmed Cell Death Protein-1 Upon B Cell Receptor Stimulation.

The functions of bone marrow plasma cells (BMPC) beyond antibody production are not fully elucidated and distinct subsets of BMPC suggest potential different functions. Phenotypic differences were identified for human BMPC depending on CD19 expression. Since CD19 is a co-stimulatory molecule of the B-cell-receptor (BCR), and IgA and IgM BMPC express the BCR on their surface, we here studied whether CD19 expression affects cellular responses, such as BCR signaling and the expression of checkpoint molecules. We analyzed 132 BM samples from individuals undergoing routine total hip arthroplasty. We found that both CD19 and CD19 BMPC expressed BCR signaling molecules. Notably, the BCR-associated kinase spleen tyrosine kinase (SYK) including pSYK was higher expressed in CD19 BMPC compared to CD19 BMPC. BCR stimulation also resulted in increased kinase phosphorylation downstream of the BCR while expression of CD19 remained stable afterwards. Interestingly, the BCR response was restricted to IgA BMPC independently of CD19 expression. With regard to the expression of checkpoint molecules, CD19 BMPC expressed higher levels of co-inhibitory molecule programmed cell death protein-1 (PD-1) than CD19 BMPC. IgA BMPC characteristically upregulated PD-1 upon BCR stimulation in contrast to other PC subsets and inhibition of the kinase SYK abrogated PD-1 upregulation. In contrast, expression of PD-1 ligand, B and T lymphocyte attenuator (BTLA) and CD28 did not change upon BCR activation of IgA BMPC. Here, we identify a distinct characteristic of IgA BMPC that is independent of the phenotypic heterogeneity of the subsets according to their CD19 expression. The data suggest that IgA BMPC underlie different regulatory principles and/or exert distinct regulatory functions.
Annika Wiedemann, Marie Lettau, Ina Wirries, Annemarie Jungmann, Abdulrahman Salhab, Gilles Gasparoni, Henrik E Mei, Carsten Perka, Jörn Walter, Andreas Radbruch, Andreia C Lino, Thomas Dörner

1022 related Products with: Human IgA-Expressing Bone Marrow Plasma Cells Characteristically Upregulate Programmed Cell Death Protein-1 Upon B Cell Receptor Stimulation.

100ug Lyophilized100ug Lyophilized1mg100ug Lyophilized100 1.00 flask100ml100ml100ul1.00 flask100ug Lyophilized15ml

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#33639170   2021/02/24 To Up

TNF receptor-associated factor 3 restrains B cell receptor signaling in normal and malignant B cells.

TRAF3 has diverse signaling functions which vary by cell type. Uniquely in B lymphocytes, TRAF3 inhibits homeostatic survival. Highlighting the role of TRAF3 as a tumor suppressor, loss of function TRAF3 mutations are associated with human B cell malignancies, while B cell-specific deletion of TRAF3 in mice leads to autoimmunity and lymphoma development. The role of TRAF3 in inhibiting non-canonical NF-κB activation, CD40 and BAFF-R signaling to B cells is well-documented. In contrast, TRAF3 enhances many T cell effector functions, through associating with and enhancing signaling by the T cell receptor (TCR)-CD28 complex. The present study was designed to determine the role of TRAF3 in signaling via the B cell antigen receptor (BCR). The BCR is crucial for antigen recognition, survival, proliferation, and antibody production, and defects in BCR signaling can promote abnormal survival of malignant B cells. Here, we show that TRAF3 associated with both CD79B and the BCR-activated kinases Syk and Btk following BCR stimulation. BCR-induced phosphorylation of Syk and additional downstream kinases was increased in TRAF3 B cells, with regulation observed in both follicular and marginal zone B cell subsets. BCR stimulation of TRAF3 B cells resulted in increased surface expression of MHC-II, CD80, and CD86 molecules. Interestingly, increased survival of TRAF3 primary B cells was resistant to inhibition of Btk, while TRAF3-deficient malignant B cell lines showed enhanced sensitivity. TRAF3 serves to restrain normal and malignant BCR signaling, with important implications for its role in normal B cell biology and abnormal survival of malignant B cells.
Amy L Whillock, Tiffany K Ybarra, Gail A Bishop

1445 related Products with: TNF receptor-associated factor 3 restrains B cell receptor signaling in normal and malignant B cells.

96T100 100 μg100ug100ug100ug2 Pieces/Box100ug Lyophilized30ml0.1ml (1mg/ml)

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#33623139   2021/02/23 To Up

IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK.

Interferon regulatory factor 4 (IRF4) is a transcriptional regulator of immune system development and function. Here, we investigated the role of IRF4 in controlling responsiveness to B-cell receptor (BCR) stimulation in chronic lymphocytic leukemia (CLL). We modulated IRF4 levels by transfecting CLL cells with an IRF4 vector or by silencing using small-interfering RNAs. Higher IRF4 levels attenuated BCR signaling by reducing AKT and ERK phosphorylation and calcium release. Conversely, IRF4 reduction improved the strength of the intracellular cascade activated by BCR engagement. Our results also indicated that IRF4 negatively regulates the expression of the spleen tyrosine kinase SYK, a crucial protein for propagation of BCR signaling, and the zinc finger DNA-binding protein IKAROS. We modulated IKAROS protein levels both by genetic manipulation and pharmacologically by treating CLL cells with lenalidomide and avadomide (IMIDs). IKAROS promoted BCR signaling by reducing the expression of inositol 5-phosphatase SHIP1. Lastly, IMIDs induced IRF4 expression, while down-regulating IKAROS and interfered with survival advantage mediated by BCR triggering, also in combination with ibrutinib. Overall, our findings elucidate the mechanism by which IRF4 tunes BCR signaling in CLL cells. Low IRF4 levels allow an efficient transmission of BCR signal throughout the accumulation of SYK and IKAROS.
Rossana Maffei, Stefania Fiorcari, Stefania Benatti, Claudio Giacinto Atene, Silvia Martinelli, Patrizia Zucchini, Leonardo Potenza, Mario Luppi, Roberto Marasca

1441 related Products with: IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK.

96 wells (1 kit)1 mg2 Pieces/Box96T1 mg

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#33616974   2020/12/08 To Up

Commensal fungi and their cell-wall β-glucans direct differential responses in human intestinal epithelial cells.

Intestinal epithelial cells (IECs) are the first to encounter luminal antigens and play an active role in intestinal immune responses. We previously reported that β-glucans, major fungal cell-wall glycans, induced chemokine secretion by IEC lines in a Dectin-1- and Syk-dependent manner. Here, we show that in contrast to β-glucans, stimulation of IEC lines with Candida albicans and Saccharomyces cerevisiae did not induce secretion of any of the proinflammatory cytokines IL-8, CCL2, CXCL1, and GM-CSF. Commensal fungi and β-glucans activated Syk and ERK in IEC lines. However, only β-glucans activated p38, JNK, and the transcription factors NF-κB p65 and c-JUN, which were necessary for cytokine secretion. Furthermore, costimulation of IEC lines with β-glucans and C. albicans yielded decreased cytokine secretion compared to stimulation with β-glucans alone. Finally, ex vivo stimulation of human colonic mucosal explants with zymosan and C. albicans, leads to epithelial Syk and ERK phosphorylation, implying recognition of fungi and similar initial signaling pathways as in IEC lines. Lack of cytokine secretion in response to commensal fungi may reflect IECs' response to fungal glycans, other than β-glucans, that contribute to mucosal tolerance. Skewed epithelial response to commensal fungi may impair homeostasis and contribute to intestinal inflammation.
Sarit Cohen-Kedar, Danielle Keizer, Suzana Schwartz, Keren M Rabinowitz, Kawsar Kaboub, Efrat Shaham Barda, Eran Sadot, Meirav Wolff-Bar, Tali Shaltiel, Iris Dotan

1041 related Products with: Commensal fungi and their cell-wall β-glucans direct differential responses in human intestinal epithelial cells.

96 wells4 X 250 ml.200 20 100ug Lyophilized100ug Lyophilized96 assays1.00 flask200 1 mg1.00 flask10 ug

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