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Results for “Syk Kinase”

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PubMed2001

The protein tyrosine kinase syk activity is reduced by clustering the mast cell function-associated antigen.

The mast cell function-associated antigen (MAFA) is a glycoprotein first identified on the membrane of rat mucosal-type mast cells (RBL-2H3 line). MAFA clustering causes a dose-dependent inhibition of these cells' secretory response to the type I Fcepsilon receptor (FcepsilonRI) stimulus. The inhibition has earlier been shown to take place upstream to the production step of inositol phosphates in the FcepsilonRI coupling cascade. To resolve further the mechanism of action of MAFA, we have investigated the events prior to the activation of phospholipase C. Activities of the non-receptor protein tyrosine kinases Lyn and Syk in untreated cells were compared with those where the FcepsilonRI, MAFA or both were clustered. Syk tyrosine phosphorylation and activation, as well as LAT (linker for activation of T cells) tyrosine phosphorylation, both induced by FcepsilonRI clustering, were found to be reduced upon MAFA clustering. In contrast, the activity of the Src homology domain 2 (SH2)-containing protein tyrosine phosphatase (SHP-2) increased. MAFA clustering also enhanced the co-isolation of SHP-2 and Syk with tyrosine-phosphorylated MAFA in both untreated and FcepsilonRI-stimulated cells. SHP-2 caused a decline in the FcepsilonRI-induced tyrosine phosphorylation of Syk, at least under in vitro conditions. Taken together, these results suggest that one possible mechanism by which MAFA affects the FcepsilonRI stimulation cascade is suppression of Syk activity, i.e. MAFA clustering leads SHP-2 to act on Syk, thereby reducing its tyrosine phosphorylation and its activity.

Animals↗
PubMed1997

Protein tyrosine kinase Syk is involved in Thy-1 signaling in rat basophilic leukemia cells.

Thy-1, a glycosyl-phosphatidylinositol-anchored surface glycoprotein, has been shown to possess transmembrane signaling capacity. In rat mast cells and rat basophilic leukemia cells (RBL) aggregation of surface Thy-1 with antibodies triggers a series of intracellular events, resembling those induced by aggregation of the high-affinity receptor for IgE (Fc epsilonRI), including tyrosine phosphorylation of multiple proteins and release of secretory components. Unlike the Fc epsilonRI-mediated activation, where both the membrane-associated protein tyrosine kinase (PTK) Lyn and the cytoplasmic PTK Syk are responsible for initiating the signaling cascade, only Lyn has been implicated in Thy-1-mediated activation in RBL cells. Here we report that Syk is also rapidly tyrosine phosphorylated upon Thy-1 cross-linking. Increased Syk tyrosine phosphorylation is observed only in cells in which extensive aggregation of Thy-1 is induced by two layers of cross-linking reagents. RBL-derived mutant cells deficient in the expression of surface Thy-1 and transfectants re-expressing surface Thy-1 were used to exclude the possibility that Syk activation reflects an interaction of the cross-linking reagents with surface molecules other than Thy-1. As Fc epsilonRI gamma subunits are well known to promote activation of Syk and its recruitment to membrane complexes, we also investigated the role of these subunits in Thy-1-mediated Syk activation, using RBL-derived mutant cells deficient in the expression of Fc epsilonRI gamma subunits and their revertants. Consistent with the lack of Fc epsilonRI expression, no IgE-induced response could be elicited, while Thy-1-inducible Syk phosphorylation was preserved. Our results suggest that Syk might be one of the kinases responsible for signal propagation upon Thy-1 cross-linking in a Fc epsilonRI-independent pathway.

Animals↗
PubMed2005

C-reactive protein mediates CD11b expression in monocytes through the non-receptor tyrosine kinase, Syk, and calcium mobilization but not through cytosolic peroxides.

OBJECTIVE: C-Reactive protein (CRP) can modulate integrin surface expression on monocytes following Fcgamma receptor engagement. We have investigated the signal transduction events causing this phenotypic alteration. METHODS: CRP-induced signalling events were examined in THP-1 and primary monocytes, measuring Syk phosphorylation by Western blotting, intracellular Ca(2+) ([Ca(2+)](i)) by Indo-1 fluorescence and surface expression of CD11b by flow cytometry. Cytosolic peroxides were determined by DCF fluorescence. RESULTS: CRP induced phosphorylation of Syk and an increase in [Ca(2+)](i) both of which were inhibitable by the Syk specific antagonist, piceatannol. Piceatannol also inhibited the CRP-induced increase in surface CD11b. In addition, pre-treatment of primary monoytes with the Ca(2+) mobiliser, thapsigargin, increased CD11b expression; this effect was accentuated in the presence of CRP but was abolished in the presence of the [Ca(2+)](i) chelator, BAPTA. CRP also increased cytosolic peroxide levels; this effect was attenuated by antioxidants (ascorbate, alpha-tocopherol), expression of surface CD11b not being inhibited by antioxidants alone. CONCLUSION: CRP induces CD11b expression in monocytes through a peroxide independent pathway involving both Syk phosphorylation and [Ca(2+)](i) release.

Antioxidants↗
PubMed2006

Involvement of Syk kinase in TNF-induced nitric oxide production by airway epithelial cells.

We have recently found that Syk is widely expressed in lung epithelial cells (EC) and participates in beta1 integrin signaling. In this study, we assessed the role of Syk in regulation of NO production. Stimulation of human bronchial EC line HS-24 by TNF caused an increased expression of inducible nitric oxide synthase (iNOS). Inhibition of Syk using siRNA or piceatannol down-regulated the iNOS expression and reduced NO production. This effect occurred in EC simultaneously stimulated via beta1 integrins, suggesting that TNF and beta1 integrins provide co-stimulatory signals. Inhibition of Syk down-regulated TNF-induced p38 and p44/42 MAPK phosphorylation and nuclear translocation of p65 NF-kappaB. Thus, TNF-induced activation of pro-inflammatory signaling in EC leading to enhanced expression of iNOS and NO production was dependent on Syk. Syk-mediated signaling regulates NO production at least partly via activating the MAPK cascade. Understanding the role of Syk in airway EC may help in developing new therapeutic tools for inflammatory lung disorders.

Bronchi↗
PubMed2004

[Expression of tyrosine kinase Syk in breast cancer and their clinical significance].

OBJECTIVE: To evaluate the effects of the Syk mRNA expression in human breast cancer on tumor growth and metastasis, and to study the correlation of expression of the Syk gene with ER, PR, p53 and HER2/neu. METHODS: Specimens from 40 breast cancer patients (tumor tissues, adjacent normal tissues), 15 fibroadenoma were detected for their expression of the Syk gene and level of Syk mRNA by semi-RT-PCR technique. Meanwhile, ER, PR, p53, HER2/neu were detected in 40 tumor tissues from breast cancer with immunohistochemical staining. RESULTS: All normal breast tissues were detected the expression of the Syk gene. Unlike normal breast tissue, 31 out of 40 breast cancer tissue did not show any detectable Syk mRNA expression, there were significant difference in two groups (chi(2) = 47.4, P < 0.05). The level of Syk mRNA in the primary breast cancer tissues were significantly lower than that in the adjacent non-cancerous breast tissues (t = 3.41, P < 0.05). Furthermore, only one breast cancer tissue in 18 patients with lymph node metastasis had the Syk mRNA expression, the rate and level of Syk mRNA expression in the patients with lymph node metastasis were lower than those without lymph node metastasis (chi(2) = 3.77, P < 0.05, t = 2.74, P < 0.05). Syk expression was correlated to p53 expression. CONCLUSION: The expression of the Syk gene may play an important role in suppressing growth and metastasis of breast cancer.

Biomarkers, Tumor↗
PubMed1997

Cross-linking of integrins induces tyrosine phosphorylation of the proto-oncogene product Vav and the protein tyrosine kinase Syk in human factor-dependent myeloid cells.

Attachment to extracellular matrix is important in the regulation of proliferation and differentiation of hematopoietic stem and progenitor cells. Post-ligand occupancy events of integrin receptors in myeloid cells are largely unknown. We examined early signaling events after stimulation of integrin receptors (outside-in signal) using a cross-linking system in a growth factor-dependent myeloid cell line, M07e, alpha 4, alpha 5, and beta 1 integrin cross-linking induced a similar pattern of transient tyrosine phosphorylation of cellular proteins. The approximate molecular weights of these phosphoproteins were M(r) 150,000, M(r) 120,000-125,000, M(r) 95,000, M(r) 70,000, M(r) 60,000, and M(r) 40,000-50,000. Vav, Syk, and Erk2 were identified as some of the tyrosine-phosphorylated proteins, and their weights were M(r) 95,000, M(r) 70,000, and M(r) 40,000-50,000, respectively. Erk2 and Vav were also tyrosine-phosphorylated by stimulation with Steel factor (SLF) and granulocyte macrophage colony-stimulating factor, whereas tyrosine phosphorylation of Syk was not induced by stimulation with these cytokines. The degree of tyrosine phosphorylation of Vav through integrin engagement was almost equal to that by SLF stimulation, whereas that of Erk2 was much weaker than with SLF stimulation. Upon integrin engagement, antibodies raised against Syk coprecipitated several tyrosine-phosphorylated proteins. In vitro binding assays demonstrated that, among these Syk-associated proteins, pp40, which differed from Erks, Crk, and Crkl, binds Syk through SH2 domains of Syk and is a prominent tyrosine-phosphorylated protein in integrin cross-linked cells. These results suggest that tyrosine phosphorylation of Vav and Erk2 in myeloid cells might be regulated by both integrins and cytokines in the bone marrow microenvironment, whereas Syk might be involved in a distinct pathway from the shared between integrins and cytokines in myeloid cells.

Blotting, Western↗
PubMed2003

Potent small molecule inhibitors of spleen tyrosine kinase (Syk).

A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).

Animals↗
PubMed2006

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk.

Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that, upon ligation with a monoclonal antibody (mAb), is a downregulator of cell growth in a Syk-dependent manner. An anti-CD33 mAb coupled to a toxin, gemtuzumab ozogamicin (GO), is used for the treatment of AML (Mylotarg). Therefore, we investigated whether the response of AML cells to GO treatment also depends on Syk expression. Forty primary AML samples (25 Syk-positive and 15 Syk-negative) were tested for their response to the anti-proliferative effects of GO and unmodified anti-CD33 mAb. A correlation between Syk expression and the response of leukemia cells to GO and anti-CD33 mAb was found. 'Blocking' of Syk by small interfering RNA resulted in unresponsiveness of AML cells to both GO and anti-CD33 mAb-mediated cytotoxicity. Syk upregulation by the de-methylating agent 5-azacytidine (5-aza) induced re-expression of Syk in some cases, resulting in enhanced GO and anti-CD33-mediated inhibition of leukemia cell growth. Thus, the cytotoxicity of both GO and anti-CD33 in primary AML samples was associated with Syk expression. 5-Aza restored Syk and increased the sensitivity of originally Syk-negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. These data have clinical significance for predicting response to GO and designing clinical trials.

Aminoglycosides↗
PubMed2003

Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk.

Members of the Cbl family of molecular adaptors play key roles in regulating tyrosine kinase-dependent signaling in a variety of cellular systems. Here we provide evidence that in B cells Cbl-b functions as a negative regulator of B cell antigen receptor (BCR) signaling during the normal course of a response. In B cells from Cbl-b-deficient mice cross-linking the BCRs resulted in sustained phosphorylation of Igalpha, Syk, and phospholipase C (PLC)-gamma2, leading to prolonged Ca2+ mobilization, and increases in extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) phosphorylation and surface expression of the activation marker, CD69. Image analysis following BCR cross-linking showed sustained polarization of the BCRs into large signaling-active caps associated with phosphorylated Syk in Cbl-b-deficient B cells in contrast to the BCRs in Cbl-b-expressing B cells that rapidly proceeded to form small, condensed, signaling inactive caps. Significantly, prolonged phosphorylation of Syk correlated with reduced ubiquitination of Syk indicating that Cbl-b negatively regulates BCR signaling by targeting Syk for ubiquitination.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells.

In this study we set out to test whether Syk was required for negative selection of immature B cells. B cells expressing a B cell antigen receptor (BCR) transgene (3-83, anti-H-2K(k)) underwent negative selection independently of Syk in both fetal liver organ culture and radiation chimera models. Furthermore, Syk-independent negative selection was not reversed by transgenic overexpression of Bcl-2. Receptor editing was not apparent in Syk-deficient B cells, presumably as a consequence of the failure of mature edited B cells to develop in the absence of Syk. Interestingly, light chain isotype exclusion by the BCR transgene failed in the absence of Syk. We observed a dramatic reduction in the overall BCR-mediated tyrosine phosphorylation of cellular proteins in Syk-deficient immature B cells. However, the tyrosine phosphorylation of a number of substrates including phospholipase C gamma 2, although reduced, was not completely abrogated. BCR ligation triggered an increase in calcium flux in the absence of Syk. Thus signaling events that mediate negative selection can still occur in the absence of Syk. This may be due to redundancy with zeta-associated protein 70 (ZAP-70), which we demonstrate to be expressed in immature B cells.

Animals↗
PubMed1997

Syk kinase, tyrosine-phosphorylated proteins and actin filaments accumulate at forming phagosomes during Fcgamma receptor-mediated phagocytosis.

Phagocytosis mediated by Fcgamma receptors (FcgammaRs) is thought to be regulated by a cascade of tyrosine phosphorylation events that finally leads to the rearrangement of submembranous actin-based cytoskeleton and internalization of particles. Suggestions concerning the functional relationship between protein tyrosine kinases, their substrates, and actin filament reorganization prompted us to determine cellular distribution of these elements during uptake of IgG-coated particles in murine thio-macrophages. We found that the onset of uptake of the particles was accompanied by tyrosine phosphorylation of several proteins, among which 90, 50, 40, 30, and 25 kDa polypeptides were distinguished. In most of the proteins the tyrosine hyperphosphorylation persisted up to 3 min of the uptake; however, kinetics of the phosphorylation of individual proteins varied. Immunofluorescence data showed that the phosphotyrosine-bearing proteins were localized in regions of the particle uptake, being concentrated at phagocytic cups and nascent phagosomes. The local enrichment in tyrosine phosphorylated proteins was correlated with accumulation of actin filaments at these early stages of phagosome formation. During phagosome maturation, both tyrosine phosphorylated proteins and microfilaments disappeared from the periphagosomal regions. Syk, one of the tyrosine kinases, was translocated to the regions where FcgammaR-mediated phagocytosis had started. On the contrary, no enrichment in phosphatidylinositol 3-kinase was detected in these places.

Actins↗
PubMed2004

A novel Syk kinase-selective inhibitor blocks antigen presentation of immune complexes in dendritic cells.

The initiation of antigen presentation by dendritic cells requires proper internalization of antigens through various mechanisms. Internalization of immune complexes via Fc receptors has been shown to be around 100 times more efficient than the internalization of non-complexed antigens. Spleen tyrosine kinase (Syk) plays an essential role in the signaling cascade initiated by immunoglobulin receptors. We used a selective Syk inhibitor, 7-(3,4-dimethoxyphenyl)-N-1H-indazol-6-ylimidazo[1,2-c]pyrimidin-5-amine dihydrochloride (compound-D), to evaluate the role of Syk in antigen presentation by mouse bone marrow-derived dendritic cells. In line with our expectation, compound-D concentration-dependently inhibited the internalization of immune complexes but not that of antigen itself. Furthermore, when dendritic cells were pretreated with compound-D, the ability of dendritic cells to present immune complex antigens to Th2 cells was attenuated, parallel by a reduced release of interleukin-4 production in Th2 cells. Therefore, Syk kinase activity is a critical component in the process of Fcgamma receptor-mediated internalization of immune complex antigens in dendritic cells, and Syk kinase inhibitors may be beneficial in selectively suppressing antibody-mediated antigen presentation in allergic diseases.

Animals↗
PubMed2003

The FcR gamma subunit and Syk kinase replace the CD3 zeta-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells.

The TCR-mediated signals required to activate resting T cells have been well characterized; however, it is not known how TCR-coupled signals are transduced in differentiated effector T cells that coordinate ongoing immune responses. Here we demonstrate that human effector CD4 T cells up-regulate the expression of the CD3zeta-related FcRgamma signaling subunit that becomes part of an altered TCR/CD3 signaling complex containing CD3epsilon, but not CD3zeta. The TCR/CD3/FcRgamma complex in effector cells recruits and activates the Syk, but not the ZAP-70, tyrosine kinase. This physiologic switch in TCR signaling occurs exclusively in effector, and not naive or memory T cells, suggesting a potential target for manipulation of effector responses in autoimmune, malignant, and infectious diseases.

Adult↗
PubMed2002

Role of protein-tyrosine kinase syk in oxidative stress signaling in B cells.

Oxidative stress induces the activation of multiple signaling pathways related to various cellular responses. In B cells, Syk has a crucial role in intracellular signal transduction induced by oxidative stress as well as antigen receptor engagement. Treatment of B cells with hydrogen peroxide (H(2)O(2)) induces enzymatic activation of Syk. Syk is essential for Ca(2+) release from intracellular pools through phospholipase C-gamma2 and the activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase-Akt survival pathway following H(2)O(2) stimulation. Oxidative stress-induced cellular responses in B cells follow different patterns, such as necrosis, apoptosis, and mitotic arrest, according to the intensity of H(2)O(2) stimulation. Syk is involved in the protection of cells from apoptosis and induction of G2/M arrest. Syk leads to the activation of the phosphatidylinositol 3-kinase-Akt survival pathway, thereby enhancing cellular resistance to oxidative stress-induced apoptosis. On the other hand, Syk-dependent phospholipase C-gamma2 activation is required for acceleration toward apoptosis following oxidative stress. These findings suggest that oxidative stress-induced Syk activation triggers the activation of several pathways, such as proapoptotic and survival pathways, and the balance among these various pathways is a key factor in determining the fate of a cell exposed to oxidative stress.

Animals↗
PubMed2006

Rubiae Radix suppresses the activation of mast cells through the inhibition of Syk kinase for anti-allergic activity.

The effect of extracts from various Oriental medicinal herbs on mast-cell-mediated allergic reactions was investigated in this study. Of these extracts, the medicinal herb Rubiae Radix exhibited the most potent activity in the cells, with an IC50 value (concentration necessary to obtain 50% inhibition of the response) of approximately 35 +/- 2.1 microg mL(-1), and its inhibition of compound-48/80-induced systemic anaphylaxis by 48.6 +/- 8.5% at 300 mg kg(-1) in mice. It also inhibited the expression of the pro-inflammatory mediator tumour necrosis factor-alpha (TNF-alpha). As for its mechanism of action, Rubiae Radix suppressed the activating phosphorylation of Syk, a key enzyme in mast-cell signalling processes, and that of Akt in a dose-dependent manner. It also inhibited the MAP kinase ERK1/2, which is critical for the production of inflammatory cytokines in mast cells, as indicated by the suppression of the activating phosphorylation of ERK1/2. These results suggest that Rubiae Radix suppresses the activation of mast cells through the inhibition of Syk for anti-allergic activity.

Animals↗
PubMed2006

Syk tyrosine kinase mediates Epstein-Barr virus latent membrane protein 2A-induced cell migration in epithelial cells.

Although spleen tyrosine kinase (Syk) is known to be important in hematopoietic cell development, the roles of Syk in epithelial cells have not been well studied. Limited data suggest that Syk plays alternate roles in carcinogenesis under different circumstances. In breast cancer, Syk has been suggested to be a tumor suppressor. In contrast, Syk is essential for murine mammary tumor virus-mediated transformation. However, the roles of Syk in tumor migration are still largely unknown. Nasopharyngeal carcinoma, an unusually highly metastatic tumor, expresses Epstein-Barr virus LMP2A (latent membrane protein 2A) in most clinical specimens. Previously, we demonstrated LMP2A triggers epithelial cell migration. LMP2A contains an immunoreceptor tyrosine-based activation motif, which is important for Syk kinase activation in B cells. In this study, we explored whether Syk is important for LMP2A-mediated epithelial cell migration. We demonstrate that LMP2A expression can activate endogenous Syk activity. The activation requires the tyrosine residues in LMP2A ITAM but not YEEA motif, which is important for Syk activation by Lyn in B cells. LMP2A interacts with Syk as demonstrated by coimmunoprecipitation and confocal microscopy. Furthermore, LMP2A-induced cell migration is inhibited by a Syk inhibitor and short interfering RNA. Tyrosines 74 and 85 in the LMP2A immunoreceptor tyrosine-based activation motif are essential for both Syk activation and LMP2A-mediated cell migration, indicating the involvement of Syk in LMP2A-triggered cell migration. The LMP2A-Syk pathway may provide suitable drug targets for treatment of nasopharyngeal carcinoma.

Amino Acid Sequence↗
PubMed1996

CD38 signal transduction in human B cell precursors. Rapid induction of tyrosine phosphorylation, activation of syk tyrosine kinase, and phosphorylation of phospholipase C-gamma and phosphatidylinositol 3-kinase.

Ligation of CD38 inhibits proliferation and induces apoptosis of human immature B cells, but the molecular mechanisms underlying this function are unknown. We found that CD38 dimerization with the specific mAbs T16 and IB4 induces rapid and transient tyrosine phosphorylation of several intracellular proteins in the immature B cell lines RS4;11, REH, 380, Nalm6, and OP-1. This effect could be markedly reduced by incubating cells with the tyrosine kinase inhibitors genistein, staurosporine, and herbimycin A. CD38 dimerization induced tyrosine phosphorylation of the protein kinase syk and increased syk kinase activity. CD38 dimerization also induced tyrosine phosphorylation of phospholipase C-gamma and of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K). The latter was accompanied by a distinct increase in PI 3-kinase activity in the immunoprecipitates obtained with an anti-phosphotyrosine Ab. In contrast to the signaling triggered by surface Ig engagement in B lymphocytes, CD38 ligation did not appear to induce tyrosine phosphorylation of the src-like protein tyrosine kinases lyn, fyn, and btk, or of vav- and ras-GTPase-activating protein, nor did it induce detectable changes in cytosolic CA2+ concentrations. CD38 signaling also differed from cytokine-induced signaling in that it did not cause tyrosine phosphorylation of Jak1 and Jak2. Finally, CD38 ligation did not inhibit IL-3-induced tyrosine phosphorylation of Jak2. These results identify CD38 as a cell surface receptor with signal transduction properties activated by dimerization. Induction of signal transduction by CD38 ligation implies the existence of a yet unidentified natural ligand of CD38.

ADP-ribosyl Cyclase↗