Potent small molecule inhibitors of spleen tyrosine kinase (Syk)

Lai, Jasmine; Cox, Paul J; Patel, Rajesh; Sadiq, Shazia; Aldous, David; Thurairatnam, Sukanthini; Smith, Keith; Wheeler, Darren; Jagpal, Savita; Parveen, Sofia; Fenton, Gary; Harrison, T.; McCarthy, Clive; Bamborough, Paul

doi:10.1016/s0960-894x(03)00658-9

Cited by 73 publications

(52 citation statements)

References 11 publications

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“…Y-27632 is a widely used inhibitor of Rho-associated protein kinases (46). 3-(1-Methyl-1H-indol-3-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-sulfonamide is a Syk inhibitor (47). None of these kinase inhibitors attenuated LeTx effects as observed with VEGFR selective compounds.…”

Section: Chemical Vegfr Blockade Counteracts Letx-induced Vascularmentioning

confidence: 99%

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Bolcome

Sullivan

Zeller

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of Bacillus anthracis, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/ vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.endothelial ͉ vascular permeability ͉ VEGF

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Section: Chemical Vegfr Blockade Counteracts Letx-induced Vascularmentioning

confidence: 99%

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Bolcome

Sullivan

Zeller

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The inhibitors of Syk family kinases, piceatannol (33) and sulfonamide-31 (34), as well as cell-permeable irreversible inhibitors of caspase-3 (DEVD-FMK) and caspase-8 (IETD-CHO) were purchased from Calbiochem. Syk inhibitors were dissolved in DMSO (SigmaAldrich), and equal volumes (2 l/well) were added to suppression assays, as described above.…”

Section: Inhibitorsmentioning

confidence: 99%

FcRγ Presence in TCR Complex of Double-Negative T Cells Is Critical for Their Regulatory Function

Thomson

Teft

Chen

et al. 2006

The Journal of Immunology

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TCRαβ+CD4−CD8− double-negative (DN) T regulatory (Treg) cells have recently been shown to suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells in humans and mice. Our previous study using cDNA microarray analysis of global gene expression showed that FcRγ was the most highly overexpressed gene in functional DN Treg cell clones compared with nonfunctional mutant clones. In this study, we demonstrate that FcRγ-deficient DN T cells display markedly reduced suppressive activity in vitro. In addition, unlike FcRγ-sufficient DN T cells, FcRγ-deficient DN T cells were unable to prolong donor-specific allograft survival when adoptively transferred to recipient mice. Protein analyses indicate that in addition to FcRγ, DN Treg cell clones also express higher levels of TCRβ, while mutant clones expressed higher levels of Zap70 and Lck. Within DN Treg cells, we found that FcRγ associates with the TCR complex and that both FcRγ and Syk are phosphorylated in response to TCR cross-linking. Inhibition of Syk signaling and FcRγ expression were both found to reduce the suppressive function of DN Treg cells in vitro. These results indicate that FcRγ deficiency significantly impairs the ability of DN Treg cells to down-regulate allogeneic immune responses both in vitro and in vivo, and that FcRγ plays a role in mediating TCR signaling in DN Treg cells.

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“…Representative images of the same magnification are shown with nuclear staining (DAPI) in blue and activated caspase-3 in red, all structures are GFP þ (not depicted). (1 mg/ml), the Syk kinase inhibitor Piceatannol (1 mg/ml), or a specific Syk inhibitor (0.25 mM) (Lai et al, 2003). Representative bright field images taken on day 6 are shown, structures are GFP þ (not depicted).…”

Section: Src and Syk Tyrosine Kinases Contribute To Itam-induced Acinmentioning

confidence: 99%

“…For each independent experiment, 50-200 structures were scored based on the parameters described in the Results section. For inhibitor studies, PP2, Piceatannol, and Syk Inhibitor 31 (Lai et al, 2003) (all from EMD) were added on day 3 of culture and scored and imaged as described above on day 6. For apoptosis assays, TNFa (R&D Systems) or TRAIL (BIOMOL Research Laboratories, Inc.) was added on day 8 of culture for 20 h and then stained for cleaved caspase-3.…”

Section: D Culturesmentioning

confidence: 99%

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

et al. 2005

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are involved in the transduction of signals necessary for activation, differentiation, and survival in hematopoietic cells. Several viruses have been shown to encode ITAM-containing transmembrane proteins. Although expression of these viral proteins has in some cases been shown to transform nonhematopoietic cells, a causal role for a functional ITAM in this process has not been elucidated. To examine the potential transforming properties of ITAM-containing proteins, a recombinant protein consisting of ITAM-containing cytoplasmic regions of the B-cell antigen receptor was expressed in immortalized murine mammary epithelial and fibroblast cells. Mammary epithelial cells expressing this construct exhibited depolarized morphology in three-dimensional cultures. This transformed phenotype was characterized by a loss of anchorage dependence and hallmarks of epithelial to mesenchymal transition. Fibroblasts expressing this ITAM construct also lost contact inhibition and anchorage dependence. The transformed phenotype seen in both cell types was abrogated upon tyrosine to phenylalanine substitutions of the ITAMs. Inhibition of Syk tyrosine kinase, which associates with the ITAM, also prevented cell transformation. Our results indicate that expression of a nonviral ITAM-containing protein is sufficient for cell transformation. Despite lacking intrinsic enzymatic activity, ITAM-containing proteins can function as potent oncoproteins by scaffolding downstream mediators.

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Potent small molecule inhibitors of spleen tyrosine kinase (Syk)

Cited by 73 publications

References 11 publications

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

FcRγ Presence in TCR Complex of Double-Negative T Cells Is Critical for Their Regulatory Function

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

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