TNF Activates Syk Protein Tyrosine Kinase Leading to TNF-Induced MAPK Activation, NF-κB Activation, and Apoptosis

Abstract

Spleen tyrosine kinase (Syk), a nonreceptor protein kinase initially found to be expressed only in hemopoietic cells, has now been shown to be expressed in nonhemopoietic cells and to mediate signaling of various cytokines. Whether Syk plays any role in TNF signaling was investigated. Treatment of Jurkat T cells with TNF activated Syk kinase but not ZAP70, another member of Syk kinase family, and the optimum activation occurred at 10 s and with 1 nM TNF. TNF also activated Syk in myeloid and epithelial cells. TNF-induced Syk activation was abolished by piceatannol (Syk-selective inhibitor), which led to the suppression of TNF-induced activation of c- JNK, p38 MAPK, and p44/p42 MAPK. Jurkat cells that did not express Syk (JCaM1, JCaM1/lck) showed lack of TNF-induced Syk, JNK, p38 MAPK, and p44/p42 MAPK activation, as well as TNF-induced IκBα phosphorylation, IκBα degradation, and NF-κB activation. TNF-induced NF-κB activation was enhanced by overexpression of Syk by Syk-cDNA and suppressed when Syk expression was down-regulated by expression of Syk-small interfering RNA (siRNA-Syk). The apoptotic effects of TNF were reduced by up-regulation of NF-κB by Syk-cDNA, and enhanced by down-regulation of NF-κB by siRNA-Syk. Immunoprecipitation of cells with Syk Abs showed TNF-dependent association of Syk with both TNFR1 and TNFR2; this association was enhanced by up-regulation of Syk expression with Syk-cDNA and suppressed by down-regulation of Syk using siRNA-Syk. Overall, our results demonstrate that Syk activation plays an essential role in TNF-induced activation of JNK, p38 MAPK, p44/p42 MAPK, NF-κB, and apoptosis.

The Tyrosine Kinase BMX Is an Essential Mediator of Inflammatory Arthritis in a Kinase-Independent Manner

“…These effects did, however, not reflect a generic inhibition of cellular signaling, as EGF-induced STAT3 phosphorylation was not affected by the siRNA against BMX. Whereas a role for tyrosine phosphorylation in TNF signaling has often been reported (55)(56)(57), direct evidence for a specific kinase is missing. Our report suggests that BMX may be the relevant tyrosine kinase in the tissues that express BMX.…”

Spleen Tyrosine Kinase (Syk), a Novel Target of Curcumin, Is Required for B Lymphoma Growth

“…Moreover, for the first time we demonstrate that the constitutively activated Syk is required for B lymphoma growth. Syk induces multiple signaling pathways including PI3K, NF-B, phospholipase C-␥, and JNK (20,57,58). Curcumin has been shown to target NF-B, Akt, JNK, JAK, STAT3, and Src kinases in tumor cells.…”

Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma

“…27 Treatment of human Jurkat Tcells with the proapoptotic and inflammatory cytokine TNF activates Syk, which consequently plays an essential role in TNF-induced activation of JNK, p38 MAPK, p44/p42 MAPK, NFkB and apoptosis. 28 We tested tissue sections of our t(5;9)(q33;q22) þ PTCLs with specific antibodies for p38 MAPK, p44/p42 MAPK and NF-kB. Nuclei of tumor cells were negative in all cases, indicating that p38 MAPK, p44/p42 MAPK and NFkB were not activated in the t(5;9)(q33;q22) þ PTCLs.…”