Tumor Necrosis Factor-α Activation of Nuclear Transcription Factor-κB in Marrow Macrophages Is Mediated by c-Src Tyrosine Phosphorylation of IκBα

Abu‐Amer, Yousef; Ross, F. Patrick; McHugh, Kevin P.; Livolsi, Antonia; Peyron, Jean François; Teitelbaum, Steven L.

doi:10.1074/jbc.273.45.29417

Cited by 140 publications

(124 citation statements)

References 60 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Tyrosine kinases of the src family also activate NF-kB at the level of IkB phosphorylation (Imbert et al, 1996;Abu-Amer et al, 1998;Takada et al, 2003). Only ectopic expression of Bcr-Abl suppresses TNF-induced NF-kB activation due to downregulation of TNFRs and subsequent inhibition of IkBa degradation (Mukhopadhyay et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…TNFa-induced NF-kB activation is mediated by various nonreceptor kinases that phosphorylate inhibitor kB (IkB) or p65 at serine residues (Vermeulen et al, 2003). In addition, tyrosine phosphorylation has been implicated in TNFa-induced activation of NF-kB (Imbert et al, 1996;Abu-Amer et al, 1998;Takada et al, 2003). Upon inhibition of TNFa-induced NF-kB activation, for example, by ultraviolet light and cytotoxic agents such as daunorubicin (Campbell et al, 2004), TNFa becomes a potent inducer of apoptosis (Karin and Lin, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

et al. 2007

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

et al. 2007

View full text Add to dashboard Cite

“…The role of c-Src in TNF-induced NF-B activation has been demonstrated (21,23). It has been shown that c-Src causes the tyrosine phosphorylation of I B kinase-␤ needed for TNF-induced NF-B activation (23).…”

Section: Discussionmentioning

confidence: 99%

“…Proline-rich tyrosine kinase (Pyk2) 3 (18,19) and p53/Lyn p56 (20) have roles in TNF-induced neutrophil activation; Etk/Bmx in TNF-induced endothelial cell migration and angiogenesis; c-Src in TNF-induced NF-B activation in the marrow macrophages (21,22); and TNF in regulation of gap junctions in airway epithelial cells (23). Pyk2 has also been implicated in TNF-induced JNK activation (24).…”

Section: Tnf Activates Syk Proteinmentioning

confidence: 99%

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

Takada

Aggarwal

2004

The Journal of Immunology

108

View full text Add to dashboard Cite

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.

show abstract

“…It is probable that PKC/c-Src lies downstream of TRAF2, because the findings that c-Src acts downstream of TRAF in response to TNF-related activation-induced cytokine or IL-2 in osteoclasts, dendritic cells (29), or 293 cells (30) have been reported. c-Src is involved in NF-B activation in bone marrow macrophages, U937 cells, and B cells (31)(32)(33). In bone marrow macrophages, TNF-␣ induces activation of c-Src, which associates with I-B␣ and phosphorylates Tyr 42 of I-B␣, leading to NF-B activation and IL-6 release (31).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine Phosphorylation of I-κB Kinase α/β by Protein Kinase C-Dependent c-Src Activation Is Involved in TNF-α-Induced Cyclooxygenase-2 Expression

Huang

Chen

Inoue

et al. 2003

The Journal of Immunology

117

106

View full text Add to dashboard Cite

The signaling pathway involved in TNF-α-induced cyclooxygenase-2 (COX-2) expression was further studied in human NCI-H292 epithelial cells. A protein kinase C (PKC) inhibitor (staurosporine), tyrosine kinase inhibitors (genistein and herbimycin A), or a Src kinase inhibitor (PP2) attenuated TNF-α- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 promoter activity. TNF-α- or TPA-induced I-κB kinase (IKK) activation was also blocked by these inhibitors, which reversed I-κBα degradation. Activation of c-Src and Lyn kinases, two Src family members, was inhibited by the PKC, tyrosine kinase, or Src kinase inhibitors. The dominant-negative c-Src (KM) mutant inhibited induction of COX-2 promoter activity by TNF-α or TPA. Overexpression of the constitutively active PKCα (PKCα A/E) or wild-type c-Src plasmids induced COX-2 promoter activity, and these effects were inhibited by the dominant-negative c-Src (KM), NF-κB-inducing kinase (NIK) (KA), or IKKβ (KM) mutant. The dominant-negative PKCα (K/R) or c-Src (KM) mutant failed to block induction of COX-2 promoter activity caused by wild-type NIK overexpression. In coimmunoprecipitation experiments, IKKα/β was found to be associated with c-Src and to be phosphorylated on its tyrosine residues after TNF-α or TPA treatment. Two tyrosine residues, Tyr188 and Tyr199, near the activation loop of IKKβ, were identified to be crucial for NF-κB activation. Substitution of these residues with phenylalanines attenuated COX-2 promoter activity and c-Src-dependent phosphorylation of IKKβ induced by TNF-α or TPA. These data suggest that, in addition to activating NIK, TNF-α also activates PKC-dependent c-Src. These two pathways cross-link between c-Src and NIK and converge at IKKα/β, and go on to activate NF-κB, via serine phosphorylation and degradation of IκB-α, and, finally, to initiate COX-2 expression.

show abstract

Tumor Necrosis Factor-α Activation of Nuclear Transcription Factor-κB in Marrow Macrophages Is Mediated by c-Src Tyrosine Phosphorylation of IκBα

Abstract: Tumor necrosis factor-␣ (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-B (NF-B). NF-B is

Cited by 140 publications

References 60 publications

Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

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

Tyrosine Phosphorylation of I-κB Kinase α/β by Protein Kinase C-Dependent c-Src Activation Is Involved in TNF-α-Induced Cyclooxygenase-2 Expression

Contact Info

Product

Resources

About