Redox-sensitive Transactivation of Epidermal Growth Factor Receptor by Tumor Necrosis Factor Confers the NF-κB Activation

Abstract

Cross-communication between different signaling systems allows the integration of the great diversity of stimuli that a cell receives under varying physiological situations. In this paper we have explored the possibility that tumor necrosis factor (TNF) receptor signal cross-talks with epidermal growth factor (EGF) receptor signal on the nuclear factor-B (NF-B) activation pathway. We have demonstrated that overexpression of the EGF receptor (EGFR) in NIH3T3 cells significantly enhances TNF-induced NF-B-dependent luciferase activity even without EGF, that EGF treatment has a synergistic effect on the induction of the reporter activity, and that this enhancement is suppressed by AG1478, EGFR-specific tyrosine kinase inhibitor. We also have shown that TNF induces tyrosine phosphorylation and internalization of the overexpressed EGFR in NIH3T3 cells and the endogenously expressed EGFR in A431 cells and that the transactivation by TNF is suppressed by N-acetyl-L-cysteine or overexpression of an endogenous reducing molecule, thioredoxin, but not by phosphatidylinositol 3-kinase inhibitors and protein kinase C inhibitor. Taken together, this evidence strongly suggests that EGFR transactivation by TNF, which is regulated in a redox-dependent manner, is playing a pivotal role in TNF-induced NF-B activation.A cardinal concept in signal transduction is that receptors are activated by highly specific interactions with cognate ligands. Hence each receptor recognizes one or a few structurally related ligands, and each ligand stereochemically "fits" one or perhaps two structurally related receptors. The specificity of biological responses generated to extracellular signals depends on adherence to this rule. For some time, however, it has been clear that structurally unrelated receptors may communicate with each other in what is termed receptor transactivation or cross-talk. Although receptor cross-talk is no doubt real, its biological importance remains unclear. Understanding the mechanism(s) by which inter-receptor communication occurs may offer the experimental means to explore the underlying biology.The initial steps in the major pathway utilized by tumor necrosis factor (TNF) 1 to activate the NF-B are fairly well understood (1, 2). The NF-B activation is usually initiated by the interaction of TNF with TNFR1 (p55), one of two distinct surface receptors, the other is TNFR2 (p75). Ligand-induced clustering of TNFR1 leads to the recruitment of TRADD to the intracellular portion of the receptor (3). Receptor-bound TRADD recruits both the protein kinase designated receptorinteracting protein (RIP) and the ring/zinc finger protein TNF receptor-associated factor 2 (TRAF2). These two adapter proteins lead to the activation of the NF-B as well as the activation of the stress-activated protein kinases such as c-Jun Nterminal kinase and p38 MAPK (3). IL-1 also activates NF-B and stress-activated protein kinases using a similar pathway initiated by ligand binding to the type 1 IL-1 receptor and involving adapter proteins MyD88, IL-...

Selective inhibition of TNF-α-induced activation of mitogen-activated protein kinases and metastatic activities by gefitinib

“…Recently, TNF-a and EGF signalling pathways have been found to play a physiological function in TNF-a signalling (Hirota et al, 2001). It has been suggested that proteolytic release of transforming growth factor-a, one of the EGFR ligands, is one possible mechanism of EGFR transactivation by TNF-a (Argast et al, 2004;Chen et al, 2004).…”

Regulation of Interleukin-1α Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease

“…This implies that EGFR transactivation is responsible for the Erk pathway activation that occurs in TPA-induced IL-1␣ synthesis. (41,42), and it has been reported that IL-1␤-induced Erk activation and subsequent MMP-1 expression in human keratinocytes requires EGFR activity (43). Given these observations, we investigated whether inhibition of the EGFR had any effect on induction of IL-1␣ or on activation of IL-1␣-dependent signaling in our system.…”

Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis

“…The other interesting finding was that when cells were also treated with GSE in PD98059+EGF study, they showed comparable DNA synthesis inhibition (82%) as observed in PD98059+GSE treatment, again suggesting an additional inhibitory effect of GSE on DNA synthesis possibly by inhibiting EGF-induced activation of an unidentified MEK1-independent mitogenic response. With regard to an additional mitogenic signaling by EGF independent of MEK1, in a recent study, it has been shown that EGFR activation through redox mechanism activates NF-kB independent of MEK1 (Hirota et al, 2001). It is also important to emphasize that NF-kB is constitutively active in DU145 PCA cells (Palayoor et al, 1999), and so does EGFR-ligand autocrine growth loop (Hirota et al, 2001).…”

“…With regard to an additional mitogenic signaling by EGF independent of MEK1, in a recent study, it has been shown that EGFR activation through redox mechanism activates NF-kB independent of MEK1 (Hirota et al, 2001). It is also important to emphasize that NF-kB is constitutively active in DU145 PCA cells (Palayoor et al, 1999), and so does EGFR-ligand autocrine growth loop (Hirota et al, 2001). Whether the observed increase in DNA synthesis by EGF in the presence of MEK1 inhibitor is because of NF-kB activation, remained to be established; however, in our ongoing studies, we observed strong inhibition of constitutively active NF-kB in DU145 cells by GSE (unpublished data).…”