LIGHT, a member of the TNF superfamily, activates Stat3 mediated by NIK pathway

Abstract

Stat3, a member of the signal transducers and activators of transcription (STAT) family, is a key signal transduction protein activated by numerous cytokines, growth factors, and oncoproteins that controls cell proliferation, differentiation, development, survival, and inflammation. Constitutive activation of Stat3 has been found frequently in a wide variety of human tumors and induces cellular transformation and tumor formation. In this study, we demonstrated that LIGHT, a member of tumor necrosis factor superfamily, activates Stat3 in cancer cells. LIGHT induces dose-dependent activation of Stat3 by phosphorylation at both the tyrosine 705 and serine 727 residues. The activation of Stat3 by LIGHT appears to be mediated by NIK phosphorylation. Expression of a kinase-inactive NIK mutant abolished LIGHT induced Stat3 activation. Overexpression of an active NIK induces Stat3 activation by phosphorylation at the both tyrosine 705 and serine 727 residues. Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays. In addition, LIGHT increases the expression of Stat3 target genes including cyclin D1, survivin, and Bcl-xL, and stimulates human LNCaP prostate cancer cell growth in vitro which can be blocked by expression of a dominant-negative Stat3 mutant. Taken together, these results indicate that in addition to activating NF-kappaB/p52, LIGHT also activates Stat3. Activation of Stat3 together with activating non-canonical NF-kappaB/p52 signaling by LIGHT may maximize its effects on cellular proliferation, survival, and inflammation.

Epstein-Barr Virus Latent Membrane Protein 1 Modulates Distinctive NF-κB Pathways through C-Terminus-Activating Region 1 To Regulate Epidermal Growth Factor Receptor Expression

“…A previous study showed that NIK could function as a serine kinase of STAT3; however, the high basal levels of serinephosphorylated STAT3 in NIK-defective cells indicate that other kinases may also phosphorylate STAT3 (39). To confirm the requirement for NIK in LMP1-induced EGFR expression, CTAR1-expressing C33A cells were transiently transfected with a dominant negative NIK construct (DNNIK), DNNIK with an aly mutation (G860R; NIK-aly), or kinase-dead NIK [NIK(K-A)] for 48 h, and the expression levels of EGFR and serine-phosphorylated STAT3 were analyzed by immunoblotting (Fig.…”

“…IKK␣ has also been implicated in the phosphorylation of several nuclear substrates, including SMRT, histone H3, and CBP (16,17,58). NIK was recently suggested to function as a serine kinase of STAT3 (39). The aberrant regulation of NF-B activation pathways has been implicated in development of many human cancers (34,44).…”

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

“…More than 40 different polypeptide ligands cause STAT phosphorylation. STAT3 is activated in response to many cytokines such as IL-6 [48], leukemia inhibitory factor (LIF) [49], cardiotrophin-1 [50], ciliary neurotrophic factor (CNTF) [51], IL-5 [52], IL-9 [53], IL-10 [54], IL-11 [55], IL-12 [56], IL-21 [57], IL-22 [58], IL-27 [59], IFN-γ [60], TNF-α [61], LIGHT, a member of the TNF superfamily [62], monocyte chemotactic protein-1 (MCP-1) [63], macrophage inflammatory protein-1α (MIP-1α) [64], CCL-5/RANTES [64], stem cell factor (SCF) [65], oncostatin M (OSM) [66]), growth factors (e.g., EGF [67], TGFα [61], PDGF [68], IGF-1 [69], G-CSF [70], M-CSF [71] and GM-CSF [52]) and oncogenic proteins through phosphorylation of tyrosine 705. In addition, numerous carcinogens (e.g.…”

Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK

“…32 Moreover, overexpressed NIK induces the phosphorylation of STAT3 in a prostate cancer cell line. 33 Notably, the catalytic activity of NIK is rapidly stimulated upon ligation of TCR and the costimulatory molecule CD28, 34 suggesting a role for NIK in regulating the signaling events involved in T-cell activation or differentiation.…”

“…32 Moreover, overexpressed NIK induces the phosphorylation of STAT3 in a prostate cancer cell line. 33 Notably, the catalytic activity of NIK is rapidly stimulated upon ligation of TCR and the costimulatory molecule CD28, 34 suggesting a role for NIK in regulating the signaling events involved in T-cell activation or differentiation.In the present study, we investigated the function of NIK in T-cell differentiation using NIK knockout mice. We show that NIK has a critical role in Th17 cell differentiation and EAE induction, although this MAP3K is dispensable for the differentiation of Th1, Th2, and iTreg cells.…”