Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB.

By Jinbo Yang, Xudong Liao, M. Agarwal, Laura Barnes, P. Auron, G. Stark. Genes & Development, 2007

662 citations recorded by the source corpus.

gp130-linked cytokines such as interleukin-6 (IL-6) stimulate the formation of tyrosine-phosphorylated signal transducer and activator of transcription 3 (P-STAT3), which activates many genes, including the STAT3 gene itself. The resulting increase in the concentration of unphosphorylated STAT3 (U-STAT3) drives a second wave of expression of genes such as RANTES, IL6, IL8, MET, and MRAS that do not respond directly to P-STAT3. Thus, U-STAT3 sustains cytokine-dependent signaling at late times through a mechanism completely distinct from that used by P-STAT3. Many U-STAT3-responsive genes have kappaB elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NFkappaB (U-NFkappaB), in competition with IkappaB. The U-STAT3/U-NFkappaB complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of kappaB-dependent genes. Additional genes respond to U-STAT3 through an NFkappaB-independent mechanism. The role of signal-dependent increases in U-STAT3 expression in regulating gene expression is likely to be important in physiological responses to gp130-linked cytokines and growth factors that activate STAT3, and in cancers that have constitutively active P-STAT3.

Subfields: Cancer Research, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/61ac9384d181bed195f89a9cddb10b07925f5843

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Citations in the corpus

Persistently-activated Stat3 maintains constitutive NF-κB activity in tumors (2009, positive): “, 2003), and nuclear translocation of unphosphorylated NF-kB by unphosphorylated Stat3 (Yang et al., 2007).”
Interferons at age 50: past, current and future impact on biomedicine (2007, background): “For example, unphosphorylated STAT3 activates a subset of κB-dependent genes by forming a complex with NFκ”
STAT3 signaling in immunity (2016, background): “, IFN-γ-activated sequence (GAS) elements), yetuSTAT3 works in collaboration with transcriptional regulators such as NF-κB to control a cadre of genes not normally affected by tyrosine-phosphorylated STAT3 [34, 44, 46].”
The molecular details of cytokine signaling via the JAK/STAT pathway (2018, background): “cases where unphosphorylated STATs also appear to play a role in gene transcription.(163,164) It has also been suggested that unphosphorylated STATs are”
STATs in cancer inflammation and immunity: a leading role for STAT3 (2009, neutral): “, it is not surprising that signalling by various STATs, particularly STAT3, is highly interconnected with NF-κB signallin”
Inflammation meets cancer, with NF-κB as the matchmaker (2011, background): “Furthermore nonphosphorylated STAT3 is reported to activate the transcription of genes encoding cytokines and growth-promoting molecules via NF-κ”
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. (2007, background): “It has been suggested that STAT3, in association with NF-κB, could bind to the IL-6 promoter through an NF-κB binding site and promote expression of the IL-6 gene (53).”
Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer (2009, background): “Indeed, the Stark lab has shown that overexpression of a constitutively active form of STAT3 in HME cells induced 427 genes, whereas TNF-a (a major NF-kB activator) induced the expression of 1225 genes and only 123 of these genes were dependent on both NF-kB and STAT3 [35].”
The complexity of NF-κB signaling in inflammation and cancer (2013, background): “Moreover, they also synergistically control a common set of genes encoding for cytokines and chemokines [109,110].”
Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. (2014, background): “However, non-phosphorylated STAT3 is also capable of dimerization and induction of transcription [35].”