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Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

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TLDR
A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Abstract
Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.

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Cell signaling by receptor-tyrosine kinases

TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
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How cells respond to interferons

TL;DR: The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interFERons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.
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STATs and Gene Regulation

TL;DR: The discovery of a STAT in Drosophila, and most recently in Dictyostelium discoideum, implies an ancient evolutionary origin for this dual-function set of proteins.
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Interferon-γ: an overview of signals, mechanisms and functions

TL;DR: The current understanding of IFN‐γ ligand, receptor, ignal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophages function during infection are reviewed.
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STATs in cancer inflammation and immunity: a leading role for STAT3

TL;DR: Signal transducer and activator of transcription proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer, and STAT3 is a promising target to redirect inflammation for cancer therapy.
References
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Journal ArticleDOI

High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both alpha and gamma interferons

TL;DR: Results indicate that the signaling pathways for the two types of IFN and double-stranded RNA share common components or that their function depends on common enzymes or transcription factors.
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Induction by EGF and interferon-gamma of tyrosine phosphorylated DNA binding proteins in mouse liver nuclei.

TL;DR: Gel shift analysis revealed that these GAF proteins, detected after either EGF or IFN-gamma administration, specifically bound to the sis-inducible element of the c-fos promoter, participate in nuclear signaling in both EGF and EGF pathways.
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Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4

TL;DR: IL-4 appears to transduce a signal to the nucleus through tyrosine phosphorylation of a latent DNA binding factor as well as a putative transcription factor found in the promoters of IL-4-responsive genes.
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Interferon response element of the human gene 6-16.

TL;DR: The data suggest that a 39 bp sequence is sufficient to confer transcriptional inducibility and can account in large part for the response of 6‐16.
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Distinct protein targets for signals acting at the c-fos serum response element.

TL;DR: Two different signaling pathways act through discrete nuclear targets at the SRE by recruitment of a pathway-specific accessory factor (p62TCF), offering a molecular mechanism to account for the biological specificity of signals that appear to act through common DNA sequence elements.
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