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Abstract
A small group of only seven transcription factors known as STATs (signal transducer and activator of transcription) are considered to be canonical determinants of specific gene activation for a plethora of ligand/receptor systems. The activation of STATs involves a family of four tyrosine kinases called JAK kinases. JAK1 and JAK2 activate STAT1 in the cytoplasm at the heterodimeric gamma interferon (IFNγ) receptor, while JAK1 and TYK2 activate STAT1 and STAT2 at the type I IFN heterodimeric receptor. The same STATs and JAKs are also involved in signaling by functionally different cytokines, growth factors, and hormones. Related to this, IFNγ-activated STAT1 binds to the IFNγ-activated sequence (GAS) element, but so do other STATs that are not involved in IFNγ signaling. Activated JAKs such as JAK2 and TYK2 are also involved in the epigenetics of nucleosome unwrapping for exposure of DNA to transcription. Furthermore, activated JAKs and STATs appear to function coordinately for specific gene activation. These complex events have not been addressed in canonical STAT signaling. Additionally, the function of noncoding enhancer RNAs, including their role in enhancer/promoter interaction is not addressed in the canonical STAT signaling model. In this perspective, we show that JAK/STAT signaling, involving membrane receptors, is essentially a variation of cytoplasmic nuclear receptor signaling. Focusing on IFN signaling, we showed that ligand, IFN receptor, the JAKs, and the STATs all undergo endocytosis and ATP-dependent nuclear translocation to promoters of genes specifically activated by IFNs. We argue here that the vacuolar ATPase (V-ATPase) proton pump probably plays a key role in endosomal membrane crossing by IFNs for receptor cytoplasmic binding. Signaling of nuclear receptors such as those of estrogen and dihydrotestosterone provides templates for making sense of the specificity of gene activation by closely related cytokines, which has implications for lymphocyte phenotypes.
Highlights
Our understanding of signaling by cytokines such as the interferons (IFNs) at the level of gene activation is stunningly deficient in mechanisms when compared to that of nuclear receptor signaling, as seen, for example, in the case of steroids and their receptors
In the determination of internalization dynamics of IFNγ receptors, we showed that the presence of IFNGR1 and IFNGR2 in the lipid microdomain on the surface of the cell was central to the endocytic events that are linked to the IFNγ noncanonical signaling pathway [40]
For the case of nuclear receptor (NR), the foundations are in place with the NR and ligand at promoters and enhancers of genes activated by the ligand
Summary
Our understanding of signaling by cytokines such as the interferons (IFNs) at the level of gene activation is stunningly deficient in mechanisms when compared to that of nuclear receptor signaling, as seen, for example, in the case of steroids and their receptors. The abundance of genetic and epigenetic mechanisms in SH/SR signaling as well as in other NR signaling at the promoters of genes activated by NRs provides a picture that contrasts with IFNγ signaling and in general with peptide and protein ligands of hormone, growth factor, and cytokine signaling. GRO-seq is a direct, high-throughpout sequencing procedure for finding RNAs and is adapted from conventional nuclear run-on methodologies These technologies provide insight into the binding of ER and androgen receptor (AR) to enhancers and subsequent transcription of eRNAs and interaction or cross talk with ER and AR promoters. There are other players in these enhancer-promoter complexes, but the foundation factors for specific gene activation are typified by E2 or DHT steroid ligands bound to their respective ER or AR nuclear receptor. We show with particular focus on IFN below that this hinders access to specific mechanisms in signaling by these factors
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