3.1.3 Non-Canonical JAK/STAT pathway
FIGURE 3 Non-canonical JAK-STAT signaling.
It’s widely aberrated that the effects of STATs are mediated by direct
transcriptional induction of STAT genes. However, in Drosophila and some
mammal cells a non-canonical JAK-STAT pathway was identified, which
directly controls the heterochromatin stability. That indicates the JAK
affects the gene expression without directly STAT transcriptional
control but by controlling cellular epigenetic STATs(Hixson, Cogswell,
Brooks-Kayal & Russek, 2019; Li, 2008). Here comes a new mode of JAK
signaling: JAK over-activation globally disrupts heterochromatin; that
would enable expression of genes not necessarily under direct STAT
transcriptional regulation(Betz & Darnell, 2006).
Different from the canonical mode of JAK-STAT (inactivated STATs
distribution in the cytoplasm), in the non-canonical mode of JAK-STAT
signaling, unphosphorylated STAT is localized on heterochromatin which
is associated with HP1 in the nucleus. JAKs or other tyrosine kinases
increase STAT phosphorylation, that induces reducing in the amount of
unphosphorylated STAT localized on heterochromatin, leads to HP1
displacement from heterochromatin and heterochromatin instability. On
the one hand, dispersed phospho-STATs bind to cognitive sites in
euchromatin to induce target-gene expression. On the other, genes
originally localized in heterochromatin are now accessible to STAT or
other transcription factors. Non-canonical JAK-STAT signaling regulates
heterochromatin stability, resulting in altered histone H3 methylation
and/or chromatin remodeling. The JAK/STAT over-activation disrupts
heterochromatin [26]. Although, it has been
demonstrated that perturbation of epigenetic gene regulation plays an
important role in many human diseases like tumorigenesis. And there is
still much that is unknown or poorly understood about the role of
non-canonical JAK/STAT signaling in ARDS or other pulmonary diseases.
There need more studies to reveal the JAK/STAT would cause how many
kinds of disease in the human being.