JAK-STAT signal path

April 17, 2020 0 Comments

The JAK-STAT signal transmission is conserved evolutionarily in vertebrates and some other multicellular organisms. The combination of receptor-activated kinases and transcription factors make this signal cascade one of the central cellular regulatory pathways.

In vertebrates, the JAK-STAT signal transmission is based on a network of protein kinases and transcription factors with which signals from different receptor systems are integrated. The multitude of stimuli includes cytokines, growth factors and hormones, the binding of which ultimately leads to processes such as the regulation of immune reactions and cell growth, survival and differentiation.

The highly conserved transmission path essentially comprises three processing levels for incoming information, depending on the function of the respective components:

Ligand binding to the receptor triggers conformational changes in receptor molecules.
This steric receptor change brings two Janus kinases (JAK), which are bound to the receptor or to receptor subunits, in close proximity and thus enable transphosphorylation. The activated JAKs then phosphorylate further targets.
The main goals of phosphorylation are STAT (Signal Transducers and Activators of Transcription). These transcription factors are inactive in the cytoplasm until phosphorylation by the JAKs. As soon as a conserved tyrosine is phosphorylated at the C-terminus of the STAT, it can act together with SH2 domains as a dimerization interface of another STAT. These activated STAT dimers are then transferred to the cell nucleus and bind to certain DNA motifs in order to activate the transcription of the target gene.
In addition, these processes are negatively regulated at various levels.

SOCS (Suppressors of Cytokine Signaling) gene transcription is stimulated by activated STATs. SOCS deactivate signal transmission by binding to the phosphorylated JAKs or receptors or by enabling JAK ubiquitination.
Protein inhibitors from activated STATs (PIAS) bind to activated STATs and thus prevent them from binding DNA.
PTPs (protein tyrosine phosphatases) reverse JAK activity.
The prototype of the JAK-STAT signal path is rather linear. Nevertheless, there is also considerable mutual interference from others and through other signal cascades such as MAPK signaling pathways and JAK-independent STAT phosphorylation by RTKs (receptor tyrosine kinases).

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