The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2 domain-containing signal transducers and activators of transcription factor or STAT. Seven types of STAT transcription factors (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) are associated with mammalian cellular responses. STATs consists of an N-terminal DNA-binding domain, an SH2 domain, and a C-terminal domain with a conserved tyrosine residue.

Unphosphorylated STATs are inactive and remain in the cytoplasm.  JAK phosphorylates STAT's C-terminal tyrosine residue once they bind to the phosphotyrosine residue of an activated cytokine receptor. Phosphorylated STATs undergo a conformational change and dissociate from the receptor. Two phosphorylated STAT monomers can now dimerize via their SH2 domain. Dimerization exposes the nuclear-localization signal (NLS) as they move to the nucleus to bind to specific cis-regulatory sequences of a gene and initiate transcription.

JAK-STAT signaling is essential for various cellular processes.  For example, erythropoietin  (Epo) binding to the EpoR receptor on the erythroid progenitor cells activates the STAT5 protein.  Activated STAT5 induces the expression of  Bcl-xL, an anti-apoptotic protein that prevents programmed cell death or apoptosis while facilitating survival and irreversible differentiation to produce red blood cells.

Once an appropriate response is elicited, the JAK-STAT pathway is shut off by one of the three mechanisms:

1. Regulation by the suppressors of cytokine signaling (SOCS) protein:  SOCS binds to the phosphotyrosines residues of an activated receptor via their SH2 domain. Next, SOCS recruits E3 ubiquitin ligases via their SOCS box domain and helps ubiquitinylate JAK kinase. Ubiquitinated JAKs are then degraded in the proteasome complex.
2. Regulation by protein tyrosine phosphatases, SHP1: SHP1 is a phosphotyrosine phosphatase enzyme containing two SH2 domains. SHP1 dephosphorylates JAKs and inactivates them.
3. Regulation by protein inhibitors of activated STATs (PIAS):  The PIAS proteins prevent activated STAT dimers from binding to the DNA, thereby shutting off the signaling cascade.

Apart from activating STATs, JAK kinase also activates other signaling proteins. Activated JAKs are a binding site for SH2 domain-containing phosphatidylinositol-3-kinase or PI-3K or SHP-2 domain-containing Grb2-SOS adaptor proteins. The binding of PI-3K activates the PI3K /mTOR pathway, whereas Grb2-SOS binding promotes the Ras-MAPK signaling cascade.