The JAK-STAT Signaling Pathway

Cytokine receptors are cell surface receptors activated by small signaling molecules called cytokines. They do not have intrinsic kinase activity but are bound by a cytosolic tyrosine kinase called the Janus kinase or JAK.

Cytokine binding dimerizes these receptors, bringing two JAKs closer. JAKs trans-phosphorylate each other and get activated.

Activated JAKs phosphorylate the tyrosine residues on the cytoplasmic tail of the receptors, which serve as binding sites for SH2 domain-containing proteins such as signal transducer and activator of transcription or STAT .

Once phosphorylated by the JAKs, STATs use their SH2 domain to form dimers and dissociate from the receptors.

STAT dimers translocate to the nucleus and bind regulatory gene sequences to initiate transcription.

STAT dimers also activate the suppressors of cytokine signaling or SOCS synthesis. SOCS proteins bind specific phosphotyrosine residues of cytokine receptors and JAKs and prevent the binding of other intracellular signaling proteins, thereby shutting the JAK-STAT pathway.