JAK-STAT pathway
/ JAK = jack; STAT = stat /
The JAK-STAT pathway is the shortest, most direct route from a cell-surface receptor to a gene — a kind of express lane. Where the MAP-kinase pathway hands the signal down a long chain of relays, JAK-STAT takes only a couple of steps to get a transcription factor moving into the nucleus. It is the pathway many of the body's hormone-like messengers of the immune and blood systems use, the ones called cytokines.
Here is the mechanism in plain steps. The receptors here have no built-in kinase of their own; instead each carries a loosely attached helper kinase called a JAK (Janus kinase, named for the two-faced Roman god because it has two similar parts). When a cytokine binds, it brings two receptor chains together, the two JAKs are now close enough to phosphorylate each other and switch on, and they then tag the receptor tails with phosphates. Those phosphate tags are docking sites for proteins called STATs (signal transducer and activator of transcription). A STAT docks, gets phosphorylated by the JAK, then lets go, pairs up with another phosphorylated STAT, and the STAT pair walks straight into the nucleus to switch on target genes. Receptor to JAK to STAT to gene — that is the whole pathway, remarkably compact.
JAK-STAT matters because it carries some of the body's most important commands: erythropoietin telling marrow to make red blood cells, growth hormone, interferons rallying antiviral defences, and many of the cytokines that drive inflammation. That central role in immunity makes it a prized drug target — a class of anti-inflammatory and anti-cancer drugs called JAK inhibitors (their names end in -tinib or -citinib) damp the pathway down to treat rheumatoid arthritis and certain blood cancers. It is also a clean reminder that not all surface receptors work through second messengers; sometimes the message reaches the genes almost in a straight shot.
When your body needs more red blood cells, the kidneys release erythropoietin (EPO). It binds receptors on blood-forming cells in the marrow, fires up the attached JAKs, which activate STATs that march to the nucleus and switch on the genes for making red cells. The same pathway, over-activated by a mutation in JAK2, drives certain blood cancers.
EPO uses JAK-STAT to order red-cell production; a JAK2 mutation in the same pathway can cause blood cancer.
Despite STAT standing for a transcription factor, the pathway still needs the JAK kinases first; the STAT cannot activate itself. And the receptors are not kinases themselves — they borrow the JAKs, which is why this differs from the receptor tyrosine kinases.