JAK-STAT Signaling

Cytokines are regulatory molecules that coordinate immune responses.  The most typical cytokine receptor is a protein that form a stable association with a cytoplasmic tyrosine kinase known as a JAnus Kinase, or JAK, for short. This type of signaling is a direct and rapid way to turn on a set of genes.

Mechanism of signaling

The tyrosine kinase activity of JAK is activated when the regulatory molecule binds and brings two receptor molecules together to form a dimer. Receptor dimerization brings the the two JAKs into close proximity, where they can phosphorylate each other. Phosphorylation further activates JAK, allowing it to phosphorylate the receptor.

The phosphotyrosine residues on the receptor proteins are binding sites for STAT proteins. "STAT" stands for Signal Transducer and Activator of Transcription. The STAT proteins are considered latent transcription factors. "Latent" means that they are always present in the cytoplasm, and waiting to be activated by JAK.

When STAT binds to the receptor, that brings it into a position where it can be phosphorylated by JAK. Once phosphorylated, two STATs can then form a STAT dimer (each STAT molecule binds to the phosphotyrosine of the other phosphorylated STAT).  The STAT dimer is an active transcription factor.  It travels to the nucleus where it binds to specific sequences in the DNA. Inactivation occurs when phosphatases remove phosphate groups from various proteins in the signaling pathway. 

Notably, there are a number of different STAT proteins in cells, and activation of different cytokine receptors will result in the formation of different STAT dimers.  Each STAT dimer binds to a specific DNA sequence found in the promoters of certain genes.  In this way, each cytokine activates a specific set of genes to cause a specific response in the cell.

Many cytokines signal through the JAK-STAT pathway, although not all do. (For instance, TNF-alpha receptors have a completely different structure and signal transduction pathway).  The table lists regulatory molecules that bind to receptors linked to JAKs: this includes some important cytokines that you have already heard about, as well as some hormones that we will discuss during the section on endocrine regulation.

regulatory molecule type effect
cytokine activation of macrophages
IFN-alpha, IFN-beta
cytokine induces antiviral state to limit viral infection
IL-2 cytokine promotes lymphocyte proliferation in specific immune response
growth hormone (GH)
hormone postnatal growth stimulation; metabolic effects
leptin hormone regulation of body weight

Drugs targeting the JAK-STAT pathway

Drugs that target the JAK-STAT pathway are used to turn down the immune response. One way to block the pathway is with a drug that blocks the cytokine receptor.  An example is the drug basiliximab, which binds to the IL-2 receptor, and is used to prevent transplant rejection.  Basiliximab is derived from a monoclonal antibody, and so is a large protein drug that needs to be injected. 

JAK inhibitors are drugs that inhibit the kinase activity of JAK.  There are many JAK inhibitors in development, and two have been approved by the FDA.  Ruxolitinib has been approved to treat a myeoloproliferative disorder (a disorder in which there is abnormal proliferation of cells in the bone marrow).  Tofacitinib is a JAK inhibitor that has been approved for the treatment of rheumatoid arthritis.  An advantage of JAK inhibitors over receptor blocking drugs is that they are small molecule drugs that can be taken orally.

Quick Quiz

Fill in Answer Correct False Correct Answer
1. Which of the proteins in the JAK-STAT signaling pathway is considered a latent transcription factor?
2. Which of the following is phosphorylated as a consequence of a cytokine binding to its receptor? [receptor protein; JAK; STAT; all of the above]   
3. What does ligand binding do that activates JAK?
4. What does STAT bind to after JAK is activated?
5. Phosphorylation of STAT enables it to form a ________, which is an active transcription factor.
6. Name the cytokine that signals via the JAK-STAT pathway, and causes activation of macrophages.

(Spelling must be correct)