JAK-STAT signalling pathway. It is very important for CSIR-UGC-NET (LIFE SCIENCES)

1. JAK STAT
MD. MEHEDI HOSSAIN
10/27/2017 JAK-STAT Signalling
Cytokines are regulatory molecules that coordinate immune responses. Responses to cytokines
include increasing or decreasing expression of membrane proteins (including cytokine receptors), cell
proliferation, and secretion of effector molecules. Cytokines may act on the cells that secrete them
(autocrine action), on nearby cells (paracrine action), or in some instances on distant cells
(endocrine action). 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 signalling is
a direct and rapid way to turn on a set of genes. JAKs are cytosolic kinases associated with cytokine
receptors. Four JAKs exist (JAK1-JAK4).
Structure and function of JAK domain
❖ The FERM domain mediates the interaction with receptor
complexes.
❖ The SH2 domain is a protein domain that binds to
phosphorylated tyrosine residues.
❖ The JH2 pseudokinase domain regulates kinase activity of
the JH1 kinase domain.
❖ P marks conserved tyrosine residues in JH1 whose
phosphorylation is essential for JAK activation.
❖ N and C indicate the amino terminus and carboxy terminus.
Structure and function of STAT domain
❖ The SH2 domain binds phosphorylated tyrosines.
❖ The carboxy terminus transactivation domain is required
for full transcriptional activation.
❖ P marks the conserved tyrosine residue whose
phosphorylation is essential for STAT activation.
Mechanism of signalling
The tyrosine kinase activity of JAK
is activated when the regulatory
molecule binds and brings two
receptor molecules together to form
a dimer. Dimerization brings the
two JAKs into 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.

2. JAK STAT
MD. MEHEDI HOSSAIN
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 signalling pathway.
Notably, there are several 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.
The JAK-STAT system is a major signalling alternative to the second messenger system. Different
patterns of JAK and STAT molecules seem to be activated by different cytokine receptors, this is
supposed to play fundamental roles in conferring specificity for cytokine responses.
In mammals, there are seven STAT genes, and each one binds to a different DNA sequence. This
affects basic cell functions, like cell growth, differentiation and death. The JAK-STAT pathway is
evolutionarily conserved, from slime molds and worms to mammals (but not fungi or plants).
Drugs targeting the JAK-STAT pathway
Drugs that target the JAK-STAT pathway are used to turn down the immune response. One type of
drug that has been approved by the FDA is a cytokine receptor blocker derived from a monoclonal
antibody. Because it is a protein, this type of drug needs to be injected. An example is Basiliximab,
which is used to prevent transplant rejection. Basiliximab binds to the IL-2 receptor.
Many drugs that inhibit the kinase activity of JAK are in development, and one, ruxolitinib, has been
approved to treat a myeolo-proliferative 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.