2. What is JAK- STAT?
• The JAK-STAT(Janus kinase-signal transducer
and activator of transcription) signalling
pathway transmits information from chemical
signals outside the cell, which causes DNA
transcription and activity in the cell.
• The JAK-STAT system is a major signalling
alternative to the second messenger system.
3. • It consists of three main components
a. Receptor
b. JAK-Janus kinases
c. STAT-Signal transducer and activator of
transcription
4.
5.
6. • In the first step the ligands (EPO) bind to its
receptor and dimerizes the receptor.
• This causes the activation of JAK.
• JAK phosphorylates tyrosine residue on itself
(auto-phosphorylation).
• The freely moving STAT molecules in the
cytoplasm goes and attaches to the
phosphorylated tyrosine residue.
• JAK also phosphorylates the STAT protein and
7. dimerizes it.
• The STAT dimer enters the nucleus and
attaches to the specific region of the DNA(in
the promoter region) and promotes
transcription of a particular sequence and the
protein thus formed show its effect.
8. CLINICAL SIGNIFICANCE
• Disrupted or disregulated JAK-STAT functionality
can result in immune deficiency syndrome and
cancer.
TYPES OF JAK PROTIEN
• Janus kinase 1
• Janus kinase 2 (most important)
• Janus kinase 3
• Tyrosine kinase 2
9. 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 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.
10. Role of JAK-STAT signalling pathway in
Cancer
• The tyrosine kinase JAK and its downstream target STAT respond to
cytokine signalling in cells.
• In response to cytokines, JAK itself is phosphorylated, leading to its
activation. The activated JAK kinase then phosphorylates specific
STATs.
• STAT proteins dimerise and translocate into the nucleus upon
phosphorylation by JAK, where they bind to DNA and regulate
transcription.
• Overactivation of the JAK‐STAT pathway can cause cancer by
bypassing apoptosis and cell cycle checkpoints.
• Unphosphorylated STAT is also found in the nuclei and
mitochondria of cells that are not stimulated by cytokines.
• Mitochondrial STAT upregulates cellular respiration and can
promote oncogenic transformation.
11. • Unphosphorylated nuclear STAT binds to HP1α and
stabilises heterochromatin. STAT5A in colon cancer
cells acts as a tumour suppressor via this mechanism.
• Nuclear JAK2 is a histone tyrosine kinase.
Phosphorylation of histone 3 tyrosine 41 displaces
HP1α/CBX5 from chromatin and contributes to
tumourigenicity.
• In some cancers, DNA methylation suppresses the
expression of inhibitory SOCS proteins, resulting in
uncontrolled JAK/STAT pathway activation.
12. REFERRENCES:
• Molecular biology of the cell by Bruce Alberts,
Dennis Bray, James Watson and Julian Lewis.
• https://courses.washington.edu
• www.google.com
