1. The JAK-STAT pathway involves cytokine binding to receptors which activates JAK proteins, leading to phosphorylation of STAT proteins. Phosphorylated STATs form dimers and translocate to the nucleus to initiate gene transcription. 2. The pathway is regulated by PIAS, PTPs, and SOCS proteins. PIAS can add SUMO groups or recruit HDACs to inhibit STATs. PTPs remove phosphates to inhibit signaling. SOCS proteins form complexes that ubiquitinate proteins like JAKs and receptors to target them for degradation. 3. In rheumatoid arthritis, overactive JAK-STAT signaling leads to excessive inflammation. Approved drugs tofacitinib, ruxolit

1. JAK STAT Pathway
(Regulation)
Zulqarnain Haider
BS Biotechnology (7th semester)
IIUI

2. Steps:
1. Binding of cytokine to cytokine receptors bring two JAK proteins close
enough so that they phosphorylate each other.
2. Phosphorylated JAK proteins then phosphorylate tyrosine kinase on
cytokine receptors creating phosphor tyrosine docking site.
3. STAT proteins moving freely in the cytoplasm then binds to these docking
sites.
4. JAK phosphorylates STAT proteins.

3. • The phosphorylated STAT dissociates from receptors.
• The STAT proteins bind to another STAT protein forming dimer.
• The STAT dimer translocates into nucleus anf binds to DNA.
• As STAT is a transcription factor, it initiates the transcription of a particular
gene.

7. Regulators
• Three major groups of proteins that cells use to regulate this signalling
pathway are;
1. Protein Inhibitors of Activated STAT (PIAS)
2. Protein Tyrosine Phosphatases (PTPs)
3. Suppressors Of Cytokine Signalling (SOCS)

8. Protein inhibitors of activated STATs
(PIAS)
There are three ways PIAS proteins can inhibit JAK-STAT signaling.
A. Adding a SUMO(small ubiquitin-like modifier) group to STATs can block
their phosphorylation, which prevents STATs entering the nucleus.
B. HDAC (histone deacetylase) recruitment can remove acetyl modifications
on histones, lowering gene expression.
C. PIAS can also prevent STATs binding to DNA

10. Protein tyrosine phosphatases (PTPs)
• Since adding phosphate groups on tyrosines is such an important part of how the
JAK-STAT signalling pathway functions, removing these phosphate groups can
inhibit signalling.
• PTPs are tyrosine phosphatases, so are able to remove these phosphates and
prevent signalling.
• PTPs can also remove phosphates from phosphorylated STATs.

11. Suppressors of cytokine signalling (SOCS)
• It has an SH2 domain and a 40-amino-acid region called the SOCS box.
• The SOCS box can interact with a number of proteins to form a protein complex,
and this complex can then cause the breakdown of JAKs and the receptors
themselves, therefore inhibiting JAK-STAT signalling.
• The protein complex does this by allowing a marker called ubiquitin to be added to
JAK or receptors, in a process called ubiquitination, which signals for a protein to
be broken down.
• The proteins, such as JAKs and the receptors, are then transported to a
compartment in the cell called the proteasome, which carries out their breakdown.

13. Rheumatoid arthritis
• The Janus kinase (JAK) family of intracellular tyrosine kinases plays a pivotal
role in transducing extracellular cytokine signaling, thereby contributing to
major processes such as cellular proliferation, homeostasis, and host defense
against infection.
• In Rheumatoid arthritis (RA), certain JAK-mediated signaling pathways are
dysfunctionally active, leading to enhanced transcription of various pro-
inflammatory genes and abnormal immune responses.

16. Approved Drugs
• Tofacitinib: The first JAK inhibitor to reach clinical trials was tofacitinib. U.S. FDA
approved it in November 2012 against JAK 3 for rheumatoid arthritis (moderately-
to-severely active) in patients who had an inadequate response or intolerance to
methotrexate.
• Ruxolitinib: Approved by the U.S. FDA in November 2011 against JAK 1/ JAK 2
for myelofibrosis (intermediate- or high-risk) and polycythemia vera, in patients with
an inadequate response or intolerance to hydroxyurea.
• Peficitinib: Approved for use in Japan in 2019. It mainly inhibits JAK3 and used for
treatment of rheumatoid arthritis.

17. • Fedratinib: Approved by U.S. FDA on 16 August 2019. It is a JAK2
inhibitor for treatment of primary myelofibrosis (including in patients those
previously treated with ruxolitinib), or secondary myelofibrosis (post-
polycythemia vera or post-essential thrombocythemia).
• Upadacitinib: Approved by U.S FDA on 16 August 2019 against JAK1 for
rheumatoid arthritis.