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1. Janus Kinase/Signal
Transducers and Activators of
Transcription (JAK/STAT)
signaling pathway
Saif Imtiyaz
M Pharm, Pharmacology
Jamia Hamdard

2. 1.Introduction 03-06
2.Mechanism of JAK-STAT pathway 07
3.Regulation 08-11
4.Response of JAK STAT transduction pathway 12- 16
5.References 17
Presentation Outlines

3. • In human body, numerous processes are required for coordinating individual
cells to support the body as a whole.
• At the cellular level, Sensing of environments and cell communication for
coordination relies on signal transduction.
• SIGNAL TRANSDUCTION is a process occurring within cells that convert one
kind of signal/stimulus into another type. It also known as cell signaling in
which the transmission of molecular signals from a cell's exterior to its interior.
• It is also defined as the ability of a cell to change behavior in response to a
receptor-ligand interaction(signal).
Introduction

4. • Cells express a family of receptors for cytokines such as γ-interferon and
hormones such as growth hormone and prolactin.
• These receptors have no intrinsic enzymatic activity; rather, binding of the
cytokine causes dimerization of the receptor and recruits a separate,
intracellular tyrosine kinase termed a JAK (Janus kinase) which binds to the
cytoplasmic tails of the receptor.
• The JAK-STAT system consists of three main components:
(1) a receptor
(2) Janus kinase (JAK) and
(3) Signal Transducer and Activator of Transcription (STAT)

5. • JAK- Family of cytoplasmic non-receptor
tyrosine kinases which get activated after
the binding of a cytokine to the cell-
surface cytokine receptor. STAT- Family
of transcription factors that become
activated when one of the tyrosine
residues is phosphorylated by JAK.
• JAKs trans-phosphorylate and lead to the
phosphorylation of the STATs (signal
transducer and activator of transcription).
The phosphorylated STATs translocate to
the nucleus and regulate transcription.
The entire pathway is termed the JAK-
STAT pathway.

6. • The JAK-STAT (Janus kinase-signal transducer and activator of transcription)
signaling pathway is a chain of interactions between proteins in a cell, and is
involved in processes such as immunity, cell division, cell death and tumor
formation.
• JAK activation stimulates cell proliferation, differentiation, cell migration and
apoptosis. These cellular events are critical to hematopoiesis, immune
development, mammary gland development and lactation and other
processes.

7. Mechanism of JAK-STAT
• In the first step the ligands 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 dimerizes it.
• Activated STAT dimers accumulate in
the cell nucleus and activate
transcription of their target genes.

8. Negative Regulation
• Protein Tyrosine Phosphatases
dephosphorylates the tyrosine kinase
receptor and STAT.
• SOCS (Suppressors of Cytokine
Signaling) inhibit STAT
phosphorylation by binding and
inhibiting JAK or competing with STAT
for phosphorylated tyrosine.
• PIAS (Protein Inhibitor of Activated
STAT) are in the nucleus and
correspond with different STATs to
inhibit Transcription.

9. 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 tyrosine is such an important part of how
the JAK-STAT signaling pathway functions, removing these phosphate
groups can inhibit signaling.
• PTPs are tyrosine phosphatases, so are able to remove these phosphates
and prevent signaling.
• 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
signaling.
• The protein complex does this by allowing a
marker called ubiquitin to be added to JAK
or receptors, which signals for a protein to
be broken down.

12. Response of JAK STAT transduction pathway
• Responses include proliferation, differentiation, migration, apoptosis, and cell
survival.
• Essential for numerous developmental and homeostatic processes, including
hematopoiesis, immune cell development, stem cell maintenance, organism
growth and mammary gland development.
• Human JAK mutations cause numerous diseases, including SCID(Severe
combined immunodeficiency), hyper IgE syndrome, certain leukemias and
other disorders.
• Small molecular weight cell membrane-permeable drugs that target this
pathways have been developed for leukemia therapy. (JAK Inhibitors)

13. Activation of JAK/STAT pathway mediated by GH
(growth hormone).
• JAK/STAT pathway components are inactive.
• GH and two Growth Hormone Receptors(GHRs) form a ternary complex that
induces association and autophosphorylation of JAK2 and of docking sites on
the cytoplasmic tail of GHRs.
• JAK2 phosphorylates cytoplasmic proteins that activate downstream
signaling pathways, including STAT5 and mediators upstream of MAPK,
once activated, STAT forms dimers that are translocated to the cell nucleus.
• The STAT dimers in the nucleus are capable of binding to IGF-I (Insulin-like
growth factor 1) promoter, which ultimately modulate gene expression.

14. • Pegvisomant is GH
analog with amino acid
substitution that disrupt
site 2.
• It binds the receptor and
cause its internalization
but cannot trigger the
conformational changes
that stimulate
downstream event in the
transduction pathway.

15. Activation of JAK/STAT pathway mediated by
Prolactin
• Prolactin exerts its effects via prolactin receptors (PLR). The binding of prolactin
to PLR activates the JAK family of kinases which in turn phosphorylate and
activate STAT5.
• This enables STAT5 to translocate to the nucleus and bind to respective STAT
response elements on DNA leading to transcription of DNA sequence motif, GAS
[milk protein genes]. STAT5 is also activated by cytokines such as IL-2. CR
(cytokines receptor) can form a complex with activated STAT5.
• This complex enhances STAT5-dependent transcription and would diminish the
levels free intracellular CS(corticosteroids)/CR complexes leading to reduced
GRE(Glucocorticoid Receptor)-mediated effects. The net effect would be
increased levels of expression of activated NF-B and STAT5.

17. ● Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), (2017). Goodman &
Gilman's: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill.
● The JAK-STAT Signaling Pathway: Input Peter J. Murray
http://www.jimmunol.org/content/178/5/2623 DOI:
10.4049/jimmunol.178.5.2623
● The JAK/STAT signaling pathway Jason S. Rawlings, Kristin M. Rosler and
Douglas A. Harrison* University of Kentucky, Department of Biology, 101 T.H.
Morgan Bldg., Lexington, KY 40506, USA
References

18. Thanks