CYTOKINE ACTIVATED JAK-

STAT SIGNALING PATHWAYS

SUBMITED BY: SWARAJ DEY
ROLL NO.- 38
3 RD SEMESTER
HUMAN PHYSIOLOGY WITH CH
 WHAT IS JAK STAT?

TheJAK-STAT(Janus kinase-signal transducer

and activator) signalling pathwaytransmits
information from extracellular chemical signals to
the nucleus resulting in DNA transcriptionand
expression of genes involvod inimmunity,
proliferation,differentiation,apoptosisand
oncogenesis.

The JAK-STAT system is major signalling

alternative to the second messenger system.
 COMPONENTS

The JAK-STAT signalling cascade consists of

three main components.
a cell surface receptor

Janas kinase(JAK) and

Signal Transducer and Activator of

Transcription(STAT)
 MECHANISM
JAK which have tyrosine kinase activity; binds to
some cell surface cytokine receptors. The binding of
the ligand to the receptor triggers activation of JAKs.

With increased kinase activity, they phosphorylate

tyrosine residues on the receptor creating binding
sites for proteins possessingSH2 domains. SH2
domain containing STATs are recruited to the receptor
where they are also tyrosine-phosphorylated by JAKs.

These activated STATs formdimers accumulate and

translocate to thecell nucleus and transcription of
target genes.
 MECHANISM
STATs may also be tyrosine phosphorylated directly
byreceptor tyrosine kinases, such as the
epidermal growth factor receptor, as well as by non-
receptor (cytoplasmic) tyrosine kinasessuch asc-src.

The pathway is negatively regulated on multiple

levels.Protein tyrosine phosphatasesremove
phosphates from cytokine receptors and activated
STATs. suppressors of cytokine signalling (SOCS)
inhibit STAT phosphorylation by binding and inhibiting
JAKs or competing with STATs for phosphotyrosine
binding sites on cytokine receptors.
DIAGRAM OF JAK- STAT
SIGNALING
 CYTOKINE SIGNALLING FROM THE
RECEPTOR TO THE NUCLEUS
The JAK-STAT pathway was originally discovered
through the study of interferon induced intracellular
signal transduction. A large number of cytokines,
hormones and growth factors have been found to
activate JAKs and STATs.

JAKs (Janus Kinases) are a unique class of tyrosine

kinases that associate with cytokine receptors. Upon
ligand binding, they activate members of the Signal
Transducers and Activators of Transcription (STAT)
family through phosphorylation on a single tyrosine.
Activated STATs form dimers, translocate to
the nucleus, bind to specific response
elements in promotors of target genes, and
transcriptionally activate these genes.
Both positive and negative regulations of the
JAK-STAT pathway have been identified. In a
positive feedback loop, interferons
transcriptionally activate the genes for
components of the interferon stimulated gene
factor 3 (ISGF3). A number of cytokines that
activate the JAK-STAT pathway,
 HOW PATHWAY WORKS
The receptor is activated by a signal from
interferon, interleukin, growth factors, or other
chemical messengers.
NEGATIVE REGULATION
 MECHANISMS OF NEGATIVE
REGULATION
The pathway is negatively regulated on multiple levels.
Protein tyrosine phosphatages remove phosphates from
cytokine receptors and activated STATs.

Suppressors of cytokine signalling(SOCS) inhibit STAT

phosphorylation.

Protein inhibitors of activated STAT(PIAS), which also act in

the nucleus through several mechanisms.

For example,PIAS1 and PIAS2 inhibit transcriptional

activation by STAT1 and STAT3 respectively by binding and
blocking access to the DNA sequences they recognize.
 REGULATION OF JAK-STAT
SIGNALING IN THE IMMUNE
SYSTEM
The cytokine-activated Janus kinase (JAK)signal
transducer and activator of transcription (STAT)
pathway has an important role in the control of
immune responses.

Dysregulation of JAKSTAT signalling is associated

with various immune disorders. The signalling
strength, kinetics and specificity of the JAKSTAT
pathway are modulated at many levels by distinct
regulatory proteins.

The regulation of the JAKSTAT pathway that

will enhance our ability to design rational
therapeutic strategies for immune diseases.
 THE JAK-STAT PATHWAY IN
NORMAL HEMATOPOIESIS
The Janus kinase-signal transducer and activator of transcription (Jak-
Stat) pathway stands as a paradigm of how diverse extracellular
signals can elicit rapid changes in gene expression in specific target
cells.

This pathway is widely used by members of the cytokine receptor

superfamily, including those for the clinically important cytokines
granulocyte colony-stimulating factor (GCSF), erythropoietin,
thrombopoietin, the interferons, and numerous interleukins, which
makes it central to hematopoietic cell.

The Jak-Stat pathway has provided a wealth of information on

hematopoiesis and hematopoietic disease.

The role of the pathway in the normal development and function of

hematopoietic cells.
 JAK-STAT PATHWAY:INPUT AND
OUTPUT INTEGRATION
Universal and essential to cytokine receptor signaling, the
JAK-STAT pathway is one of the best understood signal
transduction cascades.

Almost 40 cytokine receptors signal through

combinations of four JAK and seven STAT family
members, suggesting commonality across the JAK-STAT
signaling system.

Despite intense study, there remain substantial gaps in

understanding how the cascades are activated and
regulated. Using the examples of the IL-6 and IL-10
receptors.
 FUNCTIONAL EQUIVALENCE IN SIGNALLING
FROM RECEPTORS USING THE SAME JAK-STAT
COMBINATION IN THE SAME CELL
In macrophages stimulated with either IL-10 or IL-6,
the JAK1-STAT3 pathway is activated.
both the IL-10R and IL-6R activate a seemingly
identical process.
The major function of IL-10 is to negatively regulate
inflammatory responses from activated macrophages
and dendritic cells.
Cytokine receptors that are unrelated to the IL-10R but
activates STAT3 in a SOCS3 independent way activate
the anti inflammatory response.
Receptors that are regulated by socs3 cannot activate
the anti-inflammatory response such as IL-6R.
MUTATION OF JAK STAT PATHWAY
Dysregulation of JAK-STAT pathway in
hematological malignancies and JAK inhibitors-
JAK-STAT (Janus associated kinase-signal transducer and
activator of transcription) pathway plays a critical role in
transduction of extracellular signals from cytokines and
growth factors involved in hematopoiesis, immune
regulation, fertility, lactation, growth and embryogenesis.

JAK family contains four cytoplasmic tyrosine kinases,

JAK1-3 and Tyk2. Seven STAT proteins have been
identified in human cells, STAT1-6, including STAT5a and
STAT5b.
MUTATION OF JAK- STAT PATHWAY
Negative regulators of JAKSTAT pathways
include tyrosine phosphatases (SHP1 and 2,
CD45), protein inhibitors of activated STATs
(PIAS), suppressors of cytokine signaling
(SOCS) proteins, and cytokine-inducible SH2-
containing protein (CIS).

Dysregulation of JAK-STAT pathway have been

found to be key events in a variety of
hematological malignancies.
 CONTINUED.....
Chronic lymphocytic leukemia-

Constitutive activation of STAT1 & 3 was noticed in

transformed B-cells in patients with chronic
lymphocytic leukemia (CLL).

Activated STAT1 & 3 proteins in malignant B-cells

were phosporylated at serine instead of tyrosine
residue. It remained uncertain whether activated
STAT involved directly in the pathophysiology of this
disease or represented a pure epi-phenomenon.
Primary mediastinal B-cell
lymphoma-
Mutation in SOCS-1 has been reported in primary
mediastinal B-cell lymphoma. This results in
delayed turnover of phosphorylated JAK2 and
increased activity of STAT5, which may explain
the uncontrolled growth of malignant cells.