The JAK-STAT pathway transmits signals from extracellular chemical messengers through three main components: cell surface receptors, Janus kinases (JAKs), and signal transducers and activators of transcription (STATs). Upon ligand binding, receptor-associated JAKs become activated and phosphorylate STATs, allowing them to form dimers and translocate to the nucleus to regulate gene expression. The pathway is negatively regulated by phosphatases, suppressors of cytokine signaling, and protein inhibitors of activated STAT. Disrupted JAK-STAT signaling can cause immune deficiency, inflammation, and cancer. Drugs targeting the pathway are used to treat transplant rejection, myeloproliferative disorders, rheumatoid arthritis, and atopic

1. 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.
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2. The JAK-STAT system
consists of three main
components:
 (1) a receptor (Interleukins, Interferons, GM-CSF)
 (2) Janus kinase (JAK) (There are four Jaks, Jak1, Jak2,
Jak3, and Tyk2, which selectively bind different receptor
chains)
 (3) Signal Transducer and Activator of Transcription
(STAT) (Seven mammalian STAT family members have been
identified (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b,
STAT6)
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3. Mechanism
 Upon engagement by ligand, receptor-associated Janus Kinases (Jaks) become
activated and phosphorylate both each other and the intracellular tail of their
receptors, thereby creating docking sites for latent, cytoplasmic transcription factors
termed signal transducers and activators of transcription (STATs).
 Jak-mediated phosphorylation activates STATs, which in turn directly bind DNA and
regulate gene expression
 STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases,
such as the epidermal growth factor receptor, as well as by non-receptor tyrosine
kinases such as c-src.
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4. How Pathway Works.
 The receptor is activated by a signal from interferon, interleukin, growth factors, or
other chemical messengers.
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6. Negative
Regulation
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7. Mechanism
 The pathway is negatively regulated on multiple levels. Protein tyrosine
phosphatases 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 PIAS3 inhibit transcriptional activation by STAT1 and
STAT3 respectively by binding and blocking access to the DNA sequences they
recognize.
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Matrix metaloprotease

9. Interpreting experiments using
STAT loss-of-function systems.
 Experiments with the different STAT knockout mice, and cells
derived from these animals, have been critical for understanding
specific requirements of individual STATs in gene expression
following cytokine receptor signalling.
 For example,
STAT5a and STAT5b are essential for the expression of genes that
promote hemopoietic survival whereas STAT1 is required for the
expression of IFN-regulated genes that are involved in the protection
against pathogens .
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10. Significance of JAK STAT:-
 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.
 In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of
cytokines and growth factors. JAK activation stimulates cell proliferation, differentiation, cell
migration and apoptosis. These cellular events are critical to hematopoiesis, immune
development, mammary gland development and lactation, adipogenesis, sexually dimorphic
growth and other processes.
 Mutations that constitutively activate or fail to regulate JAK signaling properly cause
inflammatory disease, erythrocytosis, gigantism and an array of leukemias.
 The JAK-STAT pathway is evolutionarily conserved, from slime molds and worms to mammals
(but not fungi or plants).
 Disrupted or dysregulated JAK-STAT functionality (which is usually by inherited or acquired
genetic defects) can result in immune deficiency syndromes and cancers.
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ROLE IN CANCER
 Overactivation of the JAK‐STAT pathway can cause cancer by bypassing
apoptosis and cell cycle checkpoints.
 Mitochondrial STAT upregulates cellular respiration and can promote
oncogenic transformation.
 Unphosphorylated nuclear STAT binds to HP (Heterochromatin Protein)-1α
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/CBX (Chromobox protein)-5 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.

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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, 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.
Oclacitinib—Oclacitinib is a JAK inhibitor recently approved for the treatment of
atopic dermatitis