JAK STAT Signaling Pathway

1. JAK STAT SIGNALING
PATHWAY
BY DR. HAROON RIAZ

2. JAK/STAT Pathway
 The JAK-STAT system consists of three main components:
 (1) a receptor
 (2) Janus kinase (JAK)
 (3) Signal Transducer and Activator of Transcription (STAT).
 transduce a multitude of signals for development and homeostasis in animals, from
humans to flies.
DR. HAROON RIAZ

3. JAK/STAT pathway
JAK activation stimulates:
1. cell proliferation,
2. differentiation
3. cell migration
4. apoptosis.
These cellular events are critical to hematopoiesis, immune development, mammary
gland development and lactation, adipogenesis, sexually dimorphic growth and other
processes.
Note
Hematopoietic Cells: An immature cell that can develop into all types of blood cells, including white blood cells, red blood cells,
and platelets.
Sexual dimorphism is the systematic difference in form between individuals of different sex in the same species
DR. HAROON RIAZ

4. DR. HAROON RIAZ

5. Mutations in JAK/STAT pathway
 Mutations that constitutively activate or fail to properly regulate JAK signaling can cause
inflammatory disease, erythrocytosis, gigantism and an array of leukemias.
 Mutations which slow down or stop JAK/STAT pathway disrupts the process of
hematopoiesis, immune development, mammary gland development and lactation,
adipogenesis, sexually dimorphic growth and other processes.
Note
Erythrocytosis is when you have more red blood cells than normal
Adipogenesis is the process by which fat-laden cells, that is, adipocytes, develop and accumulate as adipose tissue at various sites in
the body, both as subcutaneous fat and as depots.
DR. HAROON RIAZ

6.  Cytokines contain 160 amino acids
 Example 1: Interleukins, essential for proliferation and functioning of T
cells and antibody producing B cells of the immune system.
◦ T cells: A lymphocyte (WBCs) that matures in the thymus
 Example 2: Interferon, produced and secreted by certain cell type
following virus infection
 Example 3: Erythropoietin, triggers production of RBCs and by inducing
division and differentiation of erythroid progenitor cells in the bone
marrow
Cytokines
DR. HAROON RIAZ

7.  Glossary:
 Cytokines are small proteins that are crucial in controlling the growth and activity of other immune system cells and
blood cells. When released, they signal the immune system to do its job. Cytokines affect the growth of all blood
cells and other cells that help the body's immune and inflammation responses.
Cytokines have important roles in chemically induced tissue damage repair, in cancer development and progression,
in the control of cell replication and apoptosis, and in the modulation of immune reactions such as sensitization.
Cytokine Release Syndrome (CRS) happens when your immune system responds to infection or immunotherapy
drugs more aggressively than it should. CRS symptoms include fever, nausea, fatigue and body aches. Prompt
treatment is essential, as symptoms can worsen quickly
Mortality in COVID-19 patients has been linked to the presence of the so-called “cytokine storm” induced by the
virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage
resulting in multi-organ failure and death.
 The primary function of interleukins is, therefore, to modulate growth, differentiation, and activation during
inflammatory and immune responses. Interleukins consist of a large group of proteins that can elicit many reactions
in cells and tissues by binding to high-affinity receptors in cell surfaces
 Interferon: A natural substance that helps the body's immune system fight infection and other diseases, such as
cancer. Interferons are made in the body by white blood cells and other cells, but they can also be made in the
laboratory to use as treatments for different diseases.
 Erythropoietin, also known as, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the
kidneys in response to cellular hypoxia; it stimulates red blood cell production in the bone marrow.

8. Erythropoietin and formation of RBCs
• Optimal red blood cell
(RBC) production
requires both
erythropoietin (as the
controlling factor) and
iron (as the raw
material).
• Several factors can
impair RBC production;
inhibit iron availability,
and/or shorten RBC life
span.
DR. HAROON RIAZ

9.  Intracellular activation of JAK/STAT occurs when ligand binding induces the
multimerization of receptor subunits.
 For some ligands, such as erythropoietin and growth hormone, the receptor subunits
are bound as homodimers while, for others, such as interferons and interleukins, the
receptor subunits are heteromultimers.
 For signal propagation through either homodimers or heteromultimers, the
cytoplasmic domains of two receptor subunits must be associated with JAK tyrosine
kinases.
 JAKs are distinctive in that they have kinase-homologous domains at the C-terminus.
 The first is a non-catalytic regulatory domain, whereas the second has tyrosine kinase
activity.
 In mammals, the JAK family comprises four members: JAK1, JAK2, JAK 3 and Tyk2.
 JAK activation occurs upon ligand-mediated receptor multimerization because two
JAKs are brought into close proximity, allowing trans-phosphorylation.
Signaling Mechanism
DR. HAROON RIAZ

10.  The activated JAKs subsequently phosphorylate additional targets, including both the
receptors and the major substrates, STATs.
 STATs are transcription factors that reside in the cytoplasm until activated.
 The seven mammalian STATs bear a conserved tyrosine residue near the C-terminus
that is phosphorylated by JAKs.
 This phosphotyrosine permits the dimerization of STATs through interaction with a
conserved SH2 domain.
 Phosphorylated STATs enter the nucleus by a mechanism that is dependent on
importin α-5 (also called nucleoprotein interactor 1) and the Ran nuclear import
pathway.
 Once in the nucleus, dimerized STATs bind specific regulatory sequences to activate or
repress transcription of target genes.
 Thus the JAK/STAT cascade provides a direct mechanism to translate an extracellular
signal into a transcriptional response.
Signaling Mechanism
DR. HAROON RIAZ

11. DR. HAROON RIAZ

12. DR.
HAROON
RIAZ

13. DR.
HAROON
RIAZ

14. DR. HAROON RIAZ

15. DR. HAROON RIAZ

16. DR. HAROON RIAZ

17. DR. HAROON RIAZ

18. DR. HAROON RIAZ

19. DR. HAROON RIAZ
DR. HAROON RIAZ

20. DR.
HAROON
RIAZ

21. DR.
HAROON
RIAZ