The document summarizes the JAK-STAT signaling pathway. It discusses how the pathway consists of receptors, Janus kinases (JAKs), and Signal Transducers and Activators of Transcription (STATs). When a ligand binds to a receptor, it activates associated JAKs which phosphorylate STATs. Phosphorylated STATs form dimers and translocate to the nucleus to regulate gene transcription. The pathway is negatively regulated by phosphatases, suppressors of cytokine signaling, and protein inhibitors of activated STATs. Experiments using STAT knockout cells and mice have helped elucidate the specific roles and regulation of the pathway.
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The JAK-STAT signalling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through a process called transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), Signal Transducer and Activator of Transcription proteins (STATs), and receptors (which bind the chemical signals).[1] Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
MAPK Signaling pathway (Mitogen-activated protein kinase), how the pathway helps in regulation of mitosis, It's activation and inactivation inside the cell, roles of MAPK pathway in cancerous cell, different classes of MAP kinase in human
Jump to search
The JAK-STAT signalling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through a process called transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), Signal Transducer and Activator of Transcription proteins (STATs), and receptors (which bind the chemical signals).[1] Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
MAPK Signaling pathway (Mitogen-activated protein kinase), how the pathway helps in regulation of mitosis, It's activation and inactivation inside the cell, roles of MAPK pathway in cancerous cell, different classes of MAP kinase in human
Cell cycle and Regulation
* cell Division is occur in every human but these have certaint check point to preventing from the forming the defective cell or cancerious cell.
Cell cycle and Regulation
* cell Division is occur in every human but these have certaint check point to preventing from the forming the defective cell or cancerious cell.
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3. What Is 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.
3
4. 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).
4
5. Mechanism
JAKs, which have tyrosine kinase activity, bind 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
STATs possessing SH2 domains are recruited to the receptors, and are themselves
tyrosine-phosphorylated by JAKs. Activated STAT dimers accumulate in the cell
nucleus and activate transcription of their target genes.
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.
5
6. How Pathway Works.
The receptor is activated by a signal from interferon, interleukin, growth factors, or
other chemical messengers.
6
10. 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.
10
13. 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 .
13
14. The Experiment
An initial example of this type of approach was performed by Schreiber and colleagues who
interrogated gene expression profiles induced by IFN- signalling in the absence of STAT1.
Numerous genes were induced by IFN- in the absence of STAT1, leading to the conclusion that
the IFN- R activates a STAT1-independent gene expression program.
However, inspection of the genes induced by IFN- signalling in STAT1-deficient cells shows
many to be STAT3-regulated genes such as Socs3, Gadd45, and Cebpb.
In the absence of STAT1, STAT3 signalling is dominant.
14
15. Conclusion form the
Experiment
It was concluded from experiments using STAT-deficient cells
that receptor occupancy, or lack of occupancy by the dominant
STAT that binds the receptor, causes a switch from one
activated STAT to another.
15
16. Another Example
A related example is observed when IL-6 signalling is tested in the absence
of SOCS3. SOCS3 is induced by STAT signalling from different cytokine
receptors and functions as a feedback inhibitor of the IL-6R.
However in the absence of SOCS3, STAT3 phosphorylation is greatly
increased. At the same time however, STAT1 phosphorylation is also
induced, leading to a dominant IFN-like gene expression signature.
Although loss of gene expression may be observed in a given STAT
knockout, a corresponding increase in the ectopic activation of another STAT
pathway may confound the interpretation of results in both in vitro and in
vivo systems.
16
17. Is there 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.
Even though both the IL- 10R and IL-6R activate a seemingly identical process, the
downstream readouts of signalling from these receptors are remarkably distinct.
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 activate STAT3 in a SOCS3-
independent way activate the anti inflammatory response.
By contrast, receptors that are regulated by SOCS3 cannot activate the anti-inflammatory
response, such as the IL-6R .However, the IL-6R robustly activates STAT3, even in wild-type
cells where SOCS3 is active .
17
18. Two conclusions can be drawn from
these studies that allude to an unknown
aspect of JAK-STAT signaling:
that receptors generate different pools of
the same activated STAT but have
overlapping yet distinct activities (Fig. 3).
18
19. Facts About 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.
19
20. New Players on the Field—
Recently Identified Cytokines and
Receptors
Interleukin (IL)-21 is a new member of the cytokine subfamily that binds the
common γ chain, γc, and is produced by activated T cells.
(Asao et al. 2001 and Parrish-Novak et al. 2000).
Thymic stromal lymphopoietin is another cytokine that binds the IL-7α chain,
but apparently does not require γc for signaling.
(Pandey et al. 2000 and Park et al. 2000)
Recently a new partner for p40 has been identified, p19. This new cytokine is
denoted IL-23, and it binds IL-12Rβ1 but not IL-12Rβ2.
(Oppmann et al., 2000)
20
21. References
21
Thank You
Sai Ram
The JAK-STAT Signaling Pathway: Input
and Output Integration
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
Journal of Cell Science 117, 1281-1283
Published by The Company of Biologists 2004
doi:10.1242/jcs.00963
Editor's Notes
It acts through the cell membrane, and into gene promoters on the DNA in the cell nucleus.
Many JAK-STAT pathways are expressed in white blood cells, and are therefore involved in regulation of the immune system.
and create sites for interaction with proteins that contain phosphotyrosine-binding SH2 domains.
capable of binding these phosphotyrosine residues
These phosphotyrosines then act as binding sites for SH2 domains of other STATs, mediating their dimerization. Different STATs form hetero- or homodimers.
This activates the kinase function of JAK, which autophosphorylates itself (phosphate groups act as "on" and "off" switches on proteins). The STAT protein then binds to the phosphorylated receptor, where STAT is phosphorylated by JAK. The phosphorylated STAT protein binds to another phosphorylated STAT protein (dimerizes) and translocates into the cell nucleus. In the nucleus, it binds to DNA and promotes transcription of genes responsive to STAT.
More recently identified
by binding and inhibiting JAKs or competing with STATs for phosphotyrosine binding sites on cytokine receptors. STATs are also negatively regulated by
STAT3 phosphorylation is normally induced by IFN- in wild-type cells but
A converse example is the conversion of IL-6R signaling to a dominant STAT1 activation in STAT3- deficient cells (34). This switch causes the downstream induction of the IFN gene expression pathway just as IFN- would cause in wild-type cells.
(and the G-CSFR, LIFR, and leptinR) by binding to phosphorylated Y757 on the gp130 cytoplasmic domain (see below).
Thus SOCS3 regulates both the quantity and type of STAT signal generated from the IL-6R.
.
IL-10-mediated activation of STAT3 targets one or more STAT3- regulated genes whose products are responsible for inhibiting inflammatory gene expression at the level of transcription.
. STAT binds to a DNA sequence called a promoter, which controls the expression of other DNA sequences
Predictably, mutations that reduce JAK/STAT pathway activity affect these processes (reviewed by Igaz et al., 2001; O'Shea et al., 2002). Conversely,
Here we present a general overview of the JAK/STAT pathway and illustrate the primary mechanisms of activation and regulation of this essential signaling cascade.
Here we present a general overview of the JAK/STAT pathway and illustrate the primary mechanisms of activation and regulation of this essential signaling cascade.
New cytokines and receptors are continuing to be identified, and it is likely that there are still a number yet to be characterized.
IL-12 is the product of two genes, which encode subunits designated p35 and p40, the latter having homology to cytokine receptors.
The receptor WSX-1/TCCR has homology to IL-12Rβ2, and its deficiency is associated with deficits in cell-mediated immune responses and IFN-γ production Chen et al. 2000b and Yoshida et al. 2001; this phenotype makes it a possible candidate for an IL-23R subunit.
The IFN family or Type II family of cytokine receptors includes the receptors for IFN-α/β, IFN-γ, IFN-ω, and IL-10. New members of this family include limitin, IL-19, IL-20, IL-22/ IL-TIF, IL-24 (mda-7), and IL-26 (AK155) Blumberg et al. 2001, Takahashi et al. 2001 and Xie et al. 2000. The precise physiologic functions of these new cytokines are uncertain, but this will surely be of interest.