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Robert answered on
Dec 26 2021
Signal Transduction Pathway in JAK-STAT Signalling Operating through
Cytokine Recepto
The cytokine receptors refer to the glycoproteins found on the surface of the cell and bind to
the specific cytokines for signal transduction. The pathways of signal transduction that are
triggered by these receptors help in communication of the cells with the extracellular
environment. Janus kinases (JAKs) are a family of tyrosine kinases that mediate the
hematopoietic cytokine receptor signalling along with the signal transducers and activators of
transcription (STATs). The JAK family is composed of four members, i.e. JAK1, JAK2,
JAK3 and JAK4.
The JAK-STAT signalling pathway plays a major role in expression of the genes that are
involved in various functions in the body like apoptosis, proliferation, immunity, oncogenesis
and differentiation. This is achieved by transmitting information to the nucleus from the
chemical signals located outside the cell eventually leading to the transcription of
deoxyribonucleic acid (DNA). There are three major components involved in the signalling
pathway of JAK-STAT, i.e. two STATs and a JAK.
The dimerization of the cytokines is induced by the binding of ligand at the receptors in
cytokine. The SH2 domains of the JAKs bind to the receptor causing trans-phosphorylation
of the JAKs and eventually causing phosphorylation of STATs. This is followed by the
dimerization and translocation of the activated STATs to the nucleus. As soon as, the
activated STATs reach the nucleus, they initiate the transcription of the target gene. The other
activators of STATs include non-receptor tyrosine kinases including c-src and epidermal
growth factor receptor (receptor tyrosine kinases). The complex formed when the JAK binds
at the cytokine receptor is considered as receptor tyrosine kinase composed of two
components of which one component (JAK) mediates the kinase function while the other
component (receptor) regulate high affinity interactions with the extracellular cytokines;
thereby, controlling the specificity of the interactions. There are specific sequences in the
DNA at which the STAT complexes bind and activate the process of transcription. The STAT
proteins contain seven domains, i.e. C-terminal transactivation domain, tyrosine activation
domain, SH2 domain, DNA-binding domain, coiled-coil domain, linker domain and N-
terminal domain of which the cooperation between the DNA binding domain and N-terminal
domain
ings about the binding of STAT proteins with the target genes.
There are multiple conformational changes that occur as soon as the cytokine binds at the
cytokine receptors including oligomerization and dimerization which changes the orientation
of the components of receptor before assembling. This causes the activation of kinase by
inging the JAKs associated with the cytokine receptors in the proper orientation and
proximity. The process of transphosphorylation enhances the activity of JAKs very strongly.
During this process, one residue of key tyrosine located in the opposite domain of JAK kinase
is phosphorylated by one molecule of JAK which in turn triggers a change in the structure of
the JAK kinase domain; thereby, enhancing the function of tyrosine kinase by providing an
open configuration. There are multiple tyrosine residues (including those that serve as the
docking sites for STATs) located on different substrate molecules, all of which are
phosphorylated by the activated JAKs.
The cytoplasm of the cells that are un-stimulated contains the STATS. As soon as the
cytokine receptors are engaged and there is activation of JAKs, the phosphorylated tyrosine
esidues located on the intracellular region of cytokine receptors binds to the STATs through
SH2 domains. A very important tyrosine residue which is located in the ca
oxy-terminal of
the STATs is phosphorylated when STATs is in proximity to the JAKs; thereby, triggering
the process of dimerization via reciprocal phosphotyrosine:SH2 interactions. This leads to the
accumulation of dimerized STATs in the nucleus of the cell where these proteins regulate the
gene expression either by repressing or inducing the process of transcription.
There are certain points in the JAK-STAT signal transduction pathway that provides
specificity to this signalling process that include selective recruitment of STAT to the
activated receptors, preferences of the certain JAKs for the cytokine receptors, transcriptional
esponses that are dependent on unique STATs and specific cooperation with the cell type
cofactors. The JAK/STAT pathway of signal transduction from cytokine receptors is
particularly important for the cellular responses produced in the immune system,
hematopoietic system and some other important cell systems. Any defect in this pathway can
cause several human diseases like benign erythrocytosis, severe combined
immunodeficiency, severe congenital neutropenia and atopic disease.
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