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JAK - STAT
Signaling
Behnaz Bazrafshan
P.hD student in Molecular Medicine
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Overview
The name of the JAK comes from a Roman two-faced god that implies two
domains, including a catalytic domain and a kinase-like domain.
l JAK-STAT pathway has an important role in the control of immune
responses
! Dysregulation of JAK-STAT signaling is associated with various immune
disorders
The JAK-STAT signaling pathway transmits information from extracellular
chemical signals to the nucleus resulting in DNA transcription and
expression of genes involved in immunity, proliferation, differentiation,
apoptosis and oncogenesis.
This pathway plays a prominent role in mediating signal transduction for
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JAK binding receptor
Many cytokines and growth factors transmit signals through the JAK-STAT signaling
pathway, including interleukins 2-7 (IL2-7), granulocyte-macrophage colony stimulating
factor (GM-CSF), growth hormone (GH), (Epidermal growth factor (EGF), platelet-derived
growth factors (PDGF) and interferons (IFN).
“ Many’cytokines and growth factor cytokine receptors can be divided into two groups:
thoge whose intracellular domains exhibit intrinsic protein tyrosine kinase (PTK)
tivity, and those whose intracellular domains are devoid of such activity
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Janus kinases (JAKs) represent a recently discovered family of PTKs that seem
to play a central role in mediating signal transduction of many cytokines, and
probably many non-cytokine regulatory molecules.
Have four member : JAK1, JAK2, JAK3 and Tyk2
They all exhibit molecular masses in the region of 130 kDa and approximately
40% amino acid sequence homology.
They appear to be associated with the cytoplasmic domain of many cytokine
receptors, but remain catalytically inactive until binding of the cytokine to the
receptor.
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0 JAKs are mainly regulated at the post-translational level
through various mechanisms
0 The domains JH1-JH7 are based on sequence similarity of four
known JAKs. JH1 is the kinase domain, which contains two
tyrosines that can be phosphorylated after ligand stimulation.
JH2 is the pseudo-kinase domain. The JH6 and JH7 domains
mediate the binding of JAKs to receptors.
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Signal transducer and activator of transcription
(STAT)
| STAT stands for ‘signal transducers and activators of transcription’.
As the name suggests, these proteins (a) form an integral part of
cytoplasmic signal transduction initiated by certain regulatory
molecules and (b) activate transcription of specific genes in the
nucleus. Thus far, at least six distinct mammalian STATs (STAT1-
STAT6) have been identified, in size ranging from 84-113 kDa.
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All STATs exhibit significant sequence homology and are composed of a
number of functional domains (Figure 2). A conserved (‘C’ or ‘con’) domain is
located at the N-terminus, followed by the DNA-binding domain (D). Y
represents a short sequence that contains the tyrosine residue
phosphorylated by the Janus kinase. The carboxyl terminus domain (Tr)
represents a transcriptional activation domain. The SH2 domain functions to
bind phosphotyrosine, thus docking the STAT at the activated receptor
surface. An essential tyrosine is located towards the STAT C-terminus (around
0 0 SH3 SH2 ۷ Tr
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JAK-STAT signaling cascade
In most instances, ligand binding appears to promote receptor dimerization, bringing
their associated JAKs into close proximity. The JAKs then phosphorylate—and hence
activate—each other (transphosphorylation). The activated kinases subsequently
phosphorylate specific tyrosine residues on the receptor itself. This promotes direct
association between one or more members of a family of cytoplasmic proteins (STATs)
and the receptor. Once docked at the receptor surface, the STATs are in turn
phosphorylated (and hence activated) by the JAKs. As described below, activated STATs
en translocate to the nucleus and directly regulate expression of IFN and other
cytok:
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cytoplasm Transcription
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Regulation of JAK-STAT signaling
Signaling through the JAK-STAT pathway is tightly controlled by
a number of distinct mechanisms. Key regulators of this
pathway include suppressors of cytokine signaling (SOCS),
Protein inhibitors of activated STATs (PIASs), and protein
tyrosine phosphatases (PTPs).
0
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