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Prof. D. Karunagaran
Department of Biotechnology
Module 7
Cell Signaling Mechanisms
Lecture 10
JAK-STAT Signaling
1
The Janus kinase/signal transducers and activators of transcription (JAK/STAT)
pathway has important roles in immune functions, neuronal, hematopoietic and
embryonal development
Often acts locally, on cells of the same or similar type as the cytokine-producing
cells
JAK
JAK family of tyrosine kinases has four members, JAK1-3 and tyrosine kinase 2
(TYK2)
All members possess conserved kinase domain and catalytically inactive
pseudokinase domain at the C-terminus, regulating kinase activity of JAKs
2
JAK-STAT Signaling
Cytokine activates JAK, JH1 kinase domain contains two tyrosines which get
phosphorylated
JH2 is pseudo domain
JH6 and 7 mediate binding of JAK to the receptors
Results in phosphorylation of STATs
STATs dimerize and translocate to nucleus and initiate transcription
3
Regulation of JAKs
4
Regulation of STATs
5
JAK-STAT deregulation in immune diseases
In SCID patients, various mutations have been detected in JAK3 that is required
for signaling by cytokines like IL-2, 4, 7 etc.
In Asthma patients increase in levels of STAT6, required for IL-4 signaling and
TH2 cell responses
During allergic immune disease like dermatitis and asthma, SOCS3 is involved in
onset and maintenance of TH2 cells
During infection, virus can evade host immune system by inactivating IFN
activated JAK-STAT pathway
Paramyxovirus family of RNA viruses target STATs for degradation
Epstein-Barr viruses inhibit IFN receptor expression
Human cytomegalovirus inhibits IFN- induced expression of MHC-II by
degrading JAK1
Varicella-Zoster virus inhibits STAT1 and JAK2 expression
Individuals with defects in IFN-JAK-STAT pathway show increased susceptibility
to viruses and intracellular bacteria
STAT3 deficient mice show Crohns disease, a chronic inflammatory bowel
disease like symptoms. STAT3 deregulation was observed in patients with this
disease
6
JAK-STAT inhibitors
Study Questions
Cryptotanshinone STAT5
1, 2, 3, 4, 5, 6-Hexabromocyclohexane peptide
PpYLKTK-mts JAK
N-((4-Oxo-4H-chromen-3- STAT3
yl)methylene) nicotinohydrazide