The JAK-STAT signaling pathway transmits signals from extracellular chemicals to the nucleus, activating transcription of target genes. It consists of a cell surface receptor, associated Janus kinases (JAKs), and signal transducers and activators of transcription (STATs). When a ligand binds the receptor, JAKs phosphorylate STATs, which form dimers and translocate to the nucleus to regulate gene expression. The Ras/MAPK pathway similarly relays signals from cell surface receptors via Ras, Raf, MEK, and MAPK proteins to influence transcription. Both pathways are tightly regulated and important for processes like cell growth, differentiation, and apoptosis, with dysregulation contributing to diseases.

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2.  ProteinTyrosine Kinase, of which there are about
90 in human genome, phosphorylate specific
tyrosine residues on target proteins that can
then activate one or more signalling pathways.
 There are two large and important classes of
cell-surface-receptors that activate protein
tyrosine kinase are:
1. ReceptorTyrosine kinases (RTKs)
2. Cytokine receptor (JAK Kinase)
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3.  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.
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4.  (1) a receptor
 (2) Janus kinase (JAK) and
 (3) Signal Transducer and Activator of
Transcription (STAT).
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5.  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.
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8.  The receptor is activated by a signal from interferon, interleukin, growth factors, or other
chemical messengers.
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Regulatory molecule that bind to receptors
linked to JAK.

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11.  The pathway is negatively regulated on multiple levels. Protein tyrosine
phosphatases remove phosphates from cytokine receptors and activated
STATs.
 SHP1, a protein tyrosine phosphatase, is present in an inactive form in
unstimulated cells. Binding of an SH2 domain in SHP1 to a particular
phosphotyrosine in the activated receptor unmasks its phosphatase catalytic
site . Removal of the phosphate from this tyrosine inactivates the JAK kinase.
 SOCS proteins, whose expression is induced in erythropoietin-stimulated
erythroid cells, inhibit or permanently terminate signaling over longer time
periods. Binding of SOCS to phosphotyrosine residues blocks binding of other
signaling proteins.
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13.  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.
 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.
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14.  Ras is a monomeric, GTP-binding switch protein.
 Ras alternates between an inactive state with bound
GDP and an active state with bound GTP.
 Ras is not directly linked to cell-surface receptors.
 Ras is anchored to the plasma membrane by a
hydrophobic anchor.
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15.  Ras acts as a binary signal switch cycling between ON and OFF states,
which are characterized in terms of a small molecule, a guanine
nucleotide, bound to the protein.
 In the resting cell, Ras is tightly bound to GDP which is exchanged
with GTP upon binding of extracellular stimuli to cell membrane
receptors.
 In the GTP-bound form, Ras interacts specifically with so-called
effector proteins, thereby initiating cascades of protein-protein
interactions that may finally lead to cell proliferation.
 To return to the inactive OFF state, Ras cleaves off the terminal
phosphate moeity, the intrinsic GTPase reaction.The remaining GDP-
bound Ras is no longer able to interact with effectors, it is switched
OFF.
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17.  MAP kinase pathway is activated:
 Ras activates Raf protein, a serine/ threonine
kinase, by binding to it.
 Hydrolysis of RasGTP causes the release of active
Raf.
 Raf activates MEK, another kinase.
 MEK activates MAP Kinase (MAPK).
 MAPK translocates to the nucleus , causing
induction of gene transcription.

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The JAK-STATSignaling 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
Molecular Cell Research Volume 1773, 1177- 1193,
Ras Oncogenes and their downstream Krishnaraj
Rajalingam, Ralf Schreck, Ulf R. Rapp Stefan Albert.
Molecular Cell Biology By Lodish et. al.

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