Protein Laboratory, University of Copenhagen

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Signaling pathways that control gene activity
Vladimir Berezin
Protein Laboratory Institute of Molecular
Pathology University of Copenhagen
Protein Laboratory, University of Copenhagen
http//plab.ku.dk/berezin/index.html
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Major receptors classes
1. Trimeric G protein-linked receptors (e.g.
glucagon-, serotonin- adrenalin-receptors)
2. Ion-channel receptors (ligand-gated
ion-channels, e.g. the acetylcholine receptor)
3. Receptors lacking intrinsic catalytic activity
but directly associated with cytosolic protein
tyrosine kinases
4. Receptors with intrinsic enzymatic
activity (e.g. guanylate cyclase activity,
protein phosphatase, serine/threonine kinase or
tyrosine kinase activity)
Protein Laboratory, University of Copenhagen
5. Cell adhesion molecules
6. Intracellular receptors
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Cytokine Receptors
- Cytokines are relatively small, secreted
proteins that control many aspects of growth
and differentiation of specific types of cells
(e.g. prolactin, interleukins, interferons,
granulocyte colony stimulating factor,
erythropoietin or Epo)
Low O2
Kidney cells
HIF-1a
Protein Laboratory, University of Copenhagen
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Cytokine Receptors
JAK-STAT signaling pathway
JAK is an associated tyrosine kinase. Upon
receptor activation, it phospho- rylates several
tyrosine residues on the receptor. An inactive
STAT (transcrip- tion factor) binds the
phosphorylated receptor. It is then
phosphorylated by JAK and dissociates.
Protein Laboratory, University of Copenhagen
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Cytokine Receptors
Binding of an SH2 domain in SHP1 to a particular
phosphotyrosine in the activated receptor unmasks
its phosphatase catalytic site.
Small SOCS proteins inhibit or permanently termina
te signaling over longer time periods.
Protein Laboratory, University of Copenhagen
SOCS expression is induced by estrogens (E) via
ER
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Cytokine Receptors
Cytokine receptors activate multiple signal
transduction pathways
Protein Laboratory, University of Copenhagen
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Major receptors classes
1. Trimeric G protein-linked receptors (e.g.
glucagon-, serotonin- adrenalin-receptors)
2. Ion-channel receptors (ligand-gated
ion-channels, e.g. the acetylcholine receptor)
3. Receptors lacking intrinsic catalytic activity
but directly associated with cytosolic protein
tyrosine kinases
4. Receptors with intrinsic enzymatic
activity (e.g. guanylate cyclase activity,
protein phosphatase, serine/threonine kinase or
tyrosine kinase activity)
Protein Laboratory, University of Copenhagen
5. Cell adhesion molecules
6. Intracellular receptors
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Receptor Ser/Thr Kinases
TGFß superfamily (e.g. bone morphogenic protein
BMP, transforming growth factor ß-1, GDNF family)
Cystine knot
Protein Laboratory, University of Copenhagen
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The cellular responses induced by TGFß vary among
cell types e.g. expression of ECM, PAI-1, p15.
TGFß
TGFß-Smad signaling pathway
Down-regulation of the response to
TGFß stimulation
Sloan-Kettering Cancer Institute
Protein Laboratory, University of Copenhagen
Mutations in Smad2/4 commonly occur in several
types of human tumors resulting in abnormal cell
proliferation and malignancy.
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Major receptors classes
1. Trimeric G protein-linked receptors (e.g.
glucagon-, serotonin- adrenalin-receptors)
2. Ion-channel receptors (ligand-gated
ion-channels, e.g. the acetylcholine receptor)
3. Receptors lacking intrinsic catalytic activity
but directly associated with cytosolic protein
tyrosine kinases
4. Receptors with intrinsic enzymatic
activity (e.g. guanylate cyclase activity,
protein phosphatase, serine/threonine kinase or
tyrosine kinase activity)
Protein Laboratory, University of Copenhagen
5. Cell adhesion molecules
6. Intracellular receptors
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Receptor Tyrosine Kinases (RTK)
Ligand-binding results in receptor dimerization
or activation of a pre- existing dimer.
Protein Laboratory, University of Copenhagen
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Receptor Tyrosine Kinases (RTK)
EGF-receptor signaling
Protein Laboratory, University of Copenhagen
Human carcinomas frequently express high levels
of receptors in the EGF receptor family. In the
last two decades monoclonal antibodies (MAbs)
which block activation of the EGFR and ErbB2 have
been developed. A humanized anti-ErbB2 MAb, is
active and was recently approved in combination
with paclitaxel for the therapy of patients with
metastatic ErbB2 -overexpressing breast cancer.
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RAS
Protein Laboratory, University of Copenhagen
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RAS
Signaling downstream of Ras activation
Protein Laboratory, University of Copenhagen
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MAP Kinase
ERKs activate (directly or indirectly) transcripti
on factors which control transcription of
early-response genes.
Protein Laboratory, University of Copenhagen
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MAP Kinases
There are three MAPK pathways, and their
activation results in phosphorylation of a
variety of transcription factors. There is a
crosstalk at the kinase levels between different
MAPK pathways.
Protein Laboratory, University of Copenhagen
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RTK
RTK can also activate phospholipid kinase PI-3
kinase.
Protein Laboratory, University of Copenhagen
RTK can also activate PLC?.
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Akt/PKB cell survival kinase
Protein Laboratory, University of Copenhagen
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Pathways that involve signal-induced protein
cleavage
The Amyloid-ß hypothesis of Alzheimers disease
Protein Laboratory, University of Copenhagen
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Pathways that involve signal-induced protein
cleavage
A cleaved cytosolic fragment of some receptors
transduces signal to the nucleus thereby altering
gene expression.
Protein Laboratory, University of Copenhagen
Fortini, Nature, 2002
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Main conclusions
Two receptor classes, cytokine receptors and
receptor tyrosine kinases, transduce signals
via their associated or intrinsic protein
kinases. Ligand binding triggers the formation of
functional dimeric receptors and phosphotylation
of the activation lip in the kinases, enhancing
their catalytic activity.
All cytokine receptors are closely associated
with a JAK protein tyrosine kinase, which
can activate several downstream signaling
pathways leading to changes in transcription of
target genes.
Ligand binding leads to activation of intrinsic
protein kinase activity of RTKs
and phosphorylation of tyrosine residues in its
cytosolic domain. RTKs are linked indirectly to
Ras, an intracellular GTPase switch protein which
can activate the MAP kinase enzymatic
cascade, leading to alteration in gene
transcription.
Many RTKs, and cytokine receptors can initiate
the IP3/DAG signaling pathway by
activating phospholipase C?. These receptors can
also initiate other phosphoinositide pathways
by binding PI-3 kinase and subsequently
activating a survival kinase, PKB.
Protein Laboratory, University of Copenhagen
Stimulation by TGFß leads to activation of the
intrinsic serine/threonine kinase
activity, phosphorylation of R-Smad, its
translocation to the nucleus followed by
interaction with various transcription factors.
Some receptors (e.g. Notch) upon ligand binding
undergo proteolysis with the release of cytosolic
segments that regulate gene transcription.