Transcript Prezentace aplikace PowerPoint

CYTOKINE RECEPTORS
AND SIGNAL
TRANSDUCTION
Survival factor
(eg. IGF-1)
Chemokines
Hormones
Transmitters
(e.g. Interleukins
serotonin etc.)
Growth factors
(eg TGFa)
Extracellular
matrix
Wnt
Hedgehog
Cytokines
Death factors
(eg TNF)
What is Cytokine?
Secreted polypeptide or low molecular weight
protein involved in cell-to-cell signaling.

Acts in paracrine or autocrine fashion through
specific cellular receptors.

Can be produced by cells of any tissue and act on
many cells involved in immune and inflammatory
response.

Cytokines, like hormones, can
act in autocrine, paracrine, or
endocrine fashion
Cytokine nomenclature

Lymfokines - produced by activated T lymphocytes direct
the immune system response by signaling between its cells

Interleukins - presumed targets are principally
leukocytes.

Chemokines - specific class of cytokines. Mediates
chemoattraction (chemotaxis) between cells, stimulate
leukocyte movement and regulate the migration of leukocytes
from the blood to tissues.

Monokines - derived primarily from mononuclear cells such
as macrophages.
Cytokines: main functions

Hematopoiesis (ex. CSFs, colony stimulating factors).

Inflammatory reaction (ex. IL1, TNF).

Chemotaxis (ex. IL8, MIP1- macrophage inflammatory protein 1,
BLC – B-lymphocyte chemoatractant).
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Immunostimulation (ex. IL12, IFNg).
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Suppression (ex. IL10).
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Angiogenesis (ex. VEGFs - vacsular endothelial growth factor).
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Embryogenesis (ex. TGF-b, LT - lymphotoxin).
Classification
Type I cytokine receptor or hematopoietin receptor
family : IL 2, IL 3, IL 4, IL 5, IL 6, IL7, IL 9, IL 13, IL 15, GMCSF (Granulocyte-Macrophage Colony-Stimulating Factor)
and G-CSF (Granulocyte-Colony Stimulation Factor)


Type II cytokine receptors or interferon receptors
Transforming growth factor receptor
 Tumor necrosis factor receptor
 Immunoglobulin superfamily (IgSF)
 Chemokine receptors (seven transmembrane helix)

Type I cytokine receptor
Transmembrane receptors
expressed on the surface of
cells.
These receptors are also
known under the name
hematopoetin receptors,
and share a Trp-Ser-X-SerTrp motif (WSXWS) in the
extracellular portion
adjacent to the cell
membrane.
Common g chain
The g chain (green), common to all, mediates
intracellular signaling.
Signaling through cytokine receptor
Phosphorylation through kinases:

The addition of a phosphate molecule to a polar Rgroup of Tyr can turn a hydrophobic portion of protein
into a polar and extreme hydrophilic portion of
molecule.
– Kinase is a type of enzyme that transfers phosphate group
(PO4) from high-energy donor molecules, such as ATP to
specific target molecules (substrates).
– The opposite, an enzyme that removes phosphate groups
from targets, is known as a phosphatase.
– Kinase enzymes that specifically phosphorylate tyrosine
amino acids are termed tyrosine kinases.
Signaling through cytokine receptor
The ligand-activated receptor (R) attracts a Janus (JAK) kinase (K). K phosphorylates both
itself and the receptor. A Signal Transducer and Activator of Transkription (STAT) protein (S)
binds to tyrosine-phosphorylated receptor-kinase complex. After being phosphorylated by
JAK, the STATs form active dimers that translocate into the nucleus to regulate transkription.
Type II cytokine receptors
Interferons (IFN)

Protein hormones with antiviral activity.

Secrete by cells in a response to variety of stimuli.

Type I and type II IFN and IFN-like cytokines.

Effects are mediated through cell receptors.
IFN activate cellular signalling pathway (gene induction or
repression).
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Type I IFNs consist of seven classes:
IFN-a, IFN-b, IFN-e, IFN-w, IFN-d, IFN-k and
IFN-t
Type I IFNs are major components of the innate immune
system.
 Protect against viral infection.
 The expression of type I IFNs is induced by viral
challenge.

Type II IFN consist of IFN-g only.

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IFN-g (immune interferon) is produced by certain
activated T-cells and NK cells.
IFN-g is made in response to antigen (including viral
antigens) or mitogen stimulation of lymphocytes.
Type I IFNs

Produced by macrophages, neutrophils and other
somatic cells in response to infection by viruses or bacteria.
 Inducer is double strand RNA provided by viral genom
itself.
 Receptors are expressed on most cell types.
IFN-g

IFN-g is produced in activated TH1 and NK cells,
particularly in response to IL-2 and IL-12.
 Binding of IFN-g to its receptor increases the expression
of class I MHC on all somatic cells.
 IFN-g may also activate macrophages, neutrophils and
NK cells.
Function of IFNs:
Initiation and regulation of
variety responses
 antiviral

antiproliferative activity (ability
to arrest cell growth) – treatment
for cancer

control of apoptosis

immunomodulatory (INF-g
predominantly modulates
immune response, main antiviral
cytokine).
http://www.virtualsciencefair.org/2007/sank7b2/fig1b.jpg
IFN-g receptor

Expression of on the surface almost of all cell types.
High affinity receptors are located in the T- and
B-lymphocytes, NK-cells, monocytes, macrophages,
neutrophiles, fibroblasts, endotelial cells and smooth
muscle cells.

Receptor is expressed only in response to stimulus
by antigen, only in cells of lymphoid origin (NK cells,
macrophages, and some T cells).
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IFN-g receptor has two components:
gR1 and gR2
IFN-gR1 - 90 kDa glycoprotein (472 amino acid
residues)
Extracellular domain – 228 amino acid residues
Transmembrane domain – 24 amino acid residues
Intracellular domain – 220 amino acid residues
IFN- gR2 - 62 kDa glycoprotein (315 amino acid
residues)
Extracellular domain – 226 amino acid residues
Transmembrane domain – 23 amino acid residues
Intracellular domain – 65 amino acid residues.
Ligand binds to extracellular domain of IFN-gR1 only
(in absence of IFN-gR1, IFN-gR2 cannot bind IFN g)
Signal transduction is carried out through a series of
tyrosine phosphorylation events and culminates with the
activation and nuclear translocation of STAT protein and
new mRNA synthesis is induced.
Jak proteins are brought into close
after ligand-receptor complex
formation.
 Transphosphorylation between Jak1
and Jak2 proteins (Jak2 phosphorylates
Jak1, Jak1 transphosphorylates Jak2).
 phosphorylation of IFN-gR1 (Tyr
440).
 Binding of STAT1 protein to each
IFN-gR1.
 Bound STAT1 is phosphorylated by
Jak.
 Dissociation of dimer from the
receptor and formed dimer translocates
to the nucleus.
 Induction of transcription of many
genes.
IFN a/b receptor

IFN-aR1 - 530 amino acid residues
(409 residues of protein are extracellular,
100 residues are intracellular.

IFN-aR2 - 217 AA residues in
extracellular space, 251 AA residues in
intracellular space.

Both components bind type-IFNs
cooperatively.
 Receptor has ability to bind multiple
ligands (all subspecies of IFN-a and IFNb and other types of IFN-type I).
 Interferon ligand is boud to IFN-aR1
and than to IFN-aR2 which stabilizes the
complex.
Signal transduction goes through Jak/STAT pathway.
Involves two different ligand binding proteins (kinases)
Tyk2 and Jak1.
Tyk2 associates with IFN-aR1
Jak1, STAT1 and STAT2 associate with
IFN-aR2.

Jak1 transphosphorylates Tyk2 (1). Tyk2
in turn phosphorylates Jak1 and IFN-aR1
(2).
 Phosphorylation of IFN-aR1 allows
STAT2 to bind to IFN-aR2.
 STAT2 phoshorylates STAT1.
 STAT1-STAT2 complex dissociates from
receptor.
 Dimer STAT1-STAT2 associates with
interferon regulatory factor to form the
transcription complex.
Effect of signalling through IFN-g receptor
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Induces inflammatory reaction.
Induces antibacterial effect (activation of neutrophils, NK
cells and macrophages, increased their ability to recognize, kill,
and digest foreign materials or microbes).
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Normal expression of is important in preventing the
development of cancer.

Effect of signalling through IFN-a/b receptor
Antiviral defence (protects the cell from viral replication).
Immunoglobulin superfamily (IgSF)
The immunoglobulin superfamily (IgSF)
- a large group of cell surface and soluble
proteins that are involved in the recognition,
binding, or adhesion processes of cells.

Molecules are categorized as members of
this superfamily based on shared structural
features with immunoglobulins (antibodies);
they all possess a domain known as an
immunoglobulin domain or fold.

Associated with roles in the immune
system.
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Tumor Necrosis Factor receptor
Cysteine-rich common extracellular
binding domain
Chemokine receptor
Typical structure of a chemokine receptor,
with seven transmembrane domains.
Chemokine receptors are usually linked to a
G-protein through which they signal.
Interaction with their specific chemokine
ligand, chemokine receptors trigger a flux in
intracellular calcium (Ca2+) ions (calcium
signaling) and cause cell response
(chemotaxis).
http://en.wikipedia.org/wiki/Chemokine_receptor
Transforming Growth Factor Receptor
After ligand binding, (PDGFR or
EGFR receptor tyrosine kinases (RTKs)
dimerize, undergo autophosphorylation
(P) and recruit adaptor proteins (such
as GRB2 and SHC) that activate
various downstream effectors.

RAS is an important downstream
effector and functions as a molecular
switch by cycling between the active
GTP-bound form and the inactive GDPbound form. RAS activity is regulated
positively by guanosine exchange
factors (GEFs), such as SOS, and
negatively by GTPase-activating
proteins (GAPs).

At least three downstream effectors
can be activated by RAS. The RAFmediated signalling cascade.

www.nature.com/.../v2/n8/fig_tab/nrc866_F3.html
The End
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