Download Receptor tyrosine kinases

Signal transduction: receptor
gene
1
Intercellular communication
2
Ligand
3
Surface
receptor
Intracellular signals
cell
Intracellular
receptor
nucleus
Gene regulation
Gene
1- TF activation via signalling cascades
2- TF activation at the receptor
3- TF activation by membrane soluble ligands
(TF: transcription factor)
Receptor Tyr-Kinases:
VEGFRs, Tie-Rs, EphRs (neovascularization)
Receptor Ser/Thr-Kinasen:
TGF-betaRs (growth inhibition,
pleiotropic effects)
Rezeptor-Guanylylcyclases:
ANP-R (Salt- und water balance, relaxation)
Trimeric Receptors:
TNFRs (inflammation, apoptosis)
Receptors with signalling cascades including
Proteolytic cleavages:
WNT-R (embryonal development, adult stem cells)
Receptors with enzyme function
Ligands
Rezeptors with enzyme domains
Rezeptor-Tyrosine kinases
Rezeptor-Serine/Threonine kinases
Rezeptor-Tyrosine phosphatases
Rezeptor-Guanylyl cyklases
Cell membrane
Receptors associated with enzymes
(direct or via adaptors)
Tyrosine kinases
Serine/Threonine kinases
Phosphatases
Enzym
EnzymEnzyme
domäne
Adaptor
Kinases - Phosphorylation
Phosphatasen - Dephosphorylation
Tyrosine-OH
Tyr-Kinases
Serine-OH
Threonine-OH
Ser/Thr-Kinases
„dual specificity“ Kinases
Surface receptors with enzyme domains
Families of receptor tyrosine kinases
Receptor tyrosine kinases:
(Receptors for growth, differentiation factors and a peptide hormone)
EGF-R: triggers proliferation of many different cell types
(epidermal growth factor receptor)
Insulin-R: triggers carbohydrate metabolism, protein synthesis
IGF-R: triggers growth and survival
(insulin-like growth factor receptor)
NGF-R:
triggers survival and growth of neurons
(nerve growth factor receptor)
PDGF-R:
triggers survival, growth, proliferation of different cell types
(platelet-derived growth factor receptor),
M-CSF-R: triggers proliferation and differentiation of monocytes/macrophages
(macrophage colony stimulating factor receptor)
FGF-R: triggers proliferation of different cell types, triggering signal in
(fibroblast growth factor receptor)
embryonal development
VEGF-R: triggers Angiogenesis
(vascular endothelial cell growth factor)
Tie-R: function in angiogenesis und vessel formation
Eph-R: triggers angiogenesis, directs cell and axon migration
Ephrin receptor
Example 1
VEGF/VEGFR
Example of growth factor receptor with specific activitz on
Endothelial cells (cells of the blood vessel wall)
Recptor only (mainly) expressed in endothelial cells
Induces proliferation, filopodia extension, sprouting and a
Specific function of endothelial cells, i.e. tube formation,
formation of capillaries
VEGF-R Familie
vascular endothelial cell
growth factor receptor
Blood vessels in the cornea
VEGFs and VEGF-Rs are important for angiogenesis
(blood vessel formation by sprouting from existing vessels)
and lymphangiogenesis (lymph vessel formation)
Important for wound healing
Tumor angiogenesis:
many tumors produce VEGF, leads to high vascularization
and good blood supply for tumor
dissemination of metastasis via blood and lymph vessels
3 important signaling
cascades are induced:
- Ras
- PLC-g
(Phospholipase C- g)
- PI3-Kinase
(Phosphoinositol 3-Kinase)
Docking of proteins via
SH2 (Src-homology) domains
bind P-Tyr and neighbouring amino acids
Initially described for intracellular tyr-kinase c-Src
(Oncogene of Rous Sarcoma Virus)
SOS
Grb-2 adaptor: SH2- Domain
SOS is Ras-GEF (guanine nucleotide exchange factor)
Ras: GTP-binding protein
(Oncogene detected in rat-sarcoma)
Raf
MEK
ERK
Ras activates
MAP-Kinase
pathway:
1- MAPKKK
2- MAPKK
3- MAPK
MAPK:
Mitogen-activated
Kinase
(there are 3 parallel
MAP-Kinase cascades:
MEK/ERK
P38
JNK)
3 important signaling
cascades are induced:
- Ras
- PLC-g
(Phospholipase C- g)
- PI3-Kinase
(Phosphoinositol 3-Kinase)
PLC-g pathway induced by tyrosine kinase receptors
VEGF
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Animation decompressor
are needed to see this picture.
PLC-g
Ca++
gene regulation
PKC
„Second messenger“
DAG, IP3
and
Ca++
10-3 M
10-7 M
PLC-g signaling pathway
activated PLC-g
PKC
Phosphorylates
many substrates,
can activate
MAP-kinase
pathway,
gene regulation
Ca++
Calmodulin/
Calcineurin
NFAT- transcription factor
Ca++ pathway - gene regulation
The phosphatase
calcineurin
dephosphorylates
NFAT
NFAT translocates
into the nucleus
P
I
Ca++
NFAT
Calmodulin
Calcineurin
P
NFAT= transcription factor
(nuclear factor
activated T cell)
nucleus
QuickTime™ and a
Sorenson Video 3 decompressor
are needed to see this picture.
EC “specific” factors/receptors:
VEGFR2
VEGFR1
VEGF-A, PlGF
VEGFR2
VEGF-A
VEGFR3
TIE1
TIE2
VEGF-C
Y799
ANG1,2
Y820
Src (vascular leakage)
Y925
Y936
Y951
TSAd (migration)
Y994
Y1006
Y1052
Y1057
PI-3 kinase (survival)
Y1080
Y1104
gene regulation
Y1128
Y1134
Y1175
Y1212
Y1221
Y1303
Y1307
Y1317
PLC-g
proliferation
vasculogenesis
angiogenesis
Sakurai et al.
PNAS 2005
VEGF vs. EGF signaling
PIP2
IP
VEGF
EGF
R-Tyk
R-Tyk
PLC-g
3
IP - R
3
Ras
DAG
End.Ret.
Ca
2+
PKC
2+
Ca
Raf
CAM
MEK1/2
CN
ERK1/2
NFAT
+
P
EGR-1
VEGF responsive genes
phosphorylated MAPK ERK is transprted into the nucleus,
where it phosphorylates the transcription factor TCF
ERK: extracellular signal regulated kinase
TCF: ternary complex factor
SRF: serum response factor
SRE: serum response element
(DNA binding sequence for TCF and SRF
in promoter of several genes)
genes for
cell cycle/
proliferation
PI-3 Kinase Pathway and Survival
PKB, PDK:
(PDK: PI-dependenmt kinase)
Ser/Thr kinases
Unterlagen:
http://mailbox.univie.ac.at/erhard.hofer
Student point, Vorlesungsunterlagen
[email protected]