intercellular communication intracellular signals gene regulation
DESCRIPTION
Signal transduction: receptor gene. 1. Intercellular communication Intracellular signals Gene regulation. 2. Ligand. 3. Surface receptor. cell. Intracellular receptor. nucleus. Gene. 1- TF activation via signalling cascades 2- TF activation at the receptor - PowerPoint PPT PresentationTRANSCRIPT
Intercellular communication
Intracellular signals
Gene regulation
Ligand
Surfacereceptor
Gene
cell
nucleus
Signal transduction: receptor gene
3
21
1- TF activation via signalling cascades2- TF activation at the receptor3- TF activation by membrane soluble ligands
(TF: transcription factor)
Intracellular receptor
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)
Enzym-domäne
Receptors with enzyme function
Rezeptors with enzyme domains
Rezeptor-Tyrosine kinasesRezeptor-Serine/Threonine kinases Rezeptor-Tyrosine phosphatases Rezeptor-Guanylyl cyklases
Receptors associated with enzymes(direct or via adaptors)
Tyrosine kinasesSerine/Threonine kinasesPhosphatases
Cell membrane
Ligands
EnzymEnzyme
Adaptor
Kinases - Phosphorylation
Phosphatasen - Dephosphorylation
Tyrosine-OH Tyr-Kinases
Serine-OH Ser/Thr-KinasesThreonine-OH
„dual specificity“ Kinases
Families of receptor tyrosine kinases
Surface receptors with enzyme domains
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 Example 1 (vascular endothelial cell growth factor)
Tie-R: function in angiogenesis und vessel formation
Eph-R: triggers angiogenesis, directs cell and axon migration Ephrin receptor
VEGF/VEGFR
Example of growth factor receptor with specific activitz onEndothelial cells (cells of the blood vessel wall)Recptor only (mainly) expressed in endothelial cells
Induces proliferation, filopodia extension, sprouting and aSpecific function of endothelial cells, i.e. tube formation,formation of capillaries
VEGF-R Familievascular endothelial cell growth factor receptor
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 vascularizationand good blood supply for tumordissemination of metastasis via blood and lymph vessels
Blood vessels in the cornea
3 important signalingcascades are induced:
- Ras
- PLC-(Phospholipase C-
- PI3-Kinase(Phosphoinositol 3-Kinase)
Docking of proteins viaSH2 (Src-homology) domainsbind P-Tyr and neighbouring amino acidsInitially described for intracellular tyr-kinase c-Src(Oncogene of Rous Sarcoma Virus)
Grb-2 adaptor: SH2- Domain
SOS is Ras-GEF (guanine nucleotide exchange factor)
Ras: GTP-binding protein (Oncogene detected in rat-sarcoma)
SOS
Ras activates MAP-Kinase pathway:1- MAPKKK2- MAPKK3- MAPK
MAPK: Mitogen-activated Kinase
(there are 3 parallel MAP-Kinase cascades:MEK/ERKP38JNK)
Raf
MEK
ERK
3 important signalingcascades are induced:
- Ras
- PLC-(Phospholipase C-
- PI3-Kinase(Phosphoinositol 3-Kinase)
QuickTime™ and aAnimation decompressor
are needed to see this picture.
PLC- pathway induced by tyrosine kinase receptors
VEGF
PLC- Ca++ gene regulation
PKC
10-7 M
10-3 M
„Second messenger“DAG, IP3 and Ca++
activated PLC-
PKCPhosphorylates many substrates,can activate MAP-kinase pathway,gene regulation
Ca++
Calmodulin/CalcineurinNFAT- transcription factor
PLC- signaling pathway
Ca++
Calmodulin
Calcineurin
NFAT
PI
Ca++ pathway - gene regulation
The phosphatasecalcineurindephosphorylatesNFAT
NFAT translocatesinto the nucleus
NFAT= transcription factor(nuclear factoractivated T cell)
nucleus
P
QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.
gene regulation
proliferationvasculogenesisangiogenesis
Y799
Y820
Y925
Y936
Y951Y994
Y1006
Y1052Y1057
Y1080Y1104
Y1128Y1134
Y1175Y1212Y1221
Y1303Y1307
Y1317
Src (vascular leakage)
TSAd (migration)
PI-3 kinase (survival)
PLC-
VEGFR2
Sakurai et al.PNAS 2005
EC “specific” factors/receptors:
VEGFR1 VEGF-A, PlGF
VEGFR2 VEGF-AVEGFR3 VEGF-C
TIE1TIE2 ANG1,2
VEGF
PIP2
Ca 2+
CAM
IP3- R
End.Ret.
IP3
NFAT
DAG
PKCCa
2+
MEK1/2
ERK1/2
+
CN
VEGF responsive genes
R-TykPLC-
VEGF vs. EGF signaling
Raf
EGR-1P
R-Tyk
EGF
Ras
phosphorylated MAPK ERK is transprted into the nucleus,where it phosphorylates the transcription factor TCF
ERK: extracellular signal regulated kinaseTCF: ternary complex factorSRF: serum response factorSRE: serum response element
(DNA binding sequence for TCF and SRF in promoter of several genes)
genes forcell cycle/proliferation
PKB, PDK:(PDK: PI-dependenmt kinase)
Ser/Thr kinases
PI-3 Kinase Pathway and Survival
Unterlagen:
http://mailbox.univie.ac.at/erhard.hoferStudent point, Vorlesungsunterlagen