Intercellular communication Intracellular signals Gene regulation
description
Transcript of Intercellular communication Intracellular signals Gene regulation
![Page 1: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/1.jpg)
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
![Page 2: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/2.jpg)
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)
![Page 3: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/3.jpg)
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
![Page 4: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/4.jpg)
Kinases - Phosphorylation
Phosphatasen - Dephosphorylation
Tyrosine-OH Tyr-Kinases
Serine-OH Ser/Thr-KinasesThreonine-OH
„dual specificity“ Kinases
![Page 5: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/5.jpg)
Families of receptor tyrosine kinases
Surface receptors with enzyme domains
![Page 6: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/6.jpg)
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
![Page 7: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/7.jpg)
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
![Page 8: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/8.jpg)
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
![Page 9: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/9.jpg)
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)
![Page 10: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/10.jpg)
Grb-2 adaptor: SH2- Domain
SOS is Ras-GEF (guanine nucleotide exchange factor)
Ras: GTP-binding protein (Oncogene detected in rat-sarcoma)
SOS
![Page 11: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/11.jpg)
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
![Page 12: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/12.jpg)
3 important signalingcascades are induced:
- Ras
- PLC-(Phospholipase C-
- PI3-Kinase(Phosphoinositol 3-Kinase)
![Page 13: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/13.jpg)
QuickTime™ and aAnimation decompressor
are needed to see this picture.
PLC- pathway induced by tyrosine kinase receptors
VEGF
PLC- Ca++ gene regulation
PKC
![Page 14: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/14.jpg)
10-7 M
10-3 M
„Second messenger“DAG, IP3 and Ca++
![Page 15: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/15.jpg)
activated PLC-
PKCPhosphorylates many substrates,can activate MAP-kinase pathway,gene regulation
Ca++
Calmodulin/CalcineurinNFAT- transcription factor
PLC- signaling pathway
![Page 16: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/16.jpg)
Ca++
Calmodulin
Calcineurin
NFAT
PI
Ca++ pathway - gene regulation
The phosphatasecalcineurindephosphorylatesNFAT
NFAT translocatesinto the nucleus
NFAT= transcription factor(nuclear factoractivated T cell)
nucleus
P
![Page 17: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/17.jpg)
QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.
![Page 18: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/18.jpg)
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
![Page 19: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/19.jpg)
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
![Page 20: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/20.jpg)
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
![Page 21: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/21.jpg)
PKB, PDK:(PDK: PI-dependenmt kinase)
Ser/Thr kinases
PI-3 Kinase Pathway and Survival
![Page 22: Intercellular communication Intracellular signals Gene regulation](https://reader031.fdocuments.us/reader031/viewer/2022020308/56814474550346895db109dd/html5/thumbnails/22.jpg)
Unterlagen:
http://mailbox.univie.ac.at/erhard.hoferStudent point, Vorlesungsunterlagen