SIGNAL TRANSDUCTION 2) From the cell membrane to the nucleus · SIGNAL TRANSDUCTION . 2) From the...
Transcript of SIGNAL TRANSDUCTION 2) From the cell membrane to the nucleus · SIGNAL TRANSDUCTION . 2) From the...
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SIGNAL TRANSDUCTION 2) From the cell membrane to the
nucleus
Part B
1-TM RECEPTORS AND ASSOCIATED SIGNALLING CASCADES
Erhard Hofer Department of Vascular Biology and Thrombosis Research
Vienna Competence Center, Lazarettgasse 19, A-1090 Wien
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Intercellular communication Intracellular signals Gene regulation
Ligand
Surface receptor
Gene
cell
nucleus
Signal transduction: receptor gene
3
2 1
1- TF activation via signalling cascades 2- TF activation at the receptor 3- TF activation by membrane soluble ligands (TF: transcription factor)
Intracellular receptor
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Receptor Tyr-Kinases: VEGFRs, Tie-Rs, EphRs (neovascularization) - example 1 Receptor Ser/Thr-Kinasen: TGF-betaRs (growth inhibition, - example 2 pleiotropic effects) Rezeptor-Guanylylcyclases: ANP-R (Salt- und water balance, relaxation) Receptors with signalling cascades including proteolytic cleavages: TNFRs (inflammation, apoptosis) WNT-R (embryonal development, adult stem cells)
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Enzym- domäne
Receptors with enzyme function Receptors with enzyme domains Receptor-Tyrosine kinases Receptor-Serine/Threonine kinases Receptor-Tyrosine phosphatases Receptor-Guanylyl cyclases
Receptors associated with enzymes (direct or via adaptors) Tyrosine kinases Serine/Threonine kinases Phosphatases
Cell membrane
Ligands
Enzym Enzyme
Adaptor
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Kinases - Phosphorylation Phosphatasen - Dephosphorylation Tyrosine-OH Tyr-Kinases Serine-OH Ser/Thr-Kinases Threonine-OH „dual specificity“ Kinases
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Families of receptor tyrosine kinases
Surface receptors with enzyme domains
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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
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VEGF/VEGFR Example of growth factor receptor with specific activity on endothelial cells (cells of the blood vessel wall); Receptor 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
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VEGF-R Family vascular 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 vascularization and good blood supply for tumor; dissemination of metastasis via blood and lymph vessels
Blood vessels in the cornea
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3 important signaling cascades are induced: („text book“ picture) - Ras - PLC-γ (Phospholipase C- γ) - 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)
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Grb-2 adaptor: SH2- Domain SOS is Ras-GEF (guanine nucleotide exchange factor) Ras: GTP-binding protein (Oncogene detected in rat-sarcoma)
SOS
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Ras activates MAP-Kinase pathway: 1- MAPKKK 2- MAPKK 3- MAPK MAPK: Mitogen-activated kinase (there are 3 main parallel MAP-Kinase cascades: MEK/ERK, P38, JNK)
Raf MEK ERK
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3 important signaling cascades are induced: - Ras - PLC-γ (Phospholipase C- γ) - PI3-Kinase (Phosphoinositol 3-Kinase)
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10-7 M
10-3 M
„Second messenger“ DAG, IP3 and Ca++
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activated PLC-γ
PKC Phosphorylates many substrates, can activate MAP-kinase pathway, gene regulation
Ca++ Calmodulin/ Calcineurin NFAT- transcription factor
PLC-γ signaling pathway
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Ca++
Calmodulin
Calcineurin
NFAT
P I
Ca++ pathway - gene regulation The phosphatase calcineurin dephosphorylates NFAT NFAT translocates into the nucleus NFAT= transcription factor (nuclear factor activated T cell)
nucleus
P
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gene regulation proliferation vasculogenesis angiogenesis
Y799 Y820
Y925 Y936
Y951 Y994
Y1006
Y1052 Y1057 Y1080 Y1104 Y1128 Y1134
Y1175 Y1212 Y1221 Y1303 Y1307 Y1317
Src (vascular leakage) TSAd (migration) PI-3 kinase (survival) PLC-γ
VEGFR2
Sakurai et al. PNAS 2005
EC “specific” factors/receptors: VEGFR1 VEGF-A, PlGF VEGFR2 VEGF-A VEGFR3 VEGF-C TIE1 TIE2 ANG1,2
“real life” picture: VEGFR2 has 19 tyr in cytoplasmic domain, at least one third can get phosphorylated, bind different SH2-domain proteins with different affinities, e.g. Y1175 preferentially binds PLC-γ and is essential for proliferation and angiogenesis
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VEGF
PIP 2
Ca 2+
CAM
IP 3 - R
End.Ret.
IP 3
NFAT
DAG
PKC
This image cannot currently be displayed.
Ca 2+
MEK1/2
ERK1/2
+
CN
VEGF responsive genes
R-Tyk PLC-γ
VEGF vs. EGF signaling
Raf
EGR-1 P
R-Tyk
EGF
Ras
Different tyr kinase receptors activate signalling cascades differentially, e.g. VEGFR activates preferentially PLC-γ, EGFR the Ras pathway
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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
or: PLC-γ Raf MEK
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PKB, PDK:
(PKB: protein kinas B or AKT; PDK: PI-dependent kinase)
Ser/Thr kinases
PI-3 Kinase Pathway and Survival
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1- what is angiogenesis, vasculogenesis 2- receptors important for angiogenesis Ad1) Angiogenesis Formation of capillaries by sprouting from fully differentiated endothelial cells of the vessel wall
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A small artery: connective tissue, smooth muscle cells basal lamina monocellular layer of endothelial cells
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Structure of a capillary: Endothelial cells and basal lamina, pericytes
Towards the end of a capillary a single endothelial cell can form a tube
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“sprouting angiogenesis” Sprouting of endothelial cells from differentiated endothelial cells of the vessel wall
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Wounding induces growth of capillaries: Mouse cornea chemotactic response to angiogenic factors
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Every cell has to be in a distance of 50 to 100 µm of a capillary Endothelial cells respond to signals from tissue Hypoxia HIF: hypoxia inducible factor VEGF: vascular endothelial growth factor
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Vasculogenesis
Formation of blood vessels by differentiation from (hem)angioblasts Differentiation and proliferation of EC within a non-vascularized tissue Fromation of a primitive tubular network Angiogenic remodeling to form vascular network
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Hemangioblast Angioblast EC
Classical model of endothelial and hematopoietic cell differentiation, Recently challenged by the finding that during development hematopoietic stem cells are generated from so-called hemogenic endothelium, placing EC upstream of HSC
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Receptors important for endothelial differentiation and angiogenesis
Largely endothelium-specific receptors:
VEGFRs: 3 Tie-Rs: 2
Ephrin-R: 1 receptor
non-specific receptors: bFGFR
TGF-β-R
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VEGF/VEGFR: VEGF-A: initiation of vasculogenesis and sprouting angiogenesis, Induces immature vessels, Also called vascular permeability factor, Haploid insufficiency in k.o. mice, PlGF: remodeling of adult vessels VEGF-B: heart vascularization, lipid metabolism VEGF-C: lymphatic vessels VEGF-D: lymphatic vessels VEGFR-2: growth and permeability VEGFR-1: negative role, decoy receptor in development; however synergism with VEGFR-2 in tumor angiogenesis VEGFR-3: lymphatic vessels
VEGF/VEGFR family
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Angiopoietins und Tie Receptors: Ang1: remodeling and maturation Quiescence and stability Resistance to permeability, Supports interaction with other cells and matrix, Controls vessel size (VEGF rather number of vessels), Repair of damaged vessels Ang2: natural antagonist of Ang1, Overexpression similar Ang-1 k.o. or Tie-2 k.o., Destabilization signal for initiation of vascular remodeling Either regression (w/o VEGF) or increased VEGF sensitivity Ang2 is induced in tumors Ang3 and Ang4: similar Ang1 and Ang2 Tie2: binds Ang1-4 Tie1: associates with Tie-2 without ligand binding, amplifies signal
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Ephrine und Eph-Rezeptors: Largest family of growth factor receptors (especially important e.g. for nervous system), Relevant for vascular system: Ephrin B2/ Eph B4 : remodeling and maturation Different for early arterial (Ephrin B2) and venous vessels (EphB4), Hypothesis: role for fusion of arterial/ venous vessels
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Example 2 Family of factors/receptors TGF-β (Transforming Growth Factor-β) - Receptor (other family members: Activins, Inhibins, Bone morphogenetic substances) pleiotropic activities dependent on cell type, frequently inhibition of proliferation, induce synthesis of extracellular matrix, Bone formation, Role for dorsal-ventral specification (embryonic development)
A family of receptor serine/threonine kinases activates transcription factors directly at the receptor
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Smad 1 - 8 (Name from corresponding C.elegans/Drosophila Protein)
Heterodimerisation of Type II und Type I Receptors, Phosphorylation of SMADs
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Transport of phosphorylated SMADs into nucleus
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Unterlagen: http://mailbox.univie.ac.at/erhard.hofer Student point, Vorlesungsunterlagen [email protected]