Signal transduction: receptor

1 Intercellular communication 2
Ligand

gene

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 domne Adaptor

Kinases - Phosphorylation Phosphatasen - Dephosphorylation

Tyrosine-OH
Serine-OH Threonine-OH

Tyr-Kinases
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)

Example 1

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 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

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)

MEK

ERK

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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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

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EC specific factors/receptors:

VEGFR2

VEGFR1

VEGF-A, PlGF

VEGFR2
VEGFR3 TIE1 TIE2

VEGF-A
VEGF-C ANG1,2

Y799 Y820

Src (vascular leakage)

Y925 Y936

Y951
Y994 Y1006 Y1052 Y1057 Y1080 Y1104 Y1128 Y1134

TSAd (migration) PI-3 kinase (survival)

gene regulation

Y1175 Y1212
Y1221 Y1303 Y1307 Y1317

PLC-g

proliferation vasculogenesis angiogenesis

Sakurai et al. PNAS 2005

VEGF vs. EGF signaling

VEGF EGF

PIP2
IP 3 DAG 2+ PKC

R-Tyk PLC-g

R-Tyk Ras

IP - R 3

End.Ret.
Ca 2+ Ca

CAM

Raf

MEK1/2

CN

ERK1/2

NFAT

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 erhard.hofer@univie.ac.at