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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. Signal transduction: receptor gene. 1.

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SIGNAL TRANSDUCTION 2) From the cell membrane to the nucleus Part B

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Signal transduction 2 from the cell membrane to the nucleus part b

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


Signal transduction 2 from the cell membrane to the nucleus part b

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

3- TF activation by membrane soluble ligands

(TF: transcription factor)


Signal transduction 2 from the cell membrane to the nucleus part b

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)

Trimeric Receptors:

TNFRs (inflammation, apoptosis)

Receptors with signalling cascades including

Proteolytic cleavages:

WNT-R (embryonal development, adult stem cells)


Signal transduction 2 from the cell membrane to the nucleus part b

Enzym

Enzyme

Adaptor

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

Ligands

Cell membrane

Enzym-

domäne


Signal transduction 2 from the cell membrane to the nucleus part b

Kinases - Phosphorylation

Phosphatasen - Dephosphorylation

Tyrosine-OHTyr-Kinases

Serine-OHSer/Thr-Kinases

Threonine-OH

„dual specificity“ Kinases


Signal transduction 2 from the cell membrane to the nucleus part b

Surface receptors with enzyme domains

Families of receptor tyrosine kinases


Signal transduction 2 from the cell membrane to the nucleus part b

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 AngiogenesisExample 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


Signal transduction 2 from the cell membrane to the nucleus part b

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


Signal transduction 2 from the cell membrane to the nucleus part b

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


Signal transduction 2 from the cell membrane to the nucleus part b

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)


Signal transduction 2 from the cell membrane to the nucleus part b

SOS

Grb-2 adaptor: SH2- Domain

SOS is Ras-GEF (guanine nucleotide exchange factor)

Ras: GTP-binding protein

(Oncogene detected in rat-sarcoma)


Signal transduction 2 from the cell membrane to the nucleus part b

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


Signal transduction 2 from the cell membrane to the nucleus part b

3 important signaling

cascades are induced:

- Ras

- PLC-g

(Phospholipase C- g)

- PI3-Kinase

(Phosphoinositol 3-Kinase)


Signal transduction 2 from the cell membrane to the nucleus part b

„Second messenger“

DAG, IP3 and Ca++

10-3 M

10-7 M


Signal transduction 2 from the cell membrane to the nucleus part b

PLC-g signaling pathway

activated PLC-g

PKC

Phosphorylates many substrates,

can activate

MAP-kinase pathway,

gene regulation

Ca++

Calmodulin/

Calcineurin

NFAT- transcription factor


Signal transduction 2 from the cell membrane to the nucleus part b

Ca++ pathway - gene regulation

The phosphatase

calcineurin

dephosphorylates

NFAT

NFAT translocates

into the nucleus

NFAT= transcription factor

(nuclear factor

activated T cell)

Ca++

P

I

NFAT

Calmodulin

Calcineurin

P

nucleus


Signal transduction 2 from the cell membrane to the nucleus part b

EC “specific” factors/receptors:

VEGFR1VEGF-A, PlGF

VEGFR2VEGF-A

VEGFR3VEGF-C

TIE1

TIE2ANG1,2

VEGFR2

Y799

Y820

Src (vascular leakage)

TSAd (migration)

PI-3 kinase (survival)

PLC-g

Y925

Y936

Y951

Y994

Y1006

Y1052

Y1057

Y1080

Y1104

gene regulation

proliferation

vasculogenesis

angiogenesis

Y1128

Y1134

Y1175

Y1212

Sakurai et al.

PNAS 2005

Y1221

Y1303

Y1307

Y1317


Vegf vs egf signaling

VEGF vs. EGF signaling

PLC-g

P

DAG

2+

Ca

PKC

EGF

VEGF

PIP

R-Tyk

2

R-Tyk

Ras

IP

3

IP

-

R

3

End.Ret.

2+

Ca

Raf

CAM

MEK1/2

CN

ERK1/2

+

EGR-1

VEGF responsive genes

NFAT


Signal transduction 2 from the cell membrane to the nucleus part b

phosphorylated MAPK ERK is transprted into the nucleus,

where it phosphorylates the transcription factor TCF

or:

PLC-g

Raf

MEK

genes for

cell cycle/

proliferation

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)


Signal transduction 2 from the cell membrane to the nucleus part b

PI-3 Kinase Pathway and Survival

PKB, PDK:

(PKB: protein kinas B or AKT;

PDK: PI-dependenmt kinase)

Ser/Thr kinases


Signal transduction 2 from the cell membrane to the nucleus part b

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


Signal transduction 2 from the cell membrane to the nucleus part b

A small artery:

Conective tissue,

Smooth muscle cells

basal lamina

monocellular

layer of endothelial cells


Signal transduction 2 from the cell membrane to the nucleus part b

Structure of a capillary:

Endothelial cells and basal lamina, pericytes


Signal transduction 2 from the cell membrane to the nucleus part b

“sprouting angiogenesis”

Sprouting of endothelial cells from differentiated

endothelial cells of the vessel wall


Signal transduction 2 from the cell membrane to the nucleus part b

Wounding induces growth of capillaries:

Mouse cornea

chemotactic response to angiogenic factors


Signal transduction 2 from the cell membrane to the nucleus part b

Every cell has to be in a distance of 50 to 100 mm of a capillary

Endothelial cells respond to signals from tissue

Hypoxia

HIF

VEGF


Signal transduction 2 from the cell membrane to the nucleus part b

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


Signal transduction 2 from the cell membrane to the nucleus part b

HemangioblastAngioblastEC


Signal transduction 2 from the cell membrane to the nucleus part b

Ligands and receptors

Endothelium-specific receptors:

VEGFRs: 3

Tie-Rs: 2

Ephrin-R: 1 receptor

non-specific receptors:

bFGF

PDGF

TGF-b


Signal transduction 2 from the cell membrane to the nucleus part b

VEGF/VEGFR family

VEGF/VEGFR:

VEGF-A: initiation of vasculogenesis

and sprouting angiogenesis,

Immature vessels,

Vascular permeability factor,

Haploid insufficiency in k.o. mice,

PlGF: remodeling of adult vessels

VEGF-B: heart vascularization ?

VEGF-C: lymphatic vessels

VEGF-D: lymphatic vessels ?

VEGFR-2: growth and permeability

VEGFR-1: negative role ?, decoy receptor,

synergism with VEGFR-2 in

tumor angiogenesis

VEGFR-3: lymphatic vessels


Signal transduction 2 from the cell membrane to the nucleus part b

Angiopoietins und Tie Receptors:

Ang1: remodeling and maturation

Quiescence and stability

Resistance to permeability,

Supports interaction with other cells and matrix,

Vessel size (VEGF number of vessels),

Repair of damaged vessels

Ang2: natural antagonist,

Overexpression similar Ang-1 k.o. oder Tie-2 k.o.,

Destabilization signal for initiation of vascular remodeling

Either regression or increased VEGF sensitivity

Ang2 is induced in tumors

Ang3: ?

Ang4: ?

Tie2: binds Ang1-4

Tie1: ?


Signal transduction 2 from the cell membrane to the nucleus part b

Ephrine und Eph-Rezeptors:

Largest family of growth factor receptors,

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


Signal transduction 2 from the cell membrane to the nucleus part b

A family of receptor serine/threonine kinases activates

transcription factors directly at receptor

Example 2

Family of factors/receptors

TGF-b (Transforming Growth Factor-b) - Receptor

(other family members: Activin,

Bone morphogenetic substances)

pleiotropic activities dependent on cell type,

frequently inibition of proliferation,

induce synthesis of extracellular matrix,

Bone formation,

Role for dorsal-ventral specification (embryonic development)


Signal transduction 2 from the cell membrane to the nucleus part b

Heterodimerisation of Type II und Type I Receptors,

Phosphorylation of SMADs

Smad 1 - 8

(Name of C.elegans/Drosophila Protein)


Signal transduction 2 from the cell membrane to the nucleus part b

Transport of phosphorylated SMADs into nucleus


Signal transduction 2 from the cell membrane to the nucleus part b

Unterlagen:

http://mailbox.univie.ac.at/erhard.hofer

Student point, Vorlesungsunterlagen

[email protected]


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