Manifestation of Novel Social Challenges of the European Union
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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Wnt signaling

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Wnt signaling

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen

Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011


Wnt signaling

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

Tímea Berki and Ferenc Boldizsár

Signaltransduction

Wntsignaling


Discovery of wnts

Discovery of Wnts

  • Wntgenes:

  • WinglessgeneinDrosophila melanogaster

  • Intgeneinmice

  • 24 has beendiscovered

  • 19 areexpressedinmammals

  • 10 receptor genes - Frizzleds


Wnt family proteins

Wnt familyproteins

  • Comprises of 19 secreted glycoproteins controlling avariety of developmental processes:

  • Cell fate specification

  • Cell proliferation

  • Cell polarity and cell migration

  • Different types of cancers

  • Various processes of aging


Frizzled fz family receptors

Frizzled (Fz) familyreceptors

  • They are 7-TM receptors; however, assembly of an active Wnt-Fz receptor complex also requires the presence of a co-receptors, the low-density lipoprotein related protein 5 and 6 (LRP5/6)

  • Canonicalpathwayactivators: Wnt1, Wnt3, Wnt3a, Wnt7a, Wnt7b, Wnt8

  • Non-canonical pathway activators: Wnt5a, Wnt4, Wnt11


Canonical pathway

Canonical pathway

  • In developing thymocytes or in thymic epithelium

  • Signals from the Wnt-Fz-LRP6 complex lead to the phosphorylation of three domains of Dishevelled (Dvl), a family of cytosolic signal transducer molecules.

  • Activation of Dvl ultimately leads to phosphorylation and consequently inhibition of GSK-3

  • Inhibition of GSK-3 results in stabilisation and consequent cytosolic accumulation of -catenin, which then translocates into the nucleus,

  • -catenin forms active transcription complexes with members of the T-Cell Factor (LEF1, TCF1, TCF3, TCF4) transcription factor family and transcription initiator p300.

  • Successful assembly of the transcription complex leads to the activation of various target genes including cyclin-D1, c-myc, c-jun , Fra-1 VEGFR, etc.


N on canonical pathways

Non-canonical pathways

  • Independent from b-catenin

  • Branches into the:

    • 1Polar cell polarity (PCP)or c-Jun-N Terminal Kinase (JNK)/Activating Protein (AP1) dependent

    • 2Ca2+ or Protein kinase C (PKC)/CalmodulinKinase (CaMKII)/Nuclear Factor of Activating T- cells (NFAT) dependent pathways


Wnt signaling pathways

Wntsignalingpathways

Wnt11

Wnt5a

Wnt

Frizzled

Frizzled

Frizzled

Wnt/Ca2+

Canonicalpathway

Planar cell polarity

LRP5/6

Stbm

Plasma membrane

Cytoplasm

Axin

?

G proteins?

Prickle

Dsh

Dsh

DIX

DIX

PDZ

PDZ

DEP

DEP

?

PLC

Ca2+

Daam1

RhoA

Rac

GSK3

Axin

PKC

CaMKII

APC

Calcineurin

-catenin

ROCK

JNK

-TrCP

NFAT

P

No Wntsignal

Cytoskeletal

rearrangment

-catenin

-catenin

Nucleus

LEF/

TCF

NFAT

Gene transcription


Canonical wnt pathway

CanonicalWntpathway

LRP5/6

Wnt8

Frizzled

Dkk1

Plasma membrane

Cytoplasm

Krm

Dsh

Axin

DIX

PDZ

DEP

-catenin

TCF3

Nucleus

Anterior genes


B catenin in cellular adhesion

b-cateninincellularadhesion

Wnt

Frizzled

Plasmamembrane

-catenin

-catenin

-catenin

-catenin

-catenin

-catenin

-catenin

-catenin

Dsh

Cadherin

Cadherin

Cadherin

Cadherin

GSK3b

Axin

-catenin

APC

P

-catenin

P

+ Wnt signal

No Wnt signal

-catenin

degradation

Adherens

junction

-catenin

Transcription

LEF/TCF

Nucleus

Cytoplasm


Alzheimer s disease i

Alzheimer’sdiseaseI

Activated microglia

AP

Excitotoxicity

Cell-cycleactivation

Abnormal DNA synthesis

NO

DNA damage

+

p53

Bax

Dkk1

-

Wnt

FastAP toxicity

DelayedAP toxicity

Apoptosis

Development of NFTs


Alzheimer s disease ii

Alzheimer’sdiseaseII

Wnt

Wnt

Wnt

Frizzled

Frizzled

Frizzled

Earlystage

Latestage

Dkk1

Dkk1

bAP

P

Krm

Krm

PI3K

PI3K

Akt

Akt

Dsh

Akt

GSK3

GSK3

GSK3

-catenin

↑Phosphorylation of tau

↓Phosphorylation of tau

Nucleus

-catenin

LEF/

TCF

GD3 synthase-

cyclin D1


Inhibition of wnt and tcf signaling in the canonical pathway

Inhibition of Wnt and Tcfsignalinginthecanonicalpathway

Wnt

Frp

Frizzled

DominantnegativeFrizzleds

Nkd 1 and 2

Dsh

DominantnegativeDsh-s

CK-1,2

Frat

GSK3

APC

Axin

-catenin

PP2A

b-TrCP

Nucleus

-catenin

ICAT

TCF4

TCF4

Growth


Pkc isoforms in wnt signalling

PKC isoformsinWntsignalling

  • PKCa

  • PKCd

  • PKCz


The classical view of three independent wnt signalling pathways

The classical view of three independent Wnt signalling pathways

  • 1The canonical pathway is the first and best characterized Wnt pathway. Signals arecoming through the 7 transmembranedomains of Frizzled-receptors, thanDsh is phosphorylated and signal is transmitted viab-catenin to TCF/LEF in the nucleus.

  • 2Ca-dependentWnt signaling is transmitted by Frizzled-s and G-proteins and the intracellular signaling molecules are CaMKII and different izotypes of PKCs. Inhibitory signals can use TAK and NLK to get into the nucleus. One of the key targets is NF-AT.

  • 3Planar cell polarity pathway is Ca dependent and using JNK as well as PKCs to transduce signals to the AP1 complex.


In what diseases are wnt signalling pathways involved

InwhatdiseasesareWntsignallingpathwaysinvolved ?

  • Inflammation

  • Fibrosis

  • Cancer


Wnt signaling

Wnttargetgenes

INFLAMMATION

TISSUE REPAIR AND REMODELLING

  • FGF10, TGFb, BMP4, MMP-s

  • IL-1, Il-8, IL-6, MMP-s


Rheumatoid arthritis

Rheumatoidarthritis

CD34+ bonemarrow

progenitorcellinfiltration

IncreasedWnt5a

Fz-2

Fz-5

Fz-7

Wnt1

Wnt5a

Wnt11

Wnt13

IL6, IL8, IL15,

metallo-proteinases

Inflammatory

stimuli

Synoviocytes

Leukocyteinfiltration

Jointdestruction


Molecular changes of wnt4 signaling in the aging thymus

Molecular changes of Wnt4 signalingin the aging thymus

  • Wnt4 uses mainly the b-catenin dependent canonical signaling pathway

  • Wnt4 expression is decreasing during aging in the thymus

  • The receptors of Wnt4 signaling are Frizzled-4 and Frizzled-6

  • The expression pattern of Wnt4 receptors is changing during thymic senescence

  • During aging the balance moves towards the Fz-6, transducing negative Wnt signals

  • PKCd is modulating intracellularlythe Wnt4 signaling mechanism

  • CTGF - a target gene of Wnt4 signals- expression is increasing

  • CTGF is a negative regulator of b-catenin dependent signaling

  • CTGF and its recently described receptor Fz-8 is functioning as a secondary negative feedback mechanism of Wnt4 signaling


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