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Wnt signaling

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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  1. 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

  2. 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

  3. Discovery of Wnts • Wntgenes: • WinglessgeneinDrosophila melanogaster • Intgeneinmice • 24 has beendiscovered • 19 areexpressedinmammals • 10 receptor genes - Frizzleds

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. CanonicalWntpathway LRP5/6 Wnt8 Frizzled Dkk1 Plasma membrane Cytoplasm Krm Dsh Axin DIX PDZ DEP -catenin TCF3 Nucleus Anterior genes

  10. 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

  11. 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

  12. 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

  13. 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

  14. PKC isoformsinWntsignalling • PKCa • PKCd • PKCz

  15. The classical view of three independent Wnt signalling pathways • 1 The 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. • 2 Ca-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. • 3 Planar cell polarity pathway is Ca dependent and using JNK as well as PKCs to transduce signals to the AP1 complex.

  16. InwhatdiseasesareWntsignallingpathwaysinvolved ? • Inflammation • Fibrosis • Cancer

  17. Wnttargetgenes INFLAMMATION TISSUE REPAIR AND REMODELLING • FGF10, TGFb, BMP4, MMP-s • IL-1, Il-8, IL-6, MMP-s

  18. 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

  19. 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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