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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University.

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Presentation on theme: "Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University."— Presentation transcript:

1 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP /1/A

2 Wnt signaling Tímea Berki and Ferenc Boldizsár Signal transduction
Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP /1/A Tímea Berki and Ferenc Boldizsár Signal transduction Wnt signaling

3 Discovery of Wnts Wnt genes: Wingless gene in Drosophila melanogaster
Int gene in mice 24 has been discovered 19 are expressed in mammals 10 receptor genes - Frizzleds

4 Wnt family proteins Comprises of 19 secreted glycoproteins controlling a variety of developmental processes: Cell fate specification Cell proliferation Cell polarity and cell migration Different types of cancers Various processes of aging

5 Frizzled (Fz) family receptors
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) Canonical pathway activators: 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: 1 Polar cell polarity (PCP) or c-Jun-N Terminal Kinase (JNK)/Activating Protein (AP1) dependent 2 Ca2+ or Protein kinase C (PKC)/Calmodulin Kinase (CaMKII)/Nuclear Factor of Activating T- cells (NFAT) dependent pathways

8 Wnt signaling pathways
Canonical pathway Wnt/Ca2+ Planar cell polarity LRP5/6 Wnt Frizzled Wnt5a Frizzled Wnt11 Frizzled Stbm Plasma membrane Cytoplasm Axin ? G proteins? Dsh Prickle Dsh DIX PDZ DEP DIX PDZ DEP PLC ? Ca2+ Daam1 RhoA Rac GSK3 Axin PKC CaMKII -catenin APC Calcineurin ROCK JNK -TrCP No Wnt signal P NFAT Cytoskeletal rearrangment -catenin -catenin Nucleus LEF/ TCF NFAT Gene transcription

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

10 b-catenin in cellular adhesion
Wnt Frizzled Plasma membrane -catenin Cadherin -catenin -catenin Cadherin -catenin Dsh -catenin Cadherin -catenin GSK3b -catenin Cadherin -catenin Axin -catenin P APC -catenin + Wnt signal No Wnt signal P -catenin degradation Adherens junction -catenin Transcription LEF/TCF Nucleus Cytoplasm

11 Alzheimer’s disease I AP Excitotoxicity Activated microglia
Cell-cycle activation Abnormal DNA synthesis NO DNA damage + p53 Bax Dkk1 - Fast AP toxicity Wnt Delayed AP toxicity Apoptosis Development of NFTs

12 Alzheimer’s disease II
Early stage Late stage ↑Phosphorylation of tau GSK3 Wnt Frizzled Akt PI3K Dkk1 Krm Wnt Frizzled Wnt Frizzled Dkk1 bAP Krm PI3K Akt Dsh Akt GSK3 P GSK3 -catenin ↓Phosphorylation of tau Nucleus -catenin LEF/ TCF GD3 synthase- cyclin D1

13 Inhibition of Wnt and Tcf signaling in the canonical pathway
Frp Frizzled Dominant negative Frizzleds Nkd 1 and 2 Dsh Dominant negative Dsh-s CK-1,2 Frat GSK3 APC Axin -catenin PP2A b-TrCP Nucleus -catenin ICAT TCF4 TCF4 Growth

14 PKC isoforms in Wnt signalling
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 are coming through the 7 transmembrane domains of Frizzled-receptors, than Dsh is phosphorylated and signal is transmitted via b-catenin to TCF/LEF in the nucleus. 2 Ca-dependent Wnt 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 In what diseases are Wnt signalling pathways involved ?
Inflammation Fibrosis Cancer

17 TISSUE REPAIR AND REMODELLING
Wnt target genes INFLAMMATION TISSUE REPAIR AND REMODELLING IL-1, Il-8, IL-6, MMP-s FGF10, TGFb, BMP4, MMP-s Wnt Target genes Canonical pathway (-catenin/TCF) Cyclin D1, MMP-s, c-myc, Cox-2, c-jun, Fra-1, VEGFR, EGFR Ca2+ pathway (NFAT, NFkB) IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-15, IFN-, GMCSF, TNF-, ICAM-1 PCP pathway (AP1) Cyclin D1, MMP-s, FasL, Bim, Bcl3, FL1, GMCSF

18 Rheumatoid arthritis CD34+ bone marrow progenitorcell infiltration
Increased Wnt5a Wnt1 Wnt5a Wnt11 Wnt13 Fz-2 Fz-5 Fz-7 IL6, IL8, IL15, metallo-proteinases Inflammatory stimuli Synoviocytes Leukocyte infiltration Joint destruction

19 Molecular changes of Wnt4 signaling in 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 intracellularly the 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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