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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 of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 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-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signal transduction WNT SIGNALING TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 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 Frizzled (Fz) family receptors TÁMOP-4.1.2-08/1/A-2009-0011 • 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 TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 Non-canonical pathways • Independent from -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 TÁMOP-4.1.2-08/1/A-2009-0011 Wnt signaling pathways Wnt/Ca2+ Canonical pathway Planar cell polarity LRP5/6 Wnt Wnt5a Frizzled Wnt11 Frizzled Frizzled Stbm Plasma membrane Cytoplasm Axin ? G proteins? Dsh DIX PDZ DIX DEP PLC Prickle Dsh PDZ ? Ca2+ DEP Daam1 RhoA Rac ROCK JNK GSK3 Axin -catenin No Wnt signal PKC APC -TrCP CaMKII Calcineurin P NFAT Cytoskeletal rearrangment -catenin -catenin Nucleus LEF/ TCF NFAT Gene transcription TÁMOP-4.1.2-08/1/A-2009-0011 Canonical Wnt pathway LRP5/6 Wnt8 Frizzled Dkk1 Plasma membrane Cytoplasm Krm Dsh Axin DIX PDZ DEP -catenin TCF3 Nucleus Anterior genes -catenin in cellular adhesion TÁMOP-4.1.2-08/1/A-2009-0011 Wnt Frizzled Cadherin Axin -catenin -catenin GSK3 Cadherin -catenin -catenin Cadherin Dsh -catenin -catenin Cadherin -catenin -catenin Plasma membrane -catenin APC P -catenin P + Wnt signal No Wnt signal -catenin degradation Adherens junction -catenin LEF/TCF Nucleus Cytoplasm Transcription TÁMOP-4.1.2-08/1/A-2009-0011 Alzheimer’s disease I AP Excitotoxicity Activated microglia Cell-cycle activation Abnormal DNA synthesis NO DNA damage + p53 Bax Dkk1 - Fast AP toxicity Apoptosis Wnt Delayed AP toxicity Development of NFTs TÁMOP-4.1.2-08/1/A-2009-0011 Alzheimer’s disease II Early stage Late stage Wnt Wnt Wnt Frizzled Frizzled Frizzled Dkk1 Dkk1 bAP Krm Krm Akt Dsh P PI3K PI3K Akt Akt GSK3 -catenin Nucleus -catenin LEF/ TCF GD3 synthasecyclin D1 GSK3 GSK3 ↓Phosphorylation of tau ↑Phosphorylation of tau Inhibition of Wnt and Tcf signaling in the canonical pathway TÁMOP-4.1.2-08/1/A-2009-0011 Wnt Frp Frizzled Dominant negative Frizzleds Nkd 1 and 2 Dsh Dominant negative Dsh-s CK-1,2 Frat GSK3 APC Axin -catenin PP2A Nucleus b-TrCP -catenin TCF4 ICAT TCF4 Growth PKC isoforms in Wnt signalling •PKC •PKCd •PKCz TÁMOP-4.1.2-08/1/A-2009-0011 The classical view of three independent Wnt signalling pathways TÁMOP-4.1.2-08/1/A-2009-0011 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 -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 In what diseases are Wnt signalling pathways involved ? TÁMOP-4.1.2-08/1/A-2009-0011 • Inflammation • Fibrosis • Cancer TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 Rheumatoid arthritis CD34+ bone marrow Increased Wnt5a ogenitorcell infiltration Inflammatory stimuli Leukocyte infiltration Synoviocytes Wnt1 Wnt5a Wnt11 Wnt13 Fz-2 Fz-5 Fz-7 IL6, IL8, IL15, metallo-proteinases Joint destruction Molecular changes of Wnt4 signaling in the aging thymus TÁMOP-4.1.2-08/1/A-2009-0011 • Wnt4 uses mainly the -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