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1、Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,The Wnt Signaling Pathway,Outline,Introduction,Overview of Wnt signaling,Components of Wnt signaling,Wnt proteins,Palmitoylation,Transport,Wnt receptors,Interactions with extracellul
2、ar proteins,How they signal,Cytoplasmic Signaling cascade,Nuclear Signaling Cascade,Target genes,Non-Wnt pathway genes,Feedback loop,Mutant Wnt Pathway Phenotypes,Wnt Redundancy,Wnt and Human Disease,Summary,Introduction,Important in multiple developmental events,Mutated:leads to disease,Canonical p
3、athway:,Wnt signaling through Frizzled to,-catenin,Main intracellular proteins involved:,Dishevelled(Dsh)-Glycogen synthase kinase 3,Axin(GSK-3),catenin-Adenomatous Polyposis Coli(APC),Wnt signaling inhibits degradation of,-catenin,-catenin interacts with Tf lymphoid enhancer-binding factor(TCF),Ove
4、rview of Pathway,Dsh,Dsh,APC,GSK3,Axin,-c,TCF,-c,TCF,Axin,-c,-c,-c,WNT,protein,Frizzled,LRP5/6,DNA,First Component:Wnt Proteins,Wnt Proteins,Large family of secreted molecules,350 to 400 amino acids,Signal sequence,Invariant pattern of 23-24 conserved cysteines,Name derived from first 2 members disc
5、overed:,Drosophila,W,ingless,Mouse,i,nt,-1,Involved in intercellular signaling during development,Early mesodermal patterning of embryo,Morphogenesis of brain and kidneys,Wnt Proteins,Secreted but insoluble(hydrophobic),Palmitoylated,Enzyme responsible:,porcupine,(,por,)in,Drosophila,or,mom-1,in,C.e
6、legans,Essential for function and signaling,Mutation of cysteine,Removal of palmitate,Drosophila,homologue,Wingless,Loses hydrophobicity and activity when por eliminated,Por,is necessary for lipidation/membrane targeting,Inactive WNT,Protein,Palmitoylation,WNT,H-C-CH,2,-S-H,O=C-O,-,HO-C-(CH,2,),14,C
7、H,3,O,WNT,H-C-CH,2,-S,O=C-O,-,C-(CH,2,),14,CH,3,O,Cysteine,Residue,Palmitic,Acid,Palmitoylated,WNT protein,por,mom-1,Function of Palmitoylation,Remains unclear,Experiments in:,Drosophila,Loss of,por,Excess of,Wingless,Circumvents the loss of,por,Vertebrates,Excess expression of mutant Wnt,Still some
8、 Wnt signaling,Presence of lipid moiety targets Wnt to the membrane,Absence of lipid is overcome by high concentration of Wnt protein,Transport of Wnt Proteins,Secreted from cells,Experiment in,Drosophila,Antibody to Wingless,Significant spread in imaginal discs,Concentration-dependent long-range mo
9、rphogenetic signals acting on distant neighbours,Flies have vessicles in imaginal discs,Argosomes,Might carry,Wingless,as cargo,Extracellular Binding Partners,Extracellular enhancer:,HSPG Heparin-sulfated forms of proteoglycans,Co-receptor on target cells,Drosophila,s,Dally,Lost or mutated:similar p
10、henotype to,wingless,mutants,Extracellular inhibitors:,SFRP Secreted Frizzled-related protein,Resembles ligand-binding domain of Frizzled,WIF Wnt inhibitory factor,Secreted molecules resembling extracellular portion of receptor,Might promote signaling through protection of Wnts from degradation,Extr
11、acellular Binding of Wnts,Por/mom-1,SFRP,WIF,Second Component:WNT Receptors,Wnt Receptors,Frizzled(Fz)proteins,Seven transmembrane receptors,Long N-terminal extension,Cysteine rich domain(CRD),Overexpression of,Fz,:,No Wnt signal,Co-overexpression of,Wingless,:Signaling,Fz activation is ligand depen
12、dent,Fz forms receptor complex with another single-pass transmembrane protein,LRP(Low density receptor related protein),Arrow,in,Drosophila,WNT Receptors,Derailed,Distinct from Frizzled,Transmembrane tyrosine kinase,Belongs to RYK subfamily,Contains WIF domain,In,Drosophila,:,Binds Dwnt-5,Regulator
13、of axon guidance in CNS,Cytoplasmic kinase domain dispensable,In Vertebrates:,Wnt4 and Wnt5 implicated in axon guidance,Wnt4 binds to Fz,Wnt5 receptor remains undetermined,Non-Wnt Proteins that Interact with Wnt receptors,Dickkopf Dkk1,Encodes cysteine-rich secreted protein,Binds Wnt coreceptor LRP6
14、,If Fz has Wnt bound,can still bind to Dkk1 and LRP5/6 to induce canonical signaling pathway,Also binds transmembrane protein Kremen,Endocytosed,depleting LRP6,Norrin,Ligand that binds to Fz,No sequence similarity to Wnt,Can induce canonical signaling pathway,Wnt Receptors and Non-Wnt Proteins,Dkk,D
15、kk,N,N,Canonical,Signaling,How Wnt Receptors Signal,Frizzled,Binds to Dishevelled(Dsh),Ubiquitously expressed,C-terminal cytoplasmic Lys-Thr-X-X-X-Trp motif,Required for Fz signaling,LRP,Binds to Axin,Cytoplasmic tail has several Pro-Pro-Pro-(SerTrp)Pro motifs,Phosphorylated upon Wnt binding,Axin an
16、d Dsh:DIX domains,Can heterodimerize,LRP and Fz may promote interaction between Dsh and Axin,Third Component:Cytoplasmic Cascade,Dsh,APC,Axin,Axin,-c,GSK3,Canonical Signaling,Absence of Wnt Signaling:,-catenin phosphorylated by serine/threonine kinase,Casein Kinase or GSK-3,Facilitated by scaffolding proteins APC and Axin,Degradation complex,Recognized by,-TrCP,Ubiquitinates for degradation via proteosome,Activation of Wnt signaling:,-catenin levels accumulate,Enter the nucleus to induce transcr
the wnt signaling pathway
