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1、The Wnt Signaling PathwayOutline Introduction Overview of Wnt signaling Components of Wnt signaling Wnt proteins Palmitoylation Transport Wnt receptors Interactions with extracellular proteins How they signal Cytoplasmic Signaling cascade Nuclear Signaling Cascade Target genes Non-Wnt pathway genes
2、Feedback loop Mutant Wnt Pathway Phenotypes Wnt Redundancy Wnt and Human Disease SummaryIntroduction Important in multiple developmental events Mutated:leads to disease Canonical pathway:Wnt signaling through Frizzled to-catenin Main intracellular proteins involved:Dishevelled(Dsh)-Glycogen synthase
3、 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)Overview of Pathway DshDshAPCGSK3Axin-cTCF-cTCFAxin-c-c-cWNT proteinFrizzledLRP5/6DNAFirst Component:Wnt ProteinsWnt Proteins Lar
4、ge family of secreted molecules 350 to 400 amino acids Signal sequence Invariant pattern of 23-24 conserved cysteines Name derived from first 2 members discovered:Drosophila Wingless Mouse int-1 Involved in intercellular signaling during development Early mesodermal patterning of embryo Morphogenesi
5、s of brain and kidneysWnt Proteins Secreted but insoluble(hydrophobic)Palmitoylated Enzyme responsible:porcupine(por)in Drosophila or mom-1 in C.elegans Essential for function and signaling Mutation of cysteine Removal of palmitate Drosophila homologue Wingless Loses hydrophobicity and activity when
6、 por eliminated Por is necessary for lipidation/membrane targetingInactive WNTProteinPalmitoylationWNTH-C-CH2-S-HO=C-O-HO-C-(CH2)14CH3OWNTH-C-CH2-SO=C-O-C-(CH2)14CH3OCysteineResiduePalmiticAcidPalmitoylatedWNT proteinpormom-1Function of Palmitoylation Remains unclear Experiments in:Drosophila Loss o
7、f por Excess of Wingless Circumvents the loss of por Vertebrates Excess expression of mutant Wnt Still some Wnt signaling Presence of lipid moiety targets Wnt to the membrane Absence of lipid is overcome by high concentration of Wnt proteinTransport of Wnt Proteins Secreted from cells Experiment in
8、Drosophila Antibody to Wingless Significant spread in imaginal discs Concentration-dependent long-range morphogenetic signals acting on distant neighbours Flies have vessicles in imaginal discs Argosomes Might carry Wingless as cargoExtracellular Binding Partners Extracellular enhancer:HSPG Heparin-
9、sulfated forms of proteoglycans Co-receptor on target cells Drosophilas Dally Lost or mutated:similar phenotype to wingless mutants Extracellular inhibitors:SFRP Secreted Frizzled-related protein Resembles ligand-binding domain of Frizzled WIF Wnt inhibitory factor Secreted molecules resembling extr
10、acellular portion of receptor Might promote signaling through protection of Wnts from degradationExtracellular Binding of WntsPor/mom-1SFRPWIFSecond Component:WNT ReceptorsWnt Receptors Frizzled(Fz)proteins Seven transmembrane receptors Long N-terminal extension Cysteine rich domain(CRD)Overexpressi
11、on of Fz:No Wnt signal Co-overexpression of Wingless:Signaling Fz activation is ligand dependent Fz forms receptor complex with another single-pass transmembrane protein LRP(Low density receptor related protein)Arrow in DrosophilaWNT Receptors Derailed Distinct from Frizzled Transmembrane tyrosine k
12、inase Belongs to RYK subfamily Contains WIF domain In Drosophila:Binds Dwnt-5 Regulator 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 undeterminedNon-Wnt Proteins that Interact with Wnt re
13、ceptors Dickkopf Dkk1 Encodes cysteine-rich secreted protein Binds Wnt coreceptor LRP6 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
14、to Wnt Can induce canonical signaling pathwayWnt Receptors and Non-Wnt ProteinsDkkDkkNNCanonicalSignalingHow 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 s
15、everal Pro-Pro-Pro-(SerTrp)Pro motifs Phosphorylated upon Wnt binding Axin and Dsh:DIX domains Can heterodimerize LRP and Fz may promote interaction between Dsh and AxinThird Component:Cytoplasmic CascadeDshAPCAxinAxin-cGSK3Canonical Signaling Absence of Wnt Signaling:-catenin phosphorylated by seri
16、ne/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 transcription of target genes Mutant-catenin(no phosphorylation sites)Wnt unresponsive catenin active in entering the nucleus Constitutive Wnt signaling common in neoplasmsPresence of Wnt SignalingThree ways of-catenin accumulationDisruptio
