BioPAX pathway converted from "WNT mediated activation of DVL" in the Reactome database.WNT mediated activation of DVLWNT mediated activation of DVLThe three human Dishevelled (DVL) proteins play a central and overlapping role in the transduction of the WNT signaling cascade (Lee et al, 2008; reviewed in Gao and Chen 2010). DVL activity is regulated by phosphorylation, although the details are not completely worked out. DVL likely exists as a phosphoprotein even in the absence of WNT stimulation, and is further phosphorylated upon ligand binding. Casein kinase 1epsilon (CSNK1E), casein kinase 2 (CSNK2) and PAR1 have all been reported to phosphorylate DVL (Willert et al, 1997; Sun et al, 2001; Cong et al, 2004; Ossipova et al, 2005). Upon pathway activation, phosphorylated DVL translocates to the plasma membrane through an interaction between the DVL PDZ domain and the FZD KTxxxW motif (Wong et al, 2003; Umbhauer et al, 2000; Kikuchi et al, 2011). At the plasma membrane, DVL is believed to oligomerize through its DIX domain, providing a platform for AXIN recruitment; recruitment of AXIN is also facilitated by interaction with LRP (Schwarz-Romond et al, 2007; Mao et al, 2001). DVL interacts with phosphatidylinositol-4-kinase type II (PI4KII) and phophatidylinositol-4-phosphate 5-kinase type I (PIP5KI) to promote formation of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in the membrane, which is required for the clustering and phosphorylation of LRP6 and the recruitment of AXIN (Pan et al, 2008; Qin et al, 2009).Authored: Rothfels, K, 2013-08-23Reviewed: Rajakulendran, Nishani, 2014-01-22Reviewed: van Amerongen, R, 2014-02-14Reviewed: Kikuchi, Akira, 2014-04-22Edited: Gillespie, ME, 2013-10-02Edited: Matthews, L, 2007-09-04 11:49:292.7.11CSNK2-mediated phosphorylation of DVLCSNK2-mediated phosphorylation of DVLDVL proteins from Drosophila, Xenopus, mouse and human cells have been shown to be phosphorylated, however the role of phosphorylation remains incompletely understood (Willert et al, 1997; Semenov and Synder, 1997; Yanagawa et al, 1995; Rothbächer et al, 2000). CSNK2 was identified as a DVL-associated kinase in Drosophila cells, and was shown to mediate the phosphorylation of serine and threonine residues in vitro (Willert et al, 1997). CSNK2-mediated phosphorylation of DVL may be constitutive, as DVL exists as a phosphoprotein even in the absence of WNT signaling (Bernatik et al, 2011). The association between DVL and CSNK2 may be enhanced upon WNT signaling, leading to increased levels of DVL phosphorylation (Willert et al, 2007).Authored: Rothfels, K, 2013-08-23Reviewed: Rajakulendran, Nishani, 2014-01-22Reviewed: van Amerongen, R, 2014-02-14Reviewed: Kikuchi, Akira, 2014-04-22Edited: Matthews, L, 2007-09-04 11:49:29Edited: Gillespie, ME, 2013-10-02Converted from EntitySet in ReactomeReactome DB_ID: 2017251cytosolGO0005829DVL [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDVL2 [cytosol]DVL3 [cytosol]DVL1 [cytosol]Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtO14641UniProtQ92997UniProtO14640Reactome DB_ID: 1135921ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 293701ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216Converted from EntitySet in ReactomeReactome DB_ID: 2016891p-DVL [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-DVL3 [cytosol]p-S-DVL1 [cytosol]p-DVL2 [cytosol]PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 201711Casein kinase II [cytosol]Casein kinase IICSNK2CK2Converted from EntitySet in ReactomeReactome DB_ID: 50836242CSNK2(A1:A1/A1:A2/A2:A2) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 2016932UniProt:P67870 CSNK2BCSNK2BG5ACSNK2BCK2NFUNCTION Participates in Wnt signaling (By similarity). Plays a complex role in regulating the basal catalytic activity of the alpha subunit.SUBUNIT Tetramer composed of an alpha subunit, an alpha' subunit and two beta subunits. The beta subunit dimerization is mediated by zinc ions. Interacts with TCTEX1D3 (By similarity). Interacts with CD163. Also component of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, the complex associating following UV irradiation. Interacts with MUSK; mediates phosphorylation of MUSK by CK2. Interacts with FGF1; this interaction is increased in the presence of FIBP, suggesting a possible cooperative interaction between CSNKB and FIBP in binding to FGF1.PTM Phosphorylated by alpha subunit.SIMILARITY Belongs to the casein kinase 2 subunit beta family.UniProtP67870Chain Coordinates2EQUAL215EQUALReactome Database ID Release 73201711Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201711ReactomeR-HSA-2017115Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201711.5GO0004674GO molecular functionReactome Database ID Release 73201699Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201699Reactome Database ID Release 73201717Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201717ReactomeR-HSA-2017171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201717.110698942Pubmed2000Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesisRothbächer, UteLaurent, Micheline NDeardorff, Matthew AKlein, Peter SCho, Ken WFraser, Scott EEMBO J. 19:1010-227744250Pubmed1995The dishevelled protein is modified by wingless signaling in DrosophilaYanagawa, Shin-ichivan Leeuwen, FrankWodarz, AndreasKlingensmith, JohnNusse, RoelGenes Dev. 9:1087-9721285348Pubmed2011Sequential activation and inactivation of Dishevelled in the Wnt/beta-catenin pathway by casein kinasesBernatik, OndrejGanji, Ranjani SriDijksterhuis, Jacomijn PKonik, PeterCervenka, IgorPolonio, TilmanKrejci, PSchulte, GunnarBryja, VJ. Biol. Chem. 286:10396-4109214626Pubmed1997Casein kinase 2 associates with and phosphorylates dishevelledWillert, KarlBrink, MarcelWodarz, AndreasVarmus, HNusse, RoelEMBO J. 16:3089-969192851Pubmed1997Human dishevelled genes constitute a DHR-containing multigene familySemënov, Mikhail VSnyder, MichaelGenomics 42:302-102.7.11WNT signaling stimulates CSNK1-dependent phosphorylation of DVLWNT signaling stimulates CSNK1-dependent phosphorylation of DVLCSNK1E and DVL physically interact in vivo and CSNK1E phosphorylates DVL in response to WNT signaling (Peters et al, 1999; Sakanaka et al, 1999; Kishida et al, 2001; Gao et al, 2002; Hino et al, 2003; Klimowski et al, 2006; Bernatik et al, 2011). Phosphorylation by CSNK1E in the PDZ domain of DVL appears to be required for the recruitment of AXIN and the subsequent phosphorylation of LRP6 (Bernatik et al, 2011).Authored: Rothfels, K, 2013-05-29Reviewed: Rajakulendran, Nishani, 2014-01-22Reviewed: van Amerongen, R, 2014-02-14Reviewed: Kikuchi, Akira, 2014-04-22Edited: Gillespie, ME, 2013-10-02Reactome DB_ID: 1135921Converted from EntitySet in ReactomeReactome DB_ID: 2016891Converted from EntitySet in ReactomeReactome DB_ID: 37724071pp-DVL [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitypp-DVL2 [cytosol]pp-DVL3 [cytosol]pp-DVL1 [cytosol]Reactome DB_ID: 293701PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 205877UniProt:P49674 CSNK1ECSNK1ECSNK1EFUNCTION Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates DVL1 and DVL2. Central component of the circadian clock. In balance with PP1, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. Inhibits cytokine-induced granuloytic differentiation.ACTIVITY REGULATION Phosphorylation leads to a decrease of the catalytic activity.SUBUNIT Monomer (PubMed:23106386). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Interacts with PER1 (PubMed:10790862). Interacts with ANKRD6 (By similarity). Interacts with DBNDD2 (PubMed:16618118). Interacts with LRP5 and LRP6 (PubMed:16513652). Interacts with SOCS3 (PubMed:15070676). Interacts with SNAI1 (via zinc fingers) (PubMed:20305697). Interacts with DDX3X; this interaction greatly enhances CSNK1E affinity for ATP and DVL2 phosphorylation, but inhibits DDX3X ATPase/helicase activity. In the presence of RNA, the interaction is decreased (PubMed:23413191, PubMed:29222110).TISSUE SPECIFICITY Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. Expressed in monocytes and lymphocytes but not in granulocytes.INDUCTION Down-regulated during granulocytic differentiation.PTM Autophosphorylated. Partially dephosphorylated by PPP5C. May be dephosphorylated by PP1.SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.UniProtP496741EQUAL416EQUALReactome Database ID Release 733965463Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3965463Reactome Database ID Release 733772435Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3772435ReactomeR-HSA-37724352Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3772435.211425858Pubmed2001Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase IepsilonKishida, MichikoHino, Shin-ichiroMichiue, TatsuoYamamoto, HidekiKishida, ShoseiFukui, AkimasaAsashima, MakotoKikuchi, AkiraJ. Biol. Chem. 276:33147-5510517632Pubmed1999Casein kinase I transduces Wnt signalsPeters, John MMcKay, Renée MMcKay, James PGraff, Jonathan MNature 401:345-5012556519Pubmed2003Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-cateninHino, Shin-ichiroMichiue, TatsuoAsashima, MakotoKikuchi, AkiraJ. Biol. Chem. 278:14066-7310535959Pubmed1999Casein kinase iepsilon in the wnt pathway: regulation of beta-catenin functionSakanaka, CLeong, PXu, LHarrison, SDWilliams, LTProc Natl Acad Sci U S A 96:12548-5211818547Pubmed2002Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complexGao, ZHSeeling, JMHill, VYochum, AVirshup, DMProc Natl Acad Sci U S A 99:1182-716965538Pubmed2006Site-specific casein kinase 1epsilon-dependent phosphorylation of Dishevelled modulates beta-catenin signalingKlimowski, Laura KGarcia, Benjamin AShabanowitz, JeffreyHunt, Donald FVirshup, David MFEBS J. 273:4594-602Phosphorylated DVL recruits PIP5K1B to the plasma membranePhosphorylated DVL recruits PIP5K1B to the plasma membraneDVL1 and 3 have been shown to co-immunoprecipitate with PIP5KB in HEK293 cells. This interaction is mediated by the N-terminal half of the kinase and the PDZ and DIX domain of DVL and recruits PIPK5B to the receptor complex. The interaction of DVL and PIP5KB is required for the WNT3A-dependent phosphorylation of LRP6 at serine 1490 and threonine 1479, as well as and the subsequent formation of the signalosome and recruitment of AXIN (Pan et al, 2008).Authored: Rothfels, K, 2013-05-29Reviewed: Rajakulendran, Nishani, 2014-01-22Reviewed: van Amerongen, R, 2014-02-14Reviewed: Kikuchi, Akira, 2014-04-22Edited: Gillespie, ME, 2013-10-02Converted from EntitySet in ReactomeReactome DB_ID: 37724071Reactome DB_ID: 18062161UniProt:O14986 PIP5K1BPIP5K1BPIP5K1BSTM7FUNCTION Participates in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. Mediates RAC1-dependent reorganization of actin filaments. Contributes to the activation of PLD2. Together with PIP5K1A is required after stimulation of G-protein coupled receptors for stable platelet adhesion (By similarity).SUBUNIT Interacts with RAC1, AJUBA, PLD1, PLD2 and ARF1.TISSUE SPECIFICITY Detected in heart, pancreas, brain, kidney, skeletal muscle and lung.CAUTION There is confusion in the literature with phosphatidylinositol 4-phosphate 5-kinase type I nomenclature due to the fact that frequently mouse PIP5K1B is named Phosphatidylinositol 4-phosphate 5-kinase type I alpha.UniProtO149861EQUAL540EQUALReactome DB_ID: 37724211ppDVL:PIP5K1B [cytosol]ppDVL:PIP5K1BConverted from EntitySet in ReactomeReactome DB_ID: 37724071Reactome DB_ID: 180621611EQUAL540EQUALReactome Database ID Release 733772421Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3772421ReactomeR-HSA-37724211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3772421.1Reactome Database ID Release 733772434Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3772434ReactomeR-HSA-37724341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3772434.118772438Pubmed2008Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylationPan, WeijunChoi, Sun-CheolWang, HeQin, YuanboVolpicelli-Daley, LauraSwan, LauraLucast, LouiseKhoo, CynthiaZhang, XiaowuLi, LAbrams, Charles SSokol, Sergei YWu, DianqingScience 321:1350-32.7.1.68DVL-associated PIP5K1B phosphorylates PI4P to PI(4,5)P2DVL-associated PIP5K1B phosphorylates PI4P to PI(4,5)P2Stimulation of the WNT pathway controls the activity of PIP5KB in a FZD- and DVL-dependent manner (Pan et al, 2008; Bilic et al, 2007; Cong et al, 2004; Qin et al, 2009). Activation of PIP5KB results in the formation of PI(4,5)P2 at the plasma membrane, which is required through an unclear mechanism for the phosphorylation of LRP6 at serine 1490, LRP6 aggregation into 'signalosomes' and LRP6 phosphorylation at threonine 1479. These events are required for the recruitment of AXIN to the plasma membrane (Pan et al, 2008; Qin et al, 2009).Authored: Rothfels, K, 2013-05-29Reviewed: Rajakulendran, Nishani, 2014-01-22Reviewed: van Amerongen, R, 2014-02-14Reviewed: Kikuchi, Akira, 2014-04-22Edited: Gillespie, ME, 2013-10-02Reactome DB_ID: 1135921Reactome DB_ID: 3924171plasma membraneGO00058861-phosphatidyl-1D-myo-inositol 4-phosphate [ChEBI:17526]1-phosphatidyl-1D-myo-inositol 4-phosphateChEBI17526Reactome DB_ID: 293701Reactome DB_ID: 17985611-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]1-phosphatidyl-1D-myo-inositol 4,5-bisphosphatePIP2ChEBI18348PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 3772421GO0016308GO molecular functionReactome Database ID Release 733772432Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3772432Reactome Database ID Release 733772436Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3772436ReactomeR-HSA-37724361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3772436.115459103Pubmed2004Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, Frizzled and LRPCong, FSchweizer, LVarmus, HDevelopment 131:5103-1517569865Pubmed2007Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylationBilic, JHuang, YLDavidson, GaryZimmermann, TCruciat, CMBienz, MNiehrs, CScience 316:1619-2219561074Pubmed2009Regulation of phosphatidylinositol kinases and metabolism by Wnt3a and DvlQin, YuanboLi, LPan, WeijunWu, DianqingJ. Biol. Chem. 284:22544-8Reactome Database ID Release 73201688Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201688ReactomeR-HSA-2016881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201688.120006983Pubmed2010Dishevelled: The hub of Wnt signalingGao, ChanChen, Ye-GuangCell. Signal. 22:717-2714636582Pubmed2003Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of FrizzledWong, HCBourdelas, AKrauss, ALee, HJShao, YWu, DMlodzik, MShi, DLZheng, JMol Cell 12:1251-6011336703Pubmed2001Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathwayMao, JWang, JLiu, BPan, WFarr GH, 3rdFlynn, CYuan, HTakada, SKimelman, DLi, LWu, DMol Cell 7:801-911433294Pubmed2001PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signallingSun, Tian QiangLu, BingweiFeng, Jia JiaReinhard, ChristophJan, YNFantl, Wendy JWilliams, LTNat. Cell Biol. 3:628-3615935773Pubmed2005Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate developmentOssipova, OlgaDhawan, SangeetaSokol, SergeiGreen, Jeremy B ADev. Cell 8:829-4110990458Pubmed2000The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signallingUmbhauer, MurielDjiane, AlexandreGoisset, CélinePenzo-Mendèz, AlfredoRiou, Jean-FrançoisBoucaut, Jean-ClaudeShi, De-LiEMBO J. 19:4944-5422017973Pubmed2011New insights into the mechanism of Wnt signaling pathway activationKikuchi, AkiraYamamoto, HidekiSato, AkiraMatsumoto, ShinjiInt Rev Cell Mol Biol 291:21-7117529994Pubmed2007The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerizationSchwarz-Romond, ThomasFiedler, MarcShibata, NaokiButler, P Jonathan GKikuchi, AkiraHiguchi, YoshikiBienz, MNat. Struct. Mol. Biol. 14:484-9218093802Pubmed2008Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1, -2, and -3Lee, Yi-NanGao, YuanWang, Hsien-YuCell. Signal. 20:443-52