BioPAX pathway converted from "WNT mediated activation of DVL" in the Reactome database.

WNT mediated activation of DVL

This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>

2.7.11

CSNK2-mediated phosphorylation of DVL

Reactome DB_ID: 10506629

cytosolGO0005829

UniProt:P51140 dsh

dsh

CG18361dshFUNCTION Required to establish coherent arrays of polarized cells and segments in embryos. Plays a role in wingless (wg) signaling, possibly through the reception of the wg signal by target cells and subsequent redistribution of arm protein in response to that signal in embryos. This signal seems to be required to establish planar cell polarity and identity.SUBUNIT Interacts with nkd. This interaction may require zinc.TISSUE SPECIFICITY Found in egg chambers of the ovary and ubiquitously throughout embryogenesis and in disks. Expression is not seen in salivary glands, muscles or ventral ganglia but is observed in brain lobes.DEVELOPMENTAL STAGE Expressed at high levels at 0-1 hour and from 5-17 hours. Also expressed at high levels in early pupae.PTM Phosphorylated. Wg signaling generates the hyperphosphorylated active forms.SIMILARITY Belongs to the DSH family.

Reactomehttp://www.reactome.orgDrosophila melanogaster

NCBI Taxonomy7227UniProtP51140

Chain Coordinates

EQUAL

695

EQUAL

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 10506636

O-phospho-L-serine at unknown position

O-phospho-L-serine [MOD:00046]

EQUAL

695

EQUAL

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10506660

Casein kinase II [cytosol]

Casein kinase II

Reactome DB_ID: 10506644

UniProt:P08182 CkIIbeta

CkIIbeta

CkIIbetaCask-II-bCG15224FUNCTION Participates in Wnt signaling (By similarity). Plays a complex role in regulating the basal catalytic activity of the alpha subunit.SUBUNIT Tetramer of two alpha and two beta subunits.PTM Phosphorylated by alpha subunit.SIMILARITY Belongs to the casein kinase 2 subunit beta family.

UniProtP08182

EQUAL

215

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10506658

CSNK2(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 PhysicalEntity

Reactome Database ID Release 7510506660Database 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=10506660ReactomeR-DME-201711

Reactome 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-DME-201711.1GO0004674

GO molecular function

Reactome Database ID Release 7510506661Database 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=10506661Reactome Database ID Release 7510506663Database 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=10506663ReactomeR-DME-201717

Reactome 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-DME-201717.1DVL 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).

7744250Pubmed1995The dishevelled protein is modified by wingless signaling in DrosophilaYanagawa, Shin-ichivan Leeuwen, FrankWodarz, AndreasKlingensmith, JohnNusse, RoelGenes Dev. 9:1087-979214626Pubmed1997Casein kinase 2 associates with and phosphorylates dishevelledWillert, KarlBrink, MarcelWodarz, AndreasVarmus, HNusse, RoelEMBO J. 16:3089-9610698942Pubmed2000Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesisRothbächer, UteLaurent, Micheline NDeardorff, Matthew AKlein, Peter SCho, Ken WFraser, Scott EEMBO J. 19:1010-2221285348Pubmed2011Sequential 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. 286:10396-4109192851Pubmed1997Human dishevelled genes constitute a DHR-containing multigene familySemënov, Mikhail VSnyder, MichaelGenomics 42:302-10inferred by electronic annotationIEAGOIEA

2.7.11

WNT signaling stimulates CSNK1-dependent phosphorylation of DVL

Reactome DB_ID: 10506636

O-phospho-L-serine at unknown position

EQUAL

695

EQUAL

Reactome DB_ID: 113592

Reactome DB_ID: 10506599

phosphorylated residue at unknown position

phosphorylated residue [MOD:00696]

phosphorylated residue at unknown position

EQUAL

695

EQUAL

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10537386

UniProt:O76324 dco

dco

dcoCG2048dbtFUNCTION Involved in circadian rhythms, viability and molecular oscillations of the clock genes period (per) and timeless (tim). Dbt reduces the stability and thus the accumulation of monomeric per proteins, probably through phosphorylation. No evident circadian oscillation is detected in head. Together with CkIalpha, regulates processing of ci by phosphorylating it which promotes its binding to slmb, the F-box recognition component of the SCF(slmb) E3 ubiquitin-protein ligase (PubMed:16326393).SUBUNIT Forms a complex with per (PubMed:9674431). Interacts with Dlish (PubMed:27692068).TISSUE SPECIFICITY Expressed in photoreceptor cells of the eyes as well as in the region situated between the optic lobe and the central brain.SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.

UniProtO76324

EQUAL

416

EQUAL

Reactome Database ID Release 7510537387Database 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=10537387Reactome Database ID Release 7510537389Database 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=10537389ReactomeR-DME-3772435

Reactome 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-DME-3772435.1CSNK1E 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).

12556519Pubmed2003Casein 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. 278:14066-7311425858Pubmed2001Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase IepsilonKishida, MichikoHino, Shin-ichiroMichiue, TatsuoYamamoto, HidekiKishida, ShoseiFukui, AkimasaAsashima, MakotoKikuchi, AkiraJ. Biol. Chem. 276:33147-5516965538Pubmed2006Site-specific casein kinase 1epsilon-dependent phosphorylation of Dishevelled modulates beta-catenin signalingKlimowski, Laura KGarcia, Benjamin AShabanowitz, JeffreyHunt, Donald FVirshup, David MFEBS J. 273:4594-60211818547Pubmed2002Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complexGao, ZHSeeling, JMHill, VYochum, AVirshup, DMProc Natl Acad Sci U S A 99:1182-710535959Pubmed1999Casein kinase iepsilon in the wnt pathway: regulation of beta-catenin functionSakanaka, CLeong, PXu, LHarrison, SDWilliams, LTProc Natl Acad Sci U S A 96:12548-5210517632Pubmed1999Casein kinase I transduces Wnt signalsPeters, John MMcKay, Renée MMcKay, James PGraff, Jonathan MNature 401:345-50inferred by electronic annotationIEAGOIEA

Phosphorylated DVL recruits PIP5K1B to the plasma membrane

Reactome DB_ID: 10506599

phosphorylated residue at unknown position

EQUAL

695

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10528241

Homologues of PIP5K1B [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPIP5K59B [cytosol]sktl [cytosol]

UniProtQ0E8Y1UniProtQ9W2R3

Reactome DB_ID: 10537380

ppDVL:PIP5K1B [cytosol]

ppDVL:PIP5K1B

Reactome DB_ID: 10506599

phosphorylated residue at unknown position

EQUAL

695

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10528241

Reactome Database ID Release 7510537380Database 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=10537380ReactomeR-DME-3772421

Reactome 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-DME-3772421.1Reactome Database ID Release 7510537382Database 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=10537382ReactomeR-DME-3772434

Reactome 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-DME-3772434.1DVL1 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).

18772438Pubmed2008Wnt3a-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 321:1350-3inferred by electronic annotationIEAGOIEA

2.7.1.68

DVL-associated PIP5K1B phosphorylates PI4P to PI(4,5)P2

Reactome DB_ID: 392417

plasma membraneGO0005886

1-phosphatidyl-1D-myo-inositol 4-phosphate [ChEBI:17526]

1-phosphatidyl-1D-myo-inositol 4-phosphate

ChEBI17526

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 179856

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate

PIP2

ChEBI18348PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10537380

GO0016308

GO molecular function

Reactome Database ID Release 7510537390Database 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=10537390Reactome Database ID Release 7510537392Database 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=10537392ReactomeR-DME-3772436

Reactome 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-DME-3772436.1Stimulation 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).

15459103Pubmed2004Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, Frizzled and LRPCong, FSchweizer, LVarmus, HDevelopment 131:5103-1519561074Pubmed2009Regulation of phosphatidylinositol kinases and metabolism by Wnt3a and DvlQin, YuanboLi, LPan, WeijunWu, DianqingJ. Biol. Chem. 284:22544-817569865Pubmed2007Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylationBilic, JHuang, YLDavidson, GaryZimmermann, TCruciat, CMBienz, MNiehrs, CScience 316:1619-22inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510568307Database 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=10568307ReactomeR-DME-201688

Reactome 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-DME-201688.1The 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).

14636582Pubmed2003Direct 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 12:1251-6017529994Pubmed2007The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerizationSchwarz-Romond, ThomasFiedler, MarcShibata, NaokiButler, P Jonathan GKikuchi, AkiraHiguchi, YoshikiBienz, MNat. Struct. Mol. Biol. 14:484-9211433294Pubmed2001PAR-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. 3:628-3622017973Pubmed2011New insights into the mechanism of Wnt signaling pathway activationKikuchi, AkiraYamamoto, HidekiSato, AkiraMatsumoto, ShinjiInt Rev Cell Mol Biol 291:21-7120006983Pubmed2010Dishevelled: The hub of Wnt signalingGao, ChanChen, Ye-GuangCell. Signal. 22:717-2711336703Pubmed2001Low-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 7:801-918093802Pubmed2008Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1, -2, and -3Lee, Yi-NanGao, YuanWang, Hsien-YuCell. Signal. 20:443-5215935773Pubmed2005Distinct 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. 19:4944-54inferred by electronic annotationIEAGOIEA