Beta-catenin independent WNT signaling (Homo sapiens)

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11, 46, 50, 71, 72, 9437, 40, 67, 88, 105...2, 43, 44, 63, 1258420, 57, 101, 11747, 11184, 11423, 2984, 114549150, 52, 8920, 80, 8861, 1115, 34, 41, 76, 9755, 9559, 77, 83, 87, 896320, 80, 8817, 254, 8, 14, 15, 19...16, 64, 69, 112, 11926, 49, 96, 10831, 75, 8112, 59, 6811184, 114, 11650, 52, 891, 45, 8611110, 20, 36, 76, 82...1175, 42, 69, 71, 90...37, 40, 67, 10598, 1111, 6, 78, 86, 99...7, 28, 48, 70, 74...6830, 55, 1049222, 38, 56, 63, 73...17, 25, 65, 109689120, 36, 88, 1068424, 668913, 59, 89, 9259, 1209, 15, 39, 79, 86...cytosolclathrin-coated endocytic vesicleendoplasmic reticulum lumennucleoplasmEIF2C4 GNG12 FZD3 GNG4 GNB1 GNB4 SMURF2 p-T286-CAMK2A PPP3CA GNGT2 pp-DVL2 pp-DVL1 PSMA3 pT497,T638,S657-PRKCA MYC mRNA PPP3R1 GNG2 'canonical' WNTtarget genesp-DVLGNB1 DVL2 pp-DVL3 GNB5 GTP RAC2 CALM1 PSMB6 Ca2+ GNG10 AXIN2 gene GNAO1 CALM1 ROR2 FZD3'canonical' WNTtarget genetranscriptsppDVL:DAAM1:PFN1GDPPSMB3 NLK mRNA RAC3 PRICKLE1ATPCLTC DAG H2OGNB5 VANGL2:SCRIBPSME2 FZD2 GNB1 ADPWNT:FZD:pDVLGNG7 GNG13 CLTB PSMD1 CALM1 TCF7L2 pp-DVL1 CLTA FZD7 N4GlycoAsn-PalmSWNT5A:ROR2:p-VANGL2pp-DVL2 PSMC1 PLC-beta 1/2/3p-T286,T305,T306-CAMK2AGNG2 GTP UBC(609-684) G-protein beta-gammacomplexFZD2 'canonical'WNTtargetgenes:TCF/LEF:CTNNB1PRKCB FZD2 ppDVL:DAAM1pp-DVL2 AP2B1 Ca2+ GNG3 Fe3+ UBA52(1-76) PSMA6 FZD5 GTP AGO2 PSMA8 PSMD8 GNB4 FZD5 PRKG homodimer:cGMPTCF7L1 GNG10 ITPR1 FZD5 FZD3 GNGT2 N4GlycoAsn-PalmSWNT5A(36-380)DVL2pp-DVL3 FZD2/FZD5/ROR2FZD6 GNAT2 FZD1 FZD3 pT298-NLK dimerAP2M1 NFATC1:CaN:CaMAP2A2(1-939) Fe3+ GTP Fe3+ N4GlycoAsn-PalmS WNT5A(36-380) Calcineurin (CaN)WNT5A:FZDs/RORADPGNG12 GNB5 p-DVL2 PPP3CA FZD8 PSTNRC6A GNAT2:GTPATPPRKG1 Ca2+N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmSWNT5A:ROR2:VANGL2GNAT2 CLTC GNB4 MAP3K7 N4GlycoAsn-PalmS WNT11 N4GlycoAsn-PalmS WNT5B FZD3 GNG7 cGMPGNAO1 TCF/LEF:CTNNB1GDP MYC gene GTP DAAM1 pT298-NLK dimerAP2B1 26S proteasomeN4GlycoAsn-PalmS WNT5A(36-380) ATPPSME1 GNG12 UbN4GlycoAsn-PalmS WNT1 DAAM1 ATPN4GlycoAsn-PalmS WNT1 GNG8 Zn2+ GTP GNG7 MAP3K7PSMC3 FZD1 PSMD13 NLK mRNAGNG10 AP2S1 RHOA AGO2 ADPFZD8 PRKG dimerPSMB4 GNG11 FZD4 ADPWNT5A/WNT11PLCB2 GNB1 ADPAP2A1 GNG12 unknown kinaseUBC(457-532) GNB4 UBC(381-456) WNT:FZDPPP3CB GNG8 PDE6G RAC3 N4GlycoAsn-PalmS WNT5B miR-92b RISCpp-DVL1 GNGT2 GNG11 PPP3CB GNG7 GNB2 HeterotrimericG-protein (o/t2)(inactive)FZD5 PSMB8 pp-DVL3 p-DVL2 FZD4 PSMB7 PDE6B TNRC6C p-T298-NLK FZD2 GNG5 AP2S1 N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT11 p-T286,T305,T306-CAMK2A GNG8 N4GlycoAsn-PalmS WNT1 FZD3 pS5,S82,S84-VANGL2 ATPFZD6 FZD2 PFN1 N4GlycoAsn-PalmS WNT5A(36-380) LEF1 PSMD9 GNG5 ROR2 GNB2 GNB5 PSMC4 GTP VANGL2PLCB2 GNG2 PS N4GlycoAsn-PalmS WNT5A(36-380) GNGT2 FZD7 CLTA GNG7 Ca2+ CLTB GNG10 PSMB5 SMURF2 ADPROR2 PSMA2 PSMB2 N4GlycoAsn-PalmS WNT5A(36-380) CLTB GNB2 RHOA FZD4 WNT5A:FZD4:p-DVL2:AP-2:clathrinGNG3 CTNNB1 PSMC2 GNAT2:PDE6Zn2+ AP2B1 Zn2+ Ca2+ GNB5 pp-DVL1 PPP3CA PPP3R1 pp-DVL3 GNB2 PLCB3 Zn2+ pp-DVL2 TCF7L2 PSMB10 PPP3R1 PARD6A:pp-DVL2FZD4 ROR1 pT201,T212-TCF7L2 EIF2C1 p-S257-NFATC1 ADPFZD2 CLTA DAAM1ROR1 CAMK2A CALM1:4xCa2+p-S-DVL1 TNRC6B PSMD10 GNG2 N4GlycoAsn-PalmS WNT4 N4GlycoAsn-PalmS WNT5A(36-380) Fe3+ SHFM1 p-T497,T638,S657-PRKCAAXIN2 mRNA WNT5A/11:FZDCalcineurin:Calmodulin (CaN:CaM)MYC gene GNG11 AP2S1 UBC(533-608) AP2M1 pp-DVL3 AP2A2(1-939) CAMK2:CaMPSMA4 GDP PSMD12 GNG13 AXIN2 gene CALM1 PRKCG GNG13 N4GlycoAsn-PalmS WNT11 I(1,4,5)P3TCF/LEF:CTNNB1GNAO1 GNG4 N4GlycoAsn-PalmS WNT5A(36-380) pp-DVL2 NLK mRNA:miR-92bRISCAP2A1 ITPR:I(1,4,5)P3tetramerp-T286 CAMK2:CaMp-DVL2 Mg2+ PLCB3 pp-DVL1 UBB(1-76) FZD3 FZD5 FZD3 UBB(153-228) WNT5A/11:FZD:G-protein (alpha o/t2) activePDE6B EIF2C3 GNG12 FZD6 RYKSMURF1 PS UBC(153-228) EIF2C1 I(1,4,5)P3 ATPPARD6A GNGT1 CTNNB1 VANGL2:SCRIB:FZD3PDE6G PSMB1 ITPR2 cGMP FZD5 p-T298-NLK GNAT2 ITPR3 ITPR3 PRKG2 N4GlycoAsn-PalmS WNT5A(36-380) Ca2+ PRKG1 G-protein alpha(o/t2)RAC1 TNRC6A WNT5A-binding FZDsVANGL2 GNGT2 FZD6 FZD2 CALM1 PARD6A GNG5 CTNNB1 miR-92b TNRC6B GNG13 FZD7 FZD4 GNAO1 FZD6 UBC(77-152) PiGNGT1 GNB3 GNG13 ppDVL:RAC:GTPFZD1 ROR2 FZD3 GTPCa2+ PSMA7 WNT/Ca2+ FZDsp-DVL2 p-12S-NFATC1PSMD6 FZD4 FZD3 WNT5A:FZDCAMK2A N4GlycoAsn-PalmS WNT11 GNG11 FZD6 GNG8 N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT11 PSMD5 guanosine5'-monophosphatePDE6A GNG10 GNG3 GNG2 unknown kinaseTCF7L2 p-DVL3 H2OCLTC WNT5A:FZD4:DVL2Activated Proteinkinase C (alpha,beta, gammaisoforms)TCF7 activated PKC alphaGNB1 ROR2 ADPGNGT1 PSMA5 unknown kinaseARRB2 PSMD2 GNB2 miR-92b PSME3 PSMA1 N4GlycoAsn-PalmS WNT5A(36-380) TNRC6C Mg2+ N4GlycoAsn-PalmS WNT11 AP2A1 RPS27A(1-76) pp-DVL2 UBC(229-304) p-DVL2 ITPR2 ATPPCP pathway WNTsFZD2 ATPGNG5 GNG3 PSMB11 N4GlycoAsn-PalmS-WNT5A:RYK:VANGL2TCF dependentsignaling inresponse to WNTPPP3CB GNAT2 ROR2PDE6PLCB1 PSMF1 EIF2C4 NFATC1:CaN:CaMPSMC5 FZD7 FZD2 PSMD4 N4GlycoAsn-PalmS WNT5A(36-380) p-S257-NFATC1 GNGT1 LEF1 GNB3 AP2M1 LEF1 FZD5 N4GlycoAsn-PalmS WNT5A(36-380) UBC(1-76) GNGT1 GNG5 GNAT2 FZD4 TCF7 PSMB9 NLKG-proteinbeta-gamma:PLC beta1/2/3FZD1 FZD4 p-TCF/LEF:CTNNB1GNG4 PPP3R1 GNG3 PRKCA FZD1 p-T286,305,306-CAMK2:MAP3K7RAC1 UBC(305-380) RYK PARD6A:pp-DVL2:SMURFp-T187-MAP3K7WNT5A:FZD4:p-DVL2PFN1N4GlycoAsn-PalmS WNT4 GNB3 PPP3CB GNG4 GNG11 N4GlycoAsn-PalmS WNT4 GNG8 FZD4 PSMD7 pp-DVL2 WNT5A/11:FZD:G-protein (alpha o/t2) inactiveFZD3 PSMD11 WNT5A:FZD4:p-DVL2:ARRB2:AP-2:clathrinROR1 GNB3 FZD4 UBB(77-152) FZD4N4GlycoAsn-PalmS WNT5A(36-380) RHOA:GTP:Mg2+p-S-DVL1 AP2A2(1-939) unknown kinaseMOV10 pT155,S166-LEF1 p-T286,T305,T306-CAMK2A PSMC6 TCF7L1 N4GlycoAsn-PalmS-WNT5A:FZD4FZD5 VANGL2 EIF2C3 WNT5A:FZDs/RORGNAT2 PDE6A PRKG2 RAC2 ADPSMURFVANGL2 FZD7 p-DVL2 DAG VANGL2 DAAM1 PLCB1 SCRIB N4GlycoAsn-PalmS WNT5A(36-380) FZD6 PSME4 PARD6A N4GlycoAsn-PalmS WNT5A(36-380) ARRB2p-DVL3 PI(4,5)P2N4GlycoAsn-PalmS WNT5B GNG4 ITPR1 PPP3CA PARD6A:p-DVL2N4GlycoAsn-PalmS WNT11 PCP pathway FZDsPSMD14 SMURF1 IP3 receptorhomotetramerub-PRICKLE1PSMD3 Ca2+CAMK2AFZD4 GNB4 SCRIBppDVL:DAAM1:RHOA:GTPCa2+ GNB3 N4GlycoAsn-PalmS WNT5A(36-380) FZD5 SCRIB pp-DVLATPCTNNB1 Ca2+ DAGclathrin:AP-2MOV10 CALM1 RAC:GTP50, 85, 107583, 18, 35, 51, 62...33, 583227, 12427, 124


Description

Humans and mice have 19 identified WNT proteins that were originally classified as either 'canonical' or 'non-canonical' depending upon whether they were able to transform the mouse mammary epithelial cell line C57MG and to induce secondary axis formation in Xenopus (Wong et al, 1994; Du et al, 1995). So-called canonical WNTs, including Wnt1, 3, 3a and 7, initiate signaling pathways that destabilize the destruction complex and allow beta-catenin to accumulate and translocate to the nucleus where it promotes transcription (reviewed in Saito-Diaz et al, 2013). Non-canonical WNTs, including Wnt 2, 4, 5a, 5b, 6, 7b, and Wnt11 activate beta-catenin-independent responses that regulate many aspects of morphogenesis and development, often by impinging on the cytoskeleton (reviewed in van Amerongen, 2012). Two of the main beta-catenin-independent pathways are the Planar Cell Polarity (PCP) pathway, which controls the establishment of polarity in the plane of a field of cells, and the WNT/Ca2+ pathway, which promotes the release of intracellular calcium and regulates numerous downstream effectors (reviewed in Gao, 2012; De, 2011). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 3858494
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Rothfels, Karen

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Bibliography

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  75. Wong HC, Mao J, Nguyen JT, Srinivas S, Zhang W, Liu B, Li L, Wu D, Zheng J.; ''Structural basis of the recognition of the dishevelled DEP domain in the Wnt signaling pathway.''; PubMed Europe PMC Scholia
  76. Lai SL, Chien AJ, Moon RT.; ''Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis.''; PubMed Europe PMC Scholia
  77. Andre P, Wang Q, Wang N, Gao B, Schilit A, Halford MM, Stacker SA, Zhang X, Yang Y.; ''The Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2.''; PubMed Europe PMC Scholia
  78. Tree DR, Shulman JM, Rousset R, Scott MP, Gubb D, Axelrod JD.; ''Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling.''; PubMed Europe PMC Scholia
  79. Yu A, Rual JF, Tamai K, Harada Y, Vidal M, He X, Kirchhausen T.; ''Association of Dishevelled with the clathrin AP-2 adaptor is required for Frizzled endocytosis and planar cell polarity signaling.''; PubMed Europe PMC Scholia
  80. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K.; ''The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling.''; PubMed Europe PMC Scholia
  81. Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A.; ''Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling.''; PubMed Europe PMC Scholia
  82. Habas R, Dawid IB, He X.; ''Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation.''; PubMed Europe PMC Scholia
  83. Rebecchi MJ, Pentyala SN.; ''Structure, function, and control of phosphoinositide-specific phospholipase C.''; PubMed Europe PMC Scholia
  84. Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E.; ''The way Wnt works: components and mechanism.''; PubMed Europe PMC Scholia
  85. Dutil EM, Toker A, Newton AC.; ''Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1).''; PubMed Europe PMC Scholia
  86. Minami Y, Oishi I, Endo M, Nishita M.; ''Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases.''; PubMed Europe PMC Scholia
  87. Keranen LM, Dutil EM, Newton AC.; ''Protein kinase C is regulated in vivo by three functionally distinct phosphorylations.''; PubMed Europe PMC Scholia
  88. Axelrod JD, Miller JR, Shulman JM, Moon RT, Perrimon N.; ''Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways.''; PubMed Europe PMC Scholia
  89. Malbon CC.; ''Frizzleds: new members of the superfamily of G-protein-coupled receptors.''; PubMed Europe PMC Scholia
  90. Ma L, Wang HY.; ''Suppression of cyclic GMP-dependent protein kinase is essential to the Wnt/cGMP/Ca2+ pathway.''; PubMed Europe PMC Scholia
  91. Lv L, Wan C, Chen B, Li M, Liu Y, Ni T, Yang Y, Liu Y, Cong X, Mao G, Xue Q.; ''Nemo-like kinase (NLK) inhibits the progression of NSCLC via negatively modulating WNT signaling pathway.''; PubMed Europe PMC Scholia
  92. Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC.; ''Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development.''; PubMed Europe PMC Scholia
  93. Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM.; ''Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.''; PubMed Europe PMC Scholia
  94. Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMed Europe PMC Scholia
  95. Fradkin LG, Dura JM, Noordermeer JN.; ''Ryks: new partners for Wnts in the developing and regenerating nervous system.''; PubMed Europe PMC Scholia
  96. Okamura H, Aramburu J, García-Rodríguez C, Viola JP, Raghavan A, Tahiliani M, Zhang X, Qin J, Hogan PG, Rao A.; ''Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity.''; PubMed Europe PMC Scholia
  97. Watanabe N, Higashida C.; ''Formins: processive cappers of growing actin filaments.''; PubMed Europe PMC Scholia
  98. Hogan PG, Chen L, Nardone J, Rao A.; ''Transcriptional regulation by calcium, calcineurin, and NFAT.''; PubMed Europe PMC Scholia
  99. Poy F, Lepourcelet M, Shivdasani RA, Eck MJ.; ''Structure of a human Tcf4-beta-catenin complex.''; PubMed Europe PMC Scholia
  100. Djiane A, Riou J, Umbhauer M, Boucaut J, Shi D.; ''Role of frizzled 7 in the regulation of convergent extension movements during gastrulation in Xenopus laevis.''; PubMed Europe PMC Scholia
  101. Amano M, Nakayama M, Kaibuchi K.; ''Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity.''; PubMed Europe PMC Scholia
  102. Kühl M, Sheldahl LC, Park M, Miller JR, Moon RT.; ''The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape.''; PubMed Europe PMC Scholia
  103. Guo N, Hawkins C, Nathans J.; ''Frizzled6 controls hair patterning in mice.''; PubMed Europe PMC Scholia
  104. Liu Y, Shi J, Lu CC, Wang ZB, Lyuksyutova AI, Song XJ, Zou Y.; ''Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract.''; PubMed Europe PMC Scholia
  105. Wang MT, Holderfield M, Galeas J, Delrosario R, To MD, Balmain A, McCormick F.; ''K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.''; PubMed Europe PMC Scholia
  106. Li X, Roszko I, Sepich DS, Ni M, Hamm HE, Marlow FL, Solnica-Krezel L.; ''Gpr125 modulates Dishevelled distribution and planar cell polarity signaling.''; PubMed Europe PMC Scholia
  107. De A.; ''Wnt/Ca2+ signaling pathway: a brief overview.''; PubMed Europe PMC Scholia
  108. Wang Y, Guo N, Nathans J.; ''The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells.''; PubMed Europe PMC Scholia
  109. Maung SM, Jenny A.; ''Planar cell polarity in Drosophila.''; PubMed Europe PMC Scholia
  110. Gao B.; ''Wnt regulation of planar cell polarity (PCP).''; PubMed Europe PMC Scholia
  111. Wong HC, Bourdelas A, Krauss A, Lee HJ, Shao Y, Wu D, Mlodzik M, Shi DL, Zheng J.; ''Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled.''; PubMed Europe PMC Scholia
  112. Yamamoto H, Kitadai Y, Yamamoto H, Oue N, Ohdan H, Yasui W, Kikuchi A.; ''Laminin gamma2 mediates Wnt5a-induced invasion of gastric cancer cells.''; PubMed Europe PMC Scholia
  113. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
  114. Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N, Waterman M, Bowerman B, Clevers H, Shibuya H, Matsumoto K.; ''The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF.''; PubMed Europe PMC Scholia
  115. Chen J, Zhang M.; ''The Par3/Par6/aPKC complex and epithelial cell polarity.''; PubMed Europe PMC Scholia
  116. Bazhin AV, Tambor V, Dikov B, Philippov PP, Schadendorf D, Eichmüller SB.; ''cGMP-phosphodiesterase 6, transducin and Wnt5a/Frizzled-2-signaling control cGMP and Ca(2+) homeostasis in melanoma cells.''; PubMed Europe PMC Scholia
  117. Aspenström P.; ''Formin-binding proteins: modulators of formin-dependent actin polymerization.''; PubMed Europe PMC Scholia
  118. Hanaki H, Yamamoto H, Sakane H, Matsumoto S, Ohdan H, Sato A, Kikuchi A.; ''An anti-Wnt5a antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis.''; PubMed Europe PMC Scholia
  119. Gao B, Song H, Bishop K, Elliot G, Garrett L, English MA, Andre P, Robinson J, Sood R, Minami Y, Economides AN, Yang Y.; ''Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2.''; PubMed Europe PMC Scholia
  120. Kim W, Kim M, Jho EH.; ''Wnt/β-catenin signalling: from plasma membrane to nucleus.''; PubMed Europe PMC Scholia
  121. Čajánek L, Ganji RS, Henriques-Oliveira C, Theofilopoulos S, Koník P, Bryja V, Arenas E.; ''Tiam1 regulates the Wnt/Dvl/Rac1 signaling pathway and the differentiation of midbrain dopaminergic neurons.''; PubMed Europe PMC Scholia
  122. Heasman SJ, Ridley AJ.; ''Mammalian Rho GTPases: new insights into their functions from in vivo studies.''; PubMed Europe PMC Scholia
  123. Hofmann F.; ''The biology of cyclic GMP-dependent protein kinases.''; PubMed Europe PMC Scholia
  124. Park TJ, Gray RS, Sato A, Habas R, Wallingford JB.; ''Subcellular localization and signaling properties of dishevelled in developing vertebrate embryos.''; PubMed Europe PMC Scholia
  125. Wang H, Lee Y, Malbon CC.; ''PDE6 is an effector for the Wnt/Ca2+/cGMP-signalling pathway in development.''; PubMed Europe PMC Scholia
  126. May-Simera H, Kelley MW.; ''Planar cell polarity in the inner ear.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114849view16:35, 25 January 2021ReactomeTeamReactome version 75
113295view11:36, 2 November 2020ReactomeTeamReactome version 74
112507view15:46, 9 October 2020ReactomeTeamReactome version 73
101419view11:30, 1 November 2018ReactomeTeamreactome version 66
100957view21:07, 31 October 2018ReactomeTeamreactome version 65
100494view19:41, 31 October 2018ReactomeTeamreactome version 64
100039view16:24, 31 October 2018ReactomeTeamreactome version 63
99592view14:58, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99211view12:43, 31 October 2018ReactomeTeamreactome version 62
93927view13:45, 16 August 2017ReactomeTeamreactome version 61
93513view11:25, 9 August 2017ReactomeTeamreactome version 61
87134view18:50, 18 July 2016MkutmonOntology Term : 'PW:0000008' removed !
87133view18:50, 18 July 2016MkutmonOntology Term : 'Wnt signaling, non-canonical pathway' added !
87093view14:28, 18 July 2016MkutmonOntology Term : 'Wnt signaling pathway' added !
86609view09:22, 11 July 2016ReactomeTeamreactome version 56
83448view12:25, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
'canonical'

WNT target

genes:TCF/LEF:CTNNB1		ComplexR-HSA-8944361 (Reactome)
'canonical' WNT

target gene

transcripts		ComplexR-HSA-4411358 (Reactome)
'canonical' WNT target genesComplexR-HSA-4411390 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGO2 ProteinQ9UKV8 (Uniprot-TrEMBL)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2(1-939) ProteinO94973 (Uniprot-TrEMBL)
AP2B1 ProteinP63010 (Uniprot-TrEMBL)
AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
AP2S1 ProteinP53680 (Uniprot-TrEMBL)
ARRB2 ProteinP32121 (Uniprot-TrEMBL)
ARRB2ProteinP32121 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
AXIN2 gene ProteinENSG00000168646 (Ensembl)
AXIN2 mRNA ProteinENST00000307078 (Ensembl)
Activated Protein

kinase C (alpha, beta, gamma

isoforms)		ComplexR-HSA-425832 (Reactome)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CAMK2:CaMComplexR-HSA-4332345 (Reactome)
CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
CAMK2AComplexR-HSA-4332343 (Reactome)
CLTA ProteinP09496 (Uniprot-TrEMBL)
CLTB ProteinP09497 (Uniprot-TrEMBL)
CLTC ProteinQ00610 (Uniprot-TrEMBL)
CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calcineurin (CaN)ComplexR-HSA-2025977 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)ComplexR-HSA-2025947 (Reactome)
DAAM1 ProteinQ9Y4D1 (Uniprot-TrEMBL)
DAAM1ProteinQ9Y4D1 (Uniprot-TrEMBL)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAGMetaboliteCHEBI:17815 (ChEBI)
DVL2 ProteinO14641 (Uniprot-TrEMBL)
DVL2ProteinO14641 (Uniprot-TrEMBL)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
FZD1 ProteinQ9UP38 (Uniprot-TrEMBL)
FZD2 ProteinQ14332 (Uniprot-TrEMBL)
FZD2/FZD5/ROR2ComplexR-HSA-5140732 (Reactome)
FZD3 ProteinQ9NPG1 (Uniprot-TrEMBL)
FZD3ProteinQ9NPG1 (Uniprot-TrEMBL)
FZD4 ProteinQ9ULV1 (Uniprot-TrEMBL)
FZD4ProteinQ9ULV1 (Uniprot-TrEMBL)
FZD5 ProteinQ13467 (Uniprot-TrEMBL)
FZD6 ProteinO60353 (Uniprot-TrEMBL)
FZD7 ProteinO75084 (Uniprot-TrEMBL)
FZD8 ProteinQ9H461 (Uniprot-TrEMBL)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
G-protein

beta-gamma:PLC beta

1/2/3		ComplexR-HSA-398037 (Reactome)
G-protein alpha (o/t2)ComplexR-HSA-3965383 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GNAO1 ProteinP09471 (Uniprot-TrEMBL)
GNAT2 ProteinP19087 (Uniprot-TrEMBL)
GNAT2:GTPComplexR-HSA-4085966 (Reactome)
GNAT2:PDE6ComplexR-HSA-4085970 (Reactome)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNB5 ProteinO14775 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8 ProteinQ9UK08 (Uniprot-TrEMBL)
GNGT1 ProteinP63211 (Uniprot-TrEMBL)
GNGT2 ProteinO14610 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
Heterotrimeric

G-protein (o/t2)

(inactive)		ComplexR-HSA-3965398 (Reactome)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IP3 receptor homotetramerComplexR-HSA-169686 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
ITPR:I(1,4,5)P3 tetramerComplexR-HSA-169696 (Reactome)
LEF1 ProteinQ9UJU2 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAP3K7ProteinO43318 (Uniprot-TrEMBL)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
MYC gene ProteinENSG00000136997 (Ensembl)
MYC mRNA ProteinENST00000377970 (Ensembl)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
N4GlycoAsn-PalmS WNT5A(36-380)ProteinP41221 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5A:ROR2:VANGL2ComplexR-HSA-4551543 (Reactome)
N4GlycoAsn-PalmS WNT5A:ROR2:p-VANGL2ComplexR-HSA-4551546 (Reactome)
N4GlycoAsn-PalmS WNT1 ProteinP04628 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT11 ProteinO96014 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT4 ProteinP56705 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5A(36-380) ProteinP41221 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5B ProteinQ9H1J7 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS-WNT5A:FZD4ComplexR-HSA-5099901 (Reactome)
N4GlycoAsn-PalmS-WNT5A:RYK:VANGL2ComplexR-HSA-4551548 (Reactome)
NFATC1:CaN:CaMComplexR-HSA-4551448 (Reactome)
NFATC1:CaN:CaMComplexR-HSA-4551463 (Reactome)
NLK mRNA ProteinENST00000407008 (Ensembl)
NLK mRNA:miR-92b RISCComplexR-HSA-4518571 (Reactome)
NLK mRNARnaENST00000407008 (Ensembl)
NLKProteinQ9UBE8 (Uniprot-TrEMBL)
PARD6A ProteinQ9NPB6 (Uniprot-TrEMBL)
PARD6A:p-DVL2ComplexR-HSA-5099880 (Reactome)
PARD6A:pp-DVL2:SMURFComplexR-HSA-4608811 (Reactome)
PARD6A:pp-DVL2ComplexR-HSA-4608813 (Reactome)
PCP pathway FZDsComplexR-HSA-3858485 (Reactome)
PCP pathway WNTsComplexR-HSA-3858483 (Reactome)
PDE6A ProteinP16499 (Uniprot-TrEMBL)
PDE6B ProteinP35913 (Uniprot-TrEMBL)
PDE6G ProteinP18545 (Uniprot-TrEMBL)
PDE6ComplexR-HSA-4085971 (Reactome)
PFN1 ProteinP07737 (Uniprot-TrEMBL)
PFN1ProteinP07737 (Uniprot-TrEMBL)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PLC-beta 1/2/3ComplexR-HSA-425749 (Reactome)
PLCB1 ProteinQ9NQ66 (Uniprot-TrEMBL)
PLCB2 ProteinQ00722 (Uniprot-TrEMBL)
PLCB3 ProteinQ01970 (Uniprot-TrEMBL)
PPP3CA ProteinQ08209 (Uniprot-TrEMBL)
PPP3CB ProteinP16298 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PRICKLE1ProteinQ96MT3 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCB ProteinP05771 (Uniprot-TrEMBL)
PRKCG ProteinP05129 (Uniprot-TrEMBL)
PRKG dimerComplexR-HSA-4551462 (Reactome)
PRKG homodimer:cGMPComplexR-HSA-4551456 (Reactome)
PRKG1 ProteinQ13976 (Uniprot-TrEMBL)
PRKG2 ProteinQ13237 (Uniprot-TrEMBL)
PS MetaboliteCHEBI:18303 (ChEBI)
PSMetaboliteCHEBI:18303 (ChEBI)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RAC3 ProteinP60763 (Uniprot-TrEMBL)
RAC:GTPComplexR-HSA-3858468 (Reactome)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOA:GTP:Mg2+ComplexR-HSA-3858473 (Reactome)
ROR1 ProteinQ01973 (Uniprot-TrEMBL)
ROR2 ProteinQ01974 (Uniprot-TrEMBL)
ROR2ProteinQ01974 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RYK ProteinP34925 (Uniprot-TrEMBL)
RYKProteinP34925 (Uniprot-TrEMBL)
SCRIB ProteinQ14160 (Uniprot-TrEMBL)
SCRIBProteinQ14160 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SMURF1 ProteinQ9HCE7 (Uniprot-TrEMBL)
SMURF2 ProteinQ9HAU4 (Uniprot-TrEMBL)
SMURFComplexR-HSA-173533 (Reactome)
TCF dependent

signaling in

response to WNT		PathwayR-HSA-201681 (Reactome) 19 WNT ligands and 10 FZD receptors have been identified in human cells; interactions amongst these ligands and receptors vary in a developmental and tissue-specific manner and lead to activation of so-called 'canonical' and 'non-canonical' WNT signaling. In the canonical WNT signaling pathway, binding of a WNT ligand to the Frizzled (FZD) and lipoprotein receptor-related protein (LRP) receptors results in the inactivation of the destruction complex, the stabilization and nuclear translocation of beta-catenin and subsequent activation of T-cell factor/lymphoid enhancing factor (TCF/LEF)-dependent transcription. Transcriptional activation in response to canonical WNT signaling controls processes such as cell fate, proliferation and self renewal of stem cells, as well as contributing to oncogenesis (reviewed in MacDonald et al, 2009; Saito-Diaz et al, 2013; Kim et al, 2013).
TCF/LEF:CTNNB1ComplexR-HSA-3299548 (Reactome)
TCF/LEF:CTNNB1ComplexR-HSA-4411397 (Reactome)
TCF7 ProteinP36402 (Uniprot-TrEMBL)
TCF7L1 ProteinQ9HCS4 (Uniprot-TrEMBL)
TCF7L2 ProteinQ9NQB0 (Uniprot-TrEMBL)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
VANGL2 ProteinQ9ULK5 (Uniprot-TrEMBL)
VANGL2:SCRIB:FZD3ComplexR-HSA-4608864 (Reactome)
VANGL2:SCRIBComplexR-HSA-4608863 (Reactome)
VANGL2ProteinQ9ULK5 (Uniprot-TrEMBL)
WNT/Ca2+ FZDsComplexR-HSA-3965381 (Reactome)
WNT5A-binding FZDsComplexR-HSA-5140744 (Reactome)
WNT5A/11:FZD:G-protein (alpha o/t2) activeComplexR-HSA-3965394 (Reactome)
WNT5A/11:FZD:G-protein (alpha o/t2) inactiveComplexR-HSA-3965393 (Reactome)
WNT5A/11:FZDComplexR-HSA-3965390 (Reactome)
WNT5A/WNT11ComplexR-HSA-3965385 (Reactome)
WNT5A:FZD4:DVL2ComplexR-HSA-5138436 (Reactome)
WNT5A:FZD4:p-DVL2:AP-2:clathrinComplexR-HSA-5138458 (Reactome)
WNT5A:FZD4:p-DVL2:ARRB2:AP-2:clathrinComplexR-HSA-5138437 (Reactome)
WNT5A:FZD4:p-DVL2ComplexR-HSA-5138442 (Reactome)
WNT5A:FZDComplexR-HSA-4608830 (Reactome)
WNT5A:FZDs/RORComplexR-HSA-5140740 (Reactome)
WNT5A:FZDs/RORComplexR-HSA-5140748 (Reactome)
WNT:FZD:pDVLComplexR-HSA-3858484 (Reactome)
WNT:FZDComplexR-HSA-3858486 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
activated PKC alphaComplexR-HSA-4332385 (Reactome)
cGMP MetaboliteCHEBI:16356 (ChEBI)
cGMPMetaboliteCHEBI:16356 (ChEBI)
clathrin:AP-2ComplexR-HSA-5138434 (Reactome)
guanosine 5'-monophosphateMetaboliteCHEBI:17345 (ChEBI)
miR-92b ProteinMI0003560 (miRBase mature sequence)
miR-92b RISCComplexR-HSA-4518568 (Reactome)
p-12S-NFATC1ProteinO95644 (Uniprot-TrEMBL)
p-DVL2 ProteinO14641 (Uniprot-TrEMBL)
p-DVL3 ProteinQ92997 (Uniprot-TrEMBL)
p-DVLComplexR-HSA-3858479 (Reactome)
p-S-DVL1 ProteinO14640 (Uniprot-TrEMBL)
p-S257-NFATC1 ProteinO95644 (Uniprot-TrEMBL)
p-T187-MAP3K7ProteinO43318 (Uniprot-TrEMBL)
p-T286 CAMK2:CaMComplexR-HSA-4332348 (Reactome)
p-T286,305,306-CAMK2:MAP3K7ComplexR-HSA-4332361 (Reactome)
p-T286,T305,T306-CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
p-T286,T305,T306-CAMK2AComplexR-HSA-4332355 (Reactome)
p-T286-CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
p-T298-NLK ProteinQ9UBE8 (Uniprot-TrEMBL)
p-T497,T638,S657-PRKCAProteinP17252 (Uniprot-TrEMBL)
p-TCF/LEF:CTNNB1ComplexR-HSA-4411380 (Reactome)
pS5,S82,S84-VANGL2 ProteinQ9ULK5 (Uniprot-TrEMBL)
pT155,S166-LEF1 ProteinQ9UJU2 (Uniprot-TrEMBL)
pT201,T212-TCF7L2 ProteinQ9NQB0 (Uniprot-TrEMBL)
pT298-NLK dimerComplexR-HSA-4411348 (Reactome)
pT298-NLK dimerComplexR-HSA-4411401 (Reactome)
pT497,T638,S657-PRKCA ProteinP17252 (Uniprot-TrEMBL)
pp-DVL1 ProteinO14640 (Uniprot-TrEMBL)
pp-DVL2 ProteinO14641 (Uniprot-TrEMBL)
pp-DVL3 ProteinQ92997 (Uniprot-TrEMBL)
pp-DVLComplexR-HSA-3858467 (Reactome)
ppDVL:DAAM1:PFN1ComplexR-HSA-3965386 (Reactome)
ppDVL:DAAM1:RHOA:GTPComplexR-HSA-3858474 (Reactome)
ppDVL:DAAM1ComplexR-HSA-3858472 (Reactome)
ppDVL:RAC:GTPComplexR-HSA-3858469 (Reactome)
ub-PRICKLE1ProteinQ96MT3 (Uniprot-TrEMBL)
unknown kinaseR-HSA-451336 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
'canonical'

WNT target

genes:TCF/LEF:CTNNB1		ArrowR-HSA-4411365 (Reactome)
'canonical'

WNT target

genes:TCF/LEF:CTNNB1		ArrowR-HSA-8944362 (Reactome)
'canonical' WNT

target gene

transcripts		ArrowR-HSA-4411365 (Reactome)
'canonical' WNT target genesR-HSA-4411365 (Reactome)
'canonical' WNT target genesR-HSA-8944362 (Reactome)
26S proteasomemim-catalysisR-HSA-4608855 (Reactome)
ADPArrowR-HSA-3858480 (Reactome)
ADPArrowR-HSA-4332358 (Reactome)
ADPArrowR-HSA-4332363 (Reactome)
ADPArrowR-HSA-4332388 (Reactome)
ADPArrowR-HSA-4411383 (Reactome)
ADPArrowR-HSA-4411402 (Reactome)
ADPArrowR-HSA-4551570 (Reactome)
ADPArrowR-HSA-4608825 (Reactome)
ADPArrowR-HSA-5138432 (Reactome)
ARRB2ArrowR-HSA-5138459 (Reactome)
ARRB2R-HSA-5138433 (Reactome)
ATPR-HSA-3858480 (Reactome)
ATPR-HSA-4332358 (Reactome)
ATPR-HSA-4332363 (Reactome)
ATPR-HSA-4332388 (Reactome)
ATPR-HSA-4411383 (Reactome)
ATPR-HSA-4411402 (Reactome)
ATPR-HSA-4551570 (Reactome)
ATPR-HSA-4608825 (Reactome)
ATPR-HSA-5138432 (Reactome)
Activated Protein

kinase C (alpha, beta, gamma

isoforms)		mim-catalysisR-HSA-5138432 (Reactome)
CALM1:4xCa2+ArrowR-HSA-4332358 (Reactome)
CALM1:4xCa2+R-HSA-2730872 (Reactome)
CALM1:4xCa2+R-HSA-4332359 (Reactome)
CAMK2:CaMArrowR-HSA-4332359 (Reactome)
CAMK2:CaMR-HSA-4332363 (Reactome)
CAMK2:CaMmim-catalysisR-HSA-4332363 (Reactome)
CAMK2AR-HSA-4332359 (Reactome)
Ca2+ArrowR-HSA-4420052 (Reactome)
Ca2+R-HSA-2730872 (Reactome)
Ca2+R-HSA-4332390 (Reactome)
Ca2+R-HSA-4420052 (Reactome)
Calcineurin (CaN)R-HSA-2730872 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)ArrowR-HSA-2730872 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)R-HSA-4551451 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)mim-catalysisR-HSA-4551451 (Reactome)
DAAM1R-HSA-3858489 (Reactome)
DAGArrowR-HSA-398193 (Reactome)
DAGR-HSA-4332390 (Reactome)
DVL2R-HSA-5138441 (Reactome)
FZD2/FZD5/ROR2R-HSA-5140741 (Reactome)
FZD3R-HSA-4608866 (Reactome)
FZD4R-HSA-5099899 (Reactome)
G-protein

beta-gamma:PLC beta

1/2/3		ArrowR-HSA-398040 (Reactome)
G-protein

beta-gamma:PLC beta

1/2/3		mim-catalysisR-HSA-398193 (Reactome)
G-protein alpha (o/t2)ArrowR-HSA-3965447 (Reactome)
G-protein beta-gamma complexArrowR-HSA-3965447 (Reactome)
G-protein beta-gamma complexR-HSA-398040 (Reactome)
GDPArrowR-HSA-3965444 (Reactome)
GNAT2:GTPR-HSA-4086393 (Reactome)
GNAT2:PDE6ArrowR-HSA-4086393 (Reactome)
GNAT2:PDE6mim-catalysisR-HSA-4086392 (Reactome)
GTPR-HSA-3965444 (Reactome)
H2OR-HSA-4086392 (Reactome)
H2OR-HSA-4551451 (Reactome)
Heterotrimeric

G-protein (o/t2)

(inactive)		R-HSA-3965441 (Reactome)
I(1,4,5)P3ArrowR-HSA-398193 (Reactome)
I(1,4,5)P3R-HSA-169680 (Reactome)
IP3 receptor homotetramerR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramerArrowR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramermim-catalysisR-HSA-4420052 (Reactome)
MAP3K7R-HSA-4332356 (Reactome)
N4GlycoAsn-PalmS WNT5A(36-380)R-HSA-4551555 (Reactome)
N4GlycoAsn-PalmS WNT5A(36-380)R-HSA-4551571 (Reactome)
N4GlycoAsn-PalmS WNT5A(36-380)R-HSA-5099886 (Reactome)
N4GlycoAsn-PalmS WNT5A(36-380)R-HSA-5099899 (Reactome)
N4GlycoAsn-PalmS WNT5A(36-380)R-HSA-5140741 (Reactome)
N4GlycoAsn-PalmS WNT5A:ROR2:VANGL2ArrowR-HSA-4551571 (Reactome)
N4GlycoAsn-PalmS WNT5A:ROR2:VANGL2R-HSA-4551570 (Reactome)
N4GlycoAsn-PalmS WNT5A:ROR2:p-VANGL2ArrowR-HSA-4551570 (Reactome)
N4GlycoAsn-PalmS-WNT5A:FZD4ArrowR-HSA-5099899 (Reactome)
N4GlycoAsn-PalmS-WNT5A:FZD4R-HSA-5138441 (Reactome)
N4GlycoAsn-PalmS-WNT5A:RYK:VANGL2ArrowR-HSA-4551555 (Reactome)
NFATC1:CaN:CaMArrowR-HSA-4551451 (Reactome)
NFATC1:CaN:CaMArrowR-HSA-4551465 (Reactome)
NFATC1:CaN:CaMR-HSA-4551465 (Reactome)
NLK mRNA:miR-92b RISCArrowR-HSA-4518575 (Reactome)
NLK mRNA:miR-92b RISCTBarR-HSA-4518585 (Reactome)
NLK mRNAR-HSA-4518575 (Reactome)
NLK mRNAR-HSA-4518585 (Reactome)
NLKArrowR-HSA-4518585 (Reactome)
NLKR-HSA-4411402 (Reactome)
NLKmim-catalysisR-HSA-4411402 (Reactome)
PARD6A:p-DVL2R-HSA-4608825 (Reactome)
PARD6A:pp-DVL2:SMURFArrowR-HSA-4608854 (Reactome)
PARD6A:pp-DVL2:SMURFmim-catalysisR-HSA-4608852 (Reactome)
PARD6A:pp-DVL2ArrowR-HSA-4608825 (Reactome)
PARD6A:pp-DVL2R-HSA-4608854 (Reactome)
PCP pathway FZDsR-HSA-3858491 (Reactome)
PCP pathway WNTsR-HSA-3858491 (Reactome)
PDE6R-HSA-4086393 (Reactome)
PFN1R-HSA-3965450 (Reactome)
PI(4,5)P2R-HSA-398193 (Reactome)
PLC-beta 1/2/3R-HSA-398040 (Reactome)
PRICKLE1R-HSA-4608852 (Reactome)
PRKG dimerR-HSA-4551453 (Reactome)
PRKG homodimer:cGMPArrowR-HSA-4551453 (Reactome)
PSR-HSA-4332390 (Reactome)
PiArrowR-HSA-4551451 (Reactome)
R-HSA-169680 (Reactome) The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
R-HSA-2730872 (Reactome) Calcineurin (CaN), also called protein phosphatase 2B (PP2B), is a calcium/Calmodulin (CaM)-dependent serine/threonine protein phosphatase. It exists as a heterodimer consisting of CaM-binding catalytic subunit CaN A chain and a Ca+2 binding regulatory CaN B chain. At low calcium concentrations, CaN exists in an inactive state, where the autoinhibitory domain (AID) binds to the active-site cleft. Upon an increase in calcium concentration CaM binds to Ca+2 ions and gets activated. Active CaM binds to CaN regulatory domain (RD) and this causes release of the AID and activation of the phosphatase (Rumi-Masante et al. 2012). Binding of calcium to CaN B regulatory chain also causes a conformational change of the RD of CaN A chain (Yang & Klee 2000).
R-HSA-3858475 (Reactome) WNT-dependent activation of DVL induces the activation of RAC and the formation of a RAC-DVL complex in HEK293 cells (Habas et al, 2003). Activation of RAC and stimulation of PCP/CE signaling depends on the DEP but not the DIX domain of DVL, consistent with earlier reports (Axelrod et al, 1998; Boutros et al, 1998, Habas et al, 2001, Habas et al, 2003). There are conflicting reports regarding the requirement for the DVL PDZ domain in the WNT-dependent activation of RAC (Habas et al, 2003; Cajanek et al, 2013). Activation of RAC almost certainly involves a RAC-specific GEF activity, potentially associated with DVL. In dopaminergic neurons, TIAM1 has been identified as the GEF for WNT5a- and DVL-dependent activation of RAC (Cajanek et al, 2013), however it is not clear whether this is generally true in other cell types and for other WNT ligands. In some cases, RAC activation correlates with activation of the downstream effector c-Jun N terminal kinase (JNK). This is thought to regulate reorganization of the cytoskeleton, however the mechanism of JNK activation is unknown. In other cases, JNK activation appears to be dispensable to the WNT response (Yamanaka et al, 2002; Habas et al, 2003; Rosso et al, 2005; reviewed in Heaseman and Ridley, 2008; Lai et al, 2009)
R-HSA-3858480 (Reactome) In response to WNT signaling, DVL proteins are phosphorylated within the C-terminal 143 amino-acids. This site appears to be common for both canonical and non-canonical WNT signaling as a similar phosphorylation pattern is observed upon stimulation with WNT1 and WNT5A and no discernable supershifted phosphoform is detected upon simultaneous treatment with both ligands (Gonzalez-Sancho et al, 2004). The kinase responsible for this phosphorylation has not been identified, although CK2, CK1 delta and epsilon and PAR1 have all been shown to phosphorylate DVL in vitro and in vivo under varying conditions (reviewed in Gao and Chen, 2010). WNT3a or WNT5a-induced phosphorylation sites are Ser594, Thr595 and Ser597 in Dvl2 (Gonzalez-Sancho et al, 2013).
R-HSA-3858482 (Reactome) The DEP domain of DVL is required both for PCP signaling and for membrane localization upon WNT activation (Boutros et al, 1998; Axelrod et al, 2001; Rothbacher et al, 2000, Wong et al, 2000; Park et al, 2005; Witzel et al, 2006). Although DVL interacts with FZD through its PDZ domain, disruption of this binding interface does not interfere with non-canonical signaling (Wong et al, 2003); membrane recruitment of DVL and establishment of PCP may also rely on other interacting partners (Lee et al, 2007; Li et al, 2013).
R-HSA-3858489 (Reactome) DAAM1 (Dishevelled-associated activator of morphogenesis) is a formin-homology protein that was identified in a yeast two-hybrid screen for interactors with the DVL PDZ domain (Habas et al, 2001). FH proteins play a well-characterized role in regulating cytoskeletal reorganization (reviewed in Aspenstrom, 2010). DAAM1 contains an N-terminal GTPase binding domain (GBD), two central proline-rich FH domains and a C-terminal diaphanous autoinhibitory domain (DAD). In the absence of a WNT signal, DAAM1 exists in an autoinhibited conformation mediated by an intramolecular interaction between the DBD and DAD regions (Habas et al, 2001; Liu et al, 2007). Upon WNT signaling, a direct interaction between the DAD of DAAM1 and the PDZ domain of DVL relieves the autoinhibition. In the activated conformation, DAAM1 may undergo FH-dependent oligomerization and had been shown to recruit RHOA in a GBD-dependent manner (Habas et al, 2001; Liu et al, 2007).
R-HSA-3858491 (Reactome) Detailed biochemical analyses of all the WNT ligand-receptor interactions that initiate the planar cell polarity pathway are not fully elucidated (reviewed in Gao et al, 2012). In Xenopus embryos, direct interaction between Wnt11 and Fzd7 has been shown to be required for convergent extension during gastrulation (Djiane et al, 2000), In mouse Fzd 1, 2, 3 and 6 have known roles in neural tube closure and cochlear hair orientation, two typical PCP processes, although the initiating ligands have not been clearly defined (Guo et al, 2004; Wang et al, 2006; Yu et al, 2010). Similarly, vertebrate Wnt5a and Wnt11 are implicated in numerous PCP processes including limb bud formation, neural tube closure, hair orientation and cytoskeletal rearrangements, but a direct interaction with a FZD receptor has not been demonstrated in all cases (Gao et al, 2011; Qian et al, 2007).
R-HSA-3858495 (Reactome) Activated DAAM1 recruits RHOA to the DVL complex in a WNT-dependent manner. Activated DAAM1 is able to bind to RHOA in both the GDP and GTP bound form in vitro, but displays higher affinity for GTP-bound RHOA (Habas et al, 2001; Liu et al, 2007). Studies in Xenopus have identified a DVL-associated weak guanine exchange factor (WGEF) that promotes the exchange of GDP for GTP on RHOA and is required for WNT-PCP signaling (Tanegashima et al, 2008). Evidence suggests that a similar GEF activity is associated with the DVL-DAAM1-RHOA complex in human cells, but the protein has not been definitively identified (Habas et al, 2001; Liu et al, 2007). GTP-bound RHOA relieves the auto-inhibition of RHO-associated kinases, allowing them to dimerize and effect changes to cytoskeletal organization (reviewed in Amano et al, 2010; Lai et al, 2009). DAAM1 may also play a more direct role in regulating the cytoskeleton in response to WNT signaling, since FH domains have been shown to bind actin directly to nucleate linear actin cables (Sagot et al, 2002; Watanabe and Higashida, 2004).
R-HSA-3965441 (Reactome) Studies with FZD receptors in zebrafish, Xenopus and mouse teratocarcinoma cells suggest that G-proteins are involved in signal transduction downstream of WNT5A/WNT11 signaling. Disrupting the function of G-protein alpha 0 and t2 subunits abrogates FZD-dependent calcium release and activation of potential downstream targets such as PKC, CaMK2 and calcineurin (Slusarski et al, 1997; Liu et al, 1999; Penzo-Mendez et al 2002; reviewed in Malbon et al, 2001; Angers and Moon, 2009)
R-HSA-3965444 (Reactome) After binding the FZD receptor, the G-protein alpha subunit exchanges GDP for GTP (reviewed in Malbon, 2004).
R-HSA-3965446 (Reactome) Binding of a number of 'non-canonical' WNT ligands, notably WNT5a and WNT11, to select FZD receptors has been shown to activate PLC and stimulate release of intracellular calcium stores (reviewed in De, 2011; Kuhl et al, 2000b). This WNT/Ca2+ pathway, which was first demonstrated in zebrafish and has subsequently been identified in Xenopus and human cells as well, activates CaMKII, PKC and calcineurin signaling (Slusarski et al, 1997a, b; Kuhl et al, 2000a, b; reviewed in Angers and Moon, 2009; Niehrs, 2012).
R-HSA-3965447 (Reactome) After nucleotide exchange, the G-protein alpha subunit dissociates from the beta-gamma complex (reviewed in Malbon, 2004). The G-alpha t2 and o subunits activate signaling through PDEs and promote the release of intracellular calcium (Ahumada et al, 2002; reviewed in Wang and Malbon, 2004) while the beta-gamma complex recruits PLC and initiates phosphoinositol signaling (reviewed in Smrcka, 2008), although both components may also play other roles.
R-HSA-3965450 (Reactome) The FH1 domain of DAAM1 recruits Profilin1 (PFN1) to the DVL:DAAM1 complex, and DAAM1 and PFN1 colocalize at stress fibers in response to WNT signaling (Sato et al, 2006). In addition to binding to FH domains, Profilin proteins bind to monomeric actin and in this way serve as a source of actin for polymerization of unbranched actin chains (Birbach, 2008; Goode and Eck, 2007). Depletion of PFN1 inhibits stress fiber formation in response to WNT signaling but does not affect DAAM1-mediated RHO A activation. In vivo, PFN1 is required downstream of DAAM1 for blastopore closure in Xenopus (Sato et al, 2006). In another study, PFN2 was also identified as an FH1 domain-interacting partner of DAAM1. The roles of PFN1 and PFN2 appear to be non-overlapping, however, as PFN2 is not required for blastopore closure in Xenopus but instead contributes to convergent extension (Khadka et al, 2009).
R-HSA-398040 (Reactome) G beta:gamma engages the PH domain of Phospholipase C beta, stimulating phospholipase activity, resulting in increased PIP2 hydrolysis.
R-HSA-398193 (Reactome) Phospholipase C (PLC) isozymes are a group of related proteins that cleave the polar head group from inositol phospholipids, typically in response to signals from cell surface receptors. They hydrolyze the highly phosphorylated lipid phosphatidylinositol 4,5-bisphosphate (PIP2) generating two products: inositol 1,4,5-trisphosphate (IP3), a universal calcium-mobilizing second messenger, and diacylglycerol (DAG), an activator of protein kinase C. PLC-beta isoforms are regulated by heterotrimeric GTP-binding proteins. PLC-beta 1 and 3 are widely expressed, with the highest concentrations found in (differing) specific regions of the brain. PLC-beta 2 is expressed at highest levels in cells of hematopoeitic origin; it is involved in leukocyte signaling and host defense. PLC-beta 4 is highly concentrated in cerebellar Purkinje and granule cells, the median geniculate body, whose axons terminate in the auditory cortex, and the lateral geniculate nucleus, where most retinal axons terminate in a visuotopic representation of each half of the visual field.
R-HSA-4086392 (Reactome) WNT signaling through WNT5A and FZD2 leads to a decrease in intracellular cGMP levels in a manner that is dependent on G alpha t2 and PDE6 (Ahumada et al, 2002; Ma and Wang, 2006; Ma and Wang, 2007, Bazhin et al, 2010). In response to decreasing cGMP levels, the activity of cGMP-dependent protein kinase G (PKG) also decreases, and this reduction in PKG activity is required both for intracellular calcium release and for activation of NFAT-dependent transcription in response to WNT5A (Ma and Wang, 2006).
R-HSA-4086393 (Reactome) Signaling by WNT5A and FZD2 activates PDE6 through G protein alpha subunit t2 (Liu et al, 1999; Ahumada et al, 2002). The discovery that G alpha t2 is involved in WNT:Ca2+ signaling was surprising, as this G protein subunit is best characterized for its role in visual transduction and its expression in vertebrates is almost exclusively restricted to the visual pathway (reviewed in Wang et al, 2004). Recent work in the WNT field has shown that a pathway similar to the visual transduction cascade exists in the mouse F9 teratocarcinoma cell line, CHO cells, zebrafish embryos as well as in a number of human cancer cell lines (Liu et al, 1999; Ahumada et al, 2002; Bazhin et al, 2010). PDE6 is a tetramer of two catalytic subunits, alpha and beta, held in an inactive conformation by two regulatory gamma subunits. Recruitment and binding with G alpha t2 relaxes the inhibitory effect of PDE6gamma and allows activation of the catalytic subunits (reviewed in Wensel, 2008). Activation of PDE6 in the WNT pathway may also depend on p38 MAPK (Ma and Wang, 2007).
R-HSA-4332356 (Reactome) Several studies in C. elegans and vertebrates suggest that a TAK1-NLK kinase cascade regulates the activity of the canonical WNT signaling pathway (Ishitani et al, 1999; Meneghini et al, 1999; Shin et al, 1999; Rocheleau et al, 1999). Activation of this MAPK cascade depends on CAMK2 activity downstream of WNT5a non-canonical signaling (Ishitani et al, 2003a, b). CAMK2 co-precipitates with TAK1/MAP3K7 upon co-transfection in HEK293 cells and calcium signaling activates MAP3K7 in a CAMK2-dependent manner (Ishitani et al, 2003a).
R-HSA-4332358 (Reactome) Dissociation of Ca2+/CaM from activated CAMK2 allows subsequent phosphorylations at Thr 305 and Thr 306. These phosphorylations, which occur within the CaM binding site, prevent reassociation of Ca2+/CaM (reviewed in Stratton et al, 2013).
R-HSA-4332359 (Reactome) Calcium release in response to WNT5A has been shown to activate calcium/calmodulin-dependent protein kinase 2 (CAMK2) (Kuhl et al, 2000; Ishitani et al, 2003a). Human cells have 4 genes encoding CAMK: alpha, beta, delta and gamma. Alpha and beta isoforms are expressed in neuronal tissue while delta and gamma isoforms have broad tissue distribution. The enzyme exists as either a homo- or hetero- dodecamer of ill-defined stoichiometry. In the inactive state, the autoinhibitory loop of CAMK2 blocks the active site. Upon binding of Ca2+/calmodulin, the autoinhibitory loop is displaced, allowing subsequent autophosphorylation at T286 in CAMK2 alpha and activation of the kinase (reviewed in Stratton et al, 2013).
R-HSA-4332363 (Reactome) Binding of CaM to CAMK2 displaces the autoinhibitory loop from the active site and allows CAMK2 to autophosphorylate T286, resulting in CAMK2 activation (reveiwed in Stratton et al, 2013).
R-HSA-4332388 (Reactome) Endogenous MAP3K7 is phosphorylated in a CAMK2-dependent fashion upon co-expression of WNT5A or after stimulation of calcium signaling (Ishitani et al, 2003a). Despite evidence that co-precipitated MAP3K7 is phosphorylated in vitro in the presence of CAMK2, direct phosphorylation of MAP3K7 by CAMK2 using purified proteins has not been demonstrated (Ishitani et al, 2003a). The roles of polyubiquitination and accessory proteins TAB1, 2 or 3 in MAP3K7 activation have not been investigated in the context of non-canonical WNT signaling and are therefore omitted from this reaction (reviewed in Dai et al, 2012).
R-HSA-4332390 (Reactome) Ectopic expression of Xwnt5a or Rfz2 in Xenopus embryos results in PKC translocation to the plasma membrane in a G-protein-dependent manner (Sheldahl et al, 1999; reviewed in Kuhl et al, 2000). PKC activation in response to WNT5A has also been demonstrated in human metastatic melanoma cell lines, contributing to cytoskeletal reorganization leading to invasiveness and motility as well as promoting the epithelial to mesenchymal transition (Weeraratna et al, 2002; Dissanyake et al, 2007; O'Connell et al, 2009)
R-HSA-4411365 (Reactome) The presence of a TCF/LEF:beta catenin complex at the promoter is an preliminary requirement for the activation of transcription at many WNT target genes (reviewed in Saito-Diaz et al, 2013). The ability of the TCF/LEF:beta-catenin complex to bind DNA is negatively regulated by NLK-dependent phosphorylation (Ishitani et al, 2003b). WNT targets AXIN2, DKK1, c-MYC and CCND1 all show decreased expression in A549 cells treated with shRNAs against NLK (Lv et al, 2013).
R-HSA-4411373 (Reactome) Dimerization and autophosphorylation at T298 is required for NLK nuclear localization (Ishitani et al, 2011).
R-HSA-4411383 (Reactome) Activated NLK phosphorylates TCF7L2 and LEF1 at serine and threonine residues that lie in the central region between the DNA-binding and beta-catenin interaction domains. Phosphorylation does not affect the ability of TCF/LEF to bind to beta-catenin, but the phosphorylated complex is not able to bind to target DNA or activate transcription as assessed by EMSA and reporter gene assays (Ishitani et al, 2003b).
R-HSA-4411402 (Reactome) NLK is activated in response to WNT5A in a CAMK2- and MAP3K7- dependent manner (Ishitani et al, 1999; Ishitani et al, 2003a,b). Homodimerization is required for NLK autophosphorylation at T298 and subsequent nuclear localization; mutation of C437 abolishes dimerization, kinase activity and nuclear translocation (Ishitani et al, 2011).
R-HSA-4420052 (Reactome) IP3 promotes the release of intracellular calcium after initiation of WNT signaling. As a downstream consequence of WNT ligand binding, cytosolic cGMP levels decrease, reducing the activity of PKG and relieving its repression of the IP3 receptor. Subsequent binding of IP3 to the receptor allows efflux of the intracellular calcium from the endoplasmic reticulum (Ahumada et al, 2002; Ma and Yang, 2006; reviewed in Hoffman, 2005).
R-HSA-4518575 (Reactome) NLK mRNA is a direct target of miR-92b which binds the 3' UTR and promotes degradation (Wang et al, 2013).
R-HSA-4518585 (Reactome) Translation of NLK mRNA is controlled by miR-92b. miR-92b binds the 3' UTR of NLK mRNA and promotes its degradation, resulting in decreased NLK protein levels. In this way, miR-92b positively regulates canonical TCF/LEF- and beta-catenin-dependent WNT signaling (Wang et al, 2013).
R-HSA-4551451 (Reactome) WNT/Ca2+ signaling has been shown to activate nuclear factor of activated T-cells (NFAT) in Xenopus, mouse F9 teratocarcinoma and human mammary epithelial cells (Saneyoshi et al, 2002; Ma and Wang, 2006; Demjek et al, 2006). NFAT is a transcription factor which induces genes with roles in development, cytokine production, cell-cell interaction and cancer (reviewed in Mancini and Toker, 2009). NFAT transcription activity is modulated by calcium and calcineurin concentration. In resting cells NFAT is cytoplasmic and hyperphosphorylated on fourteen conserved phosphoserine residues in three serine rich motifs termed SRR1, SP2 and SP. Upon Ca2+ induction, these serine residues are dephosphorylated by calcineurin, exposing a nuclear localization sequence and triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Among all the phosphorylation sites one of the sites in SRR-2 motif is not susceptible to dephosphorylation by CaN (Okamura et al, 2000; reviewed in Hogan et al, 2003).
R-HSA-4551453 (Reactome) Active PKG homodimers restrict Ca2+ release in the absence of stimulation by phosphorylating a component of the IP3 receptor complex. PKG homodimers are activated at high (sub- to micromolar) concentrations of cGMP. Upon binding of cGMP to the high and low affinity sites in the regulatory domain, an allosteric change in secondary structure makes the catalytic site accessible to substrate (reviewed in Hoffman, 2005). WNT5A signaling through FZD2 in mouse F9 teratocarcinoma cells results in a PDE6-dependent decrease in cGMP levels. Under low cGMP conditions, the N-terminal domain of PKG occludes the catalytic site, reducing PKG activity and promoting Ca2+ release through the IP3 receptor (Ahumada et al, 2002; Ma and Yang, 2006).
R-HSA-4551465 (Reactome) Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription (Okamura et al, 2000; Demjek et al, 2006; Saneyoshi et al, 2002; reviewed in Hogan et al, 2003).
R-HSA-4551555 (Reactome) RYK is an atypical receptor tyrosine kinase-like receptor that is required for craniofacial and skeletal development, axon guidance and neuronal differentiation. RYK has an extracellular WNT-binding WIF domain, a putative tetrabasic cleavage site, an intracellular PDZ domain and a cytosolic RTK-like catalytic site that is rendered inactive by a number of substitutions at conserved positions (reviewed in Fradkin et al, 2010; Keeble et al, 2006a). The WIF domain of RYK has been shown to interact with WNT1, 3, 3A and 5A (Keeble et al, 2006b; Liu et al, 2005; Macheda et al, 2012; Schmitt et al, 2006). RYK-deficient mice show disruptions to cochlear hair cell orientation suggesting a role for RYK in the planar cell polarity (PCP) pathway. Consistent with this, RYK binds to the PCP protein VANGL2 as assessed by co-immunoprecipitation from HEK293 cells. Formation of a RYK:VANGL2 complex appears to stabilize VANGL2 protein levels through an unknown mechanism (Macheda et al, 2012; Andre et al, 2012). RYK:VANGL may activate RHO A in response to WNT signaling (Macheda et al, 2012).
R-HSA-4551570 (Reactome) Based on studies in mouse, human VANGL2 is predicted to be phosphorylated and activated in response to WNT5A, possibly by CK1delta. Phosphorylation occurs on serine and threonine residues in 2 clusters and appears to be primed by phosphorylation at S5, S82 and S84. VANGL2 phosphorylation and activation occurs in a graded fashion in response to WNT5A distribution, helping to establish PCP asymmetry (Gao et al, 2011).
R-HSA-4551571 (Reactome) WNT5A binds ROR2 and VANGL2 to promote PCP in mouse limb buds. A complex of WNT5A:ROR2:VANGL2 is established along the WNT5A gradient in chondrocytes and regulates VANGL2 phosphorylation. This initiates the establishment of PCP asymmetry in these cells, a hallmark of the PCP pathway (Gao et al, 2011). ROR2 has been shown to function as a receptor or co-receptor for WNT5A in other mammalian systems (Oishi et al, 2003; Mikels and Nusse, 2006; reviewed in Minami et al, 2010), and WNT5A:ROR2 signaling can also negatively regulate canonical beta-catenin-dependent transcription as assessed by reporter gene activity (Mikels and Nusse, 2006; Li et al, 2008).
R-HSA-4608825 (Reactome) DVL2 is phosphorylated upon WNT5A stimulation of HEK293 cells. In human mammary carcinoma cells, DVL2 has been shown to be constititutively bound to PARD6A, irrespective of WNT stimulation and DVL phosphorylation (Narimatsu et al, 2009). PARD6A is a partitioning protein with known roles in the establishment of apico-basal polarity (reviewed in Chen and Zhang, 2013). More recently, PARD6A and the SMURF ubiquitin ligases have been implicated in the PCP pathway, targeting the core PCP protein Prickle1 for degradation (Narimatsu et al, 2009). WNT5A-dependent phosphorylation of DVL2 is required for the subsequent recruitment of SMURF1/2 ubiquitin ligases to the DVL2-PARD6A complex (Narimatsu et al, 2009)
R-HSA-4608852 (Reactome) PRICKLE1 is a conserved PCP protein with a localization pattern opposite to that of DVL. PRICKLE1 is recruited to the PARD6A:ppDVL2:SMURF complex through its interaction with DVL and is subsequently ubiquitinated by the E3 ligase activity of SMURF (Narimatsu et al, 2009; Jenny et al, 2005). This leads to localized degradation of PRICKLE1, contributing to its asymmetrical localization (Narimatsu et al, 2009). Note that in this reaction the interaction between PRICKLE1 and DVL is not shown.
R-HSA-4608854 (Reactome) The E3 ubiquitin ligases SMURF1/2 are recruited to the DVL:PARD6A complex after WNT5A stimulation. Recruitment depends on DVL2 phosphorylation and is mediated by the DEP domain of DVL2 that is important for PCP signaling (Narimatsu et al, 2009; Boutros et al, 1998). Smurf1 and 2 mutant mice show defects in convergent extension and neural tube closure, as well as misorientation of sensory hairs in the inner ear, phenotypes consistent with a role for SMURFs in the PCP pathway (Narimatsu et al, 2009).
R-HSA-4608855 (Reactome) Localized degradation of ub-PRICKLE1 contributes to asymmetric localization of the protein (Narimatsu et al, 2009).
R-HSA-4608862 (Reactome) VANGL2 is a core PCP protein. In Drosophila, asymmetric localization of Stbm (the fly VANGL homologue) and Fz to opposite membranes is a hallmark of the establishment of planar cell polarity (reviewed in Maung and Jenny, 2011). In the mouse inner-ear sensory hair cells, VANGL2 is also asymmetrically distributed in the membrane (Montcouquiol et al, 2003, 2006), and this distribution depends on a direct interaction with SCRIB, a peripheral membrane protein with no known role in fly PCP (reviewed in May-Simera and Kelley, 2012). Asymmetric VANGL2 localization in the mouse inner ear also depends on CELSR1, homologue to the Drosophila core PCP protein Flamingo, however a direct interaction between VANGL2 and CELSR1 has not been demonstrated (Montcouquiol et al, 2006).
R-HSA-4608866 (Reactome) FZD3 shows an asymmetric distribution in the membrane of the mouse inner-ear sensory hair cells in a manner that depends on a direct interaction with VANGL2 (Montcouquiol et al, 2006). In this respect, the vertebrate PCP pathway differs from that of flies, where Vangl2 and Fz are localized to opposing membranes within a single cell (reviewed in Maung and Jenny, 2011). Note that although this reaction depicts a complex of VANGL2:FZD3 with SCRIB, the existence of this ternary complex has not been demonstrated.
R-HSA-5099886 (Reactome) Binding of WNT5A to FZD receptors triggers the phosphorylation of DVL2 in the constitutive DVL2:PARD6A complex and is required for the SMURF-mediated degradation of the core PCP protein PRICKLE1 (Narimatsu et al, 2009)
R-HSA-5099899 (Reactome) WNT5A stimulation of FZD4-expressing HEK293 cells promotes internalization of the receptor, suggesting a receptor-ligand interaction (Chen et al, 2003).
R-HSA-5138432 (Reactome) WNT5A-dependent phosphorylation of DVL2 by PKC is required for the internalization of FZD4 (Chen et al, 2003; Yu et al, 2007). Endogenous PKC alpha beta and gamma co-immunoprecipitate with myc-DVL2, and phosphorylation increases the association with beta-arrestin 2 (ARRB2) (Chen et al, 2003).
R-HSA-5138433 (Reactome) Evidence suggests that FZD4 is endocytosed in a clathrin- and AP-2-dependent manner upon stimulation with WNT5A. Direct interactions have been demonstrated between DVL2 and the AP-2 component mu 2 mediated by simultaneous interaction with the DEP domain and a tetrapeptide motif YHEL of DVL2. Mutation of these regions abrogates FZD4 internalization and PCP signaling (Yu et al, 2007; Yu et al, 2010). DVL2 also interacts with beta-arrestin2 (ARBB2) in a PKC-dependent manner, and in vitro phosphorylation of DVL2 by PKC enhances the interaction between DVL2 and ARBB2 as assessed by co-immunoprecipitation (Chen et al, 2003). There is conflicting evidence on the requirement for ARBB2 for the internalization of FZD4 upon WNT5A signaling, however (Chen et al, 2003; Yu et al, 2007).
R-HSA-5138441 (Reactome) DVL2 is recruited to the WNT5A:FZD4 receptor complex as assessed by co-localization and co-immunoprecipitation (Chen et al, 2003).
R-HSA-5138459 (Reactome) WNT5A-dependent FZD4 uptake into clathrin-coated vesicles depends upon AP-2 and possibly ARBB2 (Chen et al, 2003; Yu et al, 2007). Evidence suggests that ARBB2 dissociates from the receptor-ligand complex before internalization (Chen et al, 2003).
R-HSA-5140741 (Reactome) WNT5A induces the internalization of FZD2, FZD5 and ROR2 in a clathrin-mediated route, but the activation of PKC is not required (Kurayoshi et al, 2007; Sato et al, 2010; Hanaki et al, 2012).
R-HSA-5140747 (Reactome) Stimulation of HEK293, HeLaS3 or KKLS gastric cancer cells with WNT5A promotes the internalization of FZD2, FZD5 and ROR2. Internalization is required for RAC activation downstream of WNT5A and subsequent activation of laminin gamma 2 gene expression which is associated with metastasis and invasion in gastric cancer (Sato et al, 2010; Hanaki et al, 2012; Yamamoto et al, 2009). Knockdown or inhibition of clathrin abrogates receptor internalization and RAC activation suggesting that clathrin-mediated endocytosis is required for this WNT5A-dependent signaling (Sato et al, 2010; Hanaki et al, 2012).
R-HSA-8944362 (Reactome) Transcription of canonical WNT target genes depends on the formation of a TCF/LEF:CTNNB1 complex at the WNT-responsive element (WRE) of the promoter (reviewed in Saito-Diaz et al, 2013). The ability of the TCF/LEF:beta-catenin complex to bind DNA is negatively regulated by NLK-dependent phosphorylation (Ishitani et al, 2003b). WNT targets AXIN2, DKK1, c-MYC and CCND1 all show decreased expression in A549 cells treated with shRNAs against NLK (Lv et al, 2013).
RAC:GTPR-HSA-3858475 (Reactome)
RHOA:GTP:Mg2+R-HSA-3858495 (Reactome)
ROR2R-HSA-4551571 (Reactome)
RYKR-HSA-4551555 (Reactome)
SCRIBR-HSA-4608862 (Reactome)
SMURFR-HSA-4608854 (Reactome)
TCF/LEF:CTNNB1R-HSA-4411383 (Reactome)
TCF/LEF:CTNNB1R-HSA-8944362 (Reactome)
UbR-HSA-4608852 (Reactome)
VANGL2:SCRIB:FZD3ArrowR-HSA-4608866 (Reactome)
VANGL2:SCRIBArrowR-HSA-4608862 (Reactome)
VANGL2:SCRIBR-HSA-4608866 (Reactome)
VANGL2R-HSA-4551555 (Reactome)
VANGL2R-HSA-4551571 (Reactome)
VANGL2R-HSA-4608862 (Reactome)
WNT/Ca2+ FZDsR-HSA-3965446 (Reactome)
WNT5A-binding FZDsR-HSA-5099886 (Reactome)
WNT5A/11:FZD:G-protein (alpha o/t2) activeArrowR-HSA-3965444 (Reactome)
WNT5A/11:FZD:G-protein (alpha o/t2) activeR-HSA-3965447 (Reactome)
WNT5A/11:FZD:G-protein (alpha o/t2) inactiveArrowR-HSA-3965441 (Reactome)
WNT5A/11:FZD:G-protein (alpha o/t2) inactiveR-HSA-3965444 (Reactome)
WNT5A/11:FZD:G-protein (alpha o/t2) inactivemim-catalysisR-HSA-3965444 (Reactome)
WNT5A/11:FZDArrowR-HSA-3965446 (Reactome)
WNT5A/11:FZDArrowR-HSA-3965447 (Reactome)
WNT5A/11:FZDR-HSA-3965441 (Reactome)
WNT5A/WNT11R-HSA-3965446 (Reactome)
WNT5A:FZD4:DVL2ArrowR-HSA-5138441 (Reactome)
WNT5A:FZD4:DVL2R-HSA-5138432 (Reactome)
WNT5A:FZD4:p-DVL2:AP-2:clathrinArrowR-HSA-5138459 (Reactome)
WNT5A:FZD4:p-DVL2:ARRB2:AP-2:clathrinArrowR-HSA-5138433 (Reactome)
WNT5A:FZD4:p-DVL2:ARRB2:AP-2:clathrinR-HSA-5138459 (Reactome)
WNT5A:FZD4:p-DVL2ArrowR-HSA-5138432 (Reactome)
WNT5A:FZD4:p-DVL2R-HSA-5138433 (Reactome)
WNT5A:FZDArrowR-HSA-4608825 (Reactome)
WNT5A:FZDArrowR-HSA-5099886 (Reactome)
WNT5A:FZDs/RORArrowR-HSA-5140741 (Reactome)
WNT5A:FZDs/RORArrowR-HSA-5140747 (Reactome)
WNT5A:FZDs/RORR-HSA-5140747 (Reactome)
WNT:FZD:pDVLArrowR-HSA-3858482 (Reactome)
WNT:FZD:pDVLR-HSA-3858480 (Reactome)
WNT:FZDArrowR-HSA-3858480 (Reactome)
WNT:FZDArrowR-HSA-3858491 (Reactome)
WNT:FZDR-HSA-3858482 (Reactome)
activated PKC alphaArrowR-HSA-4332390 (Reactome)
cGMPR-HSA-4086392 (Reactome)
cGMPR-HSA-4551453 (Reactome)
clathrin:AP-2ArrowR-HSA-5140747 (Reactome)
clathrin:AP-2R-HSA-5138433 (Reactome)
guanosine 5'-monophosphateArrowR-HSA-4086392 (Reactome)
miR-92b RISCR-HSA-4518575 (Reactome)
p-12S-NFATC1R-HSA-4551451 (Reactome)
p-DVLR-HSA-3858482 (Reactome)
p-T187-MAP3K7ArrowR-HSA-4332388 (Reactome)
p-T187-MAP3K7ArrowR-HSA-4411402 (Reactome)
p-T286 CAMK2:CaMArrowR-HSA-4332363 (Reactome)
p-T286 CAMK2:CaMR-HSA-4332358 (Reactome)
p-T286 CAMK2:CaMmim-catalysisR-HSA-4332358 (Reactome)
p-T286,305,306-CAMK2:MAP3K7ArrowR-HSA-4332356 (Reactome)
p-T286,305,306-CAMK2:MAP3K7R-HSA-4332388 (Reactome)
p-T286,T305,T306-CAMK2AArrowR-HSA-4332358 (Reactome)
p-T286,T305,T306-CAMK2AArrowR-HSA-4332388 (Reactome)
p-T286,T305,T306-CAMK2AR-HSA-4332356 (Reactome)
p-T497,T638,S657-PRKCAR-HSA-4332390 (Reactome)
p-TCF/LEF:CTNNB1ArrowR-HSA-4411383 (Reactome)
pT298-NLK dimerArrowR-HSA-4411373 (Reactome)
pT298-NLK dimerArrowR-HSA-4411402 (Reactome)
pT298-NLK dimerR-HSA-4411373 (Reactome)
pT298-NLK dimerTBarR-HSA-8944362 (Reactome)
pT298-NLK dimermim-catalysisR-HSA-4411383 (Reactome)
pp-DVLArrowR-HSA-3858480 (Reactome)
pp-DVLR-HSA-3858475 (Reactome)
pp-DVLR-HSA-3858489 (Reactome)
ppDVL:DAAM1:PFN1ArrowR-HSA-3965450 (Reactome)
ppDVL:DAAM1:RHOA:GTPArrowR-HSA-3858495 (Reactome)
ppDVL:DAAM1ArrowR-HSA-3858489 (Reactome)
ppDVL:DAAM1R-HSA-3858495 (Reactome)
ppDVL:DAAM1R-HSA-3965450 (Reactome)
ppDVL:RAC:GTPArrowR-HSA-3858475 (Reactome)
ub-PRICKLE1ArrowR-HSA-4608852 (Reactome)
ub-PRICKLE1R-HSA-4608855 (Reactome)
unknown kinasemim-catalysisR-HSA-3858480 (Reactome)
unknown kinasemim-catalysisR-HSA-4332388 (Reactome)
unknown kinasemim-catalysisR-HSA-4551570 (Reactome)
unknown kinasemim-catalysisR-HSA-4608825 (Reactome)
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