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.
Rothbächer U, Laurent MN, Deardorff MA, Klein PS, Cho KW, Fraser SE.; ''Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis.''; PubMedEurope PMCScholia
Malbon CC, Wang H, Moon RT.; ''Wnt signaling and heterotrimeric G-proteins: strange bedfellows or a classic romance?''; PubMedEurope PMCScholia
Smrcka AV.; ''G protein βγ subunits: central mediators of G protein-coupled receptor signaling.''; PubMedEurope PMCScholia
Keeble TR, Cooper HM.; ''Ryk: a novel Wnt receptor regulating axon pathfinding.''; PubMedEurope PMCScholia
Shen X, Li H, Ou Y, Tao W, Dong A, Kong J, Ji C, Yu S.; ''The secondary structure of calcineurin regulatory region and conformational change induced by calcium/calmodulin binding.''; PubMedEurope PMCScholia
Mancini M, Toker A.; ''NFAT proteins: emerging roles in cancer progression.''; PubMedEurope PMCScholia
Macheda ML, Sun WW, Kugathasan K, Hogan BM, Bower NI, Halford MM, Zhang YF, Jacques BE, Lieschke GJ, Dabdoub A, Stacker SA.; ''The Wnt receptor Ryk plays a role in mammalian planar cell polarity signaling.''; PubMedEurope PMCScholia
Brantjes H, Roose J, van De Wetering M, Clevers H.; ''All Tcf HMG box transcription factors interact with Groucho-related co-repressors.''; PubMedEurope PMCScholia
Du SJ, Purcell SM, Christian JL, McGrew LL, Moon RT.; ''Identification of distinct classes and functional domains of Wnts through expression of wild-type and chimeric proteins in Xenopus embryos.''; PubMedEurope PMCScholia
Slusarski DC, Yang-Snyder J, Busa WB, Moon RT.; ''Modulation of embryonic intracellular Ca2+ signaling by Wnt-5A.''; PubMedEurope PMCScholia
Yu H, Smallwood PM, Wang Y, Vidaltamayo R, Reed R, Nathans J.; ''Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes.''; PubMedEurope PMCScholia
Ishitani T, Ninomiya-Tsuji J, Matsumoto K.; ''Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling.''; PubMedEurope PMCScholia
Qian D, Jones C, Rzadzinska A, Mark S, Zhang X, Steel KP, Dai X, Chen P.; ''Wnt5a functions in planar cell polarity regulation in mice.''; PubMedEurope PMCScholia
Slusarski DC, Corces VG, Moon RT.; ''Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
Angers S, Moon RT.; ''Proximal events in Wnt signal transduction.''; PubMedEurope PMCScholia
Lee RH, Iioka H, Ohashi M, Iemura S, Natsume T, Kinoshita N.; ''XRab40 and XCullin5 form a ubiquitin ligase complex essential for the noncanonical Wnt pathway.''; PubMedEurope PMCScholia
Chen TY, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.; ''Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.''; PubMedEurope PMCScholia
Liu W, Sato A, Khadka D, Bharti R, Diaz H, Runnels LW, Habas R.; ''Mechanism of activation of the Formin protein Daam1.''; PubMedEurope PMCScholia
Narimatsu M, Bose R, Pye M, Zhang L, Miller B, Ching P, Sakuma R, Luga V, Roncari L, Attisano L, Wrana JL.; ''Regulation of planar cell polarity by Smurf ubiquitin ligases.''; PubMedEurope PMCScholia
Wong GT, Gavin BJ, McMahon AP.; ''Differential transformation of mammary epithelial cells by Wnt genes.''; PubMedEurope PMCScholia
Yu A, Xing Y, Harrison SC, Kirchhausen T.; ''Structural analysis of the interaction between Dishevelled2 and clathrin AP-2 adaptor, a critical step in noncanonical Wnt signaling.''; PubMedEurope PMCScholia
Korinek V, Barker N, Willert K, Molenaar M, Roose J, Wagenaar G, Markman M, Lamers W, Destree O, Clevers H.; ''Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse.''; PubMedEurope PMCScholia
Witzel S, Zimyanin V, Carreira-Barbosa F, Tada M, Heisenberg CP.; ''Wnt11 controls cell contact persistence by local accumulation of Frizzled 7 at the plasma membrane.''; PubMedEurope PMCScholia
Stratton MM, Chao LH, Schulman H, Kuriyan J.; ''Structural studies on the regulation of Ca2+/calmodulin dependent protein kinase II.''; PubMedEurope PMCScholia
Meneghini MD, Ishitani T, Carter JC, Hisamoto N, Ninomiya-Tsuji J, Thorpe CJ, Hamill DR, Matsumoto K, Bowerman B.; ''MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans.''; PubMedEurope PMCScholia
González-Sancho JM, Brennan KR, Castelo-Soccio LA, Brown AM.; ''Wnt proteins induce dishevelled phosphorylation via an LRP5/6- independent mechanism, irrespective of their ability to stabilize beta-catenin.''; PubMedEurope PMCScholia
González-Sancho JM, Greer YE, Abrahams CL, Takigawa Y, Baljinnyam B, Lee KH, Lee KS, Rubin JS, Brown AM.; ''Functional consequences of Wnt-induced dishevelled 2 phosphorylation in canonical and noncanonical Wnt signaling.''; PubMedEurope PMCScholia
O'Connell MP, Fiori JL, Baugher KM, Indig FE, French AD, Camilli TC, Frank BP, Earley R, Hoek KS, Hasskamp JH, Elias EG, Taub DD, Bernier M, Weeraratna AT.; ''Wnt5A activates the calpain-mediated cleavage of filamin A.''; PubMedEurope PMCScholia
Goode BL, Eck MJ.; ''Mechanism and function of formins in the control of actin assembly.''; PubMedEurope PMCScholia
Ahumada A, Slusarski DC, Liu X, Moon RT, Malbon CC, Wang HY.; ''Signaling of rat Frizzled-2 through phosphodiesterase and cyclic GMP.''; PubMedEurope PMCScholia
Keeble TR, Halford MM, Seaman C, Kee N, Macheda M, Anderson RB, Stacker SA, Cooper HM.; ''The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum.''; PubMedEurope PMCScholia
Graham TA, Weaver C, Mao F, Kimelman D, Xu W.; ''Crystal structure of a beta-catenin/Tcf complex.''; PubMedEurope PMCScholia
Kühl M, Sheldahl LC, Malbon CC, Moon RT.; ''Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus.''; PubMedEurope PMCScholia
Tanegashima K, Zhao H, Dawid IB.; ''WGEF activates Rho in the Wnt-PCP pathway and controls convergent extension in Xenopus gastrulation.''; PubMedEurope PMCScholia
Khadka DK, Liu W, Habas R.; ''Non-redundant roles for Profilin2 and Profilin1 during vertebrate gastrulation.''; PubMedEurope PMCScholia
Montcouquiol M, Sans N, Huss D, Kach J, Dickman JD, Forge A, Rachel RA, Copeland NG, Jenkins NA, Bogani D, Murdoch J, Warchol ME, Wenthold RJ, Kelley MW.; ''Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals.''; PubMedEurope PMCScholia
Axelrod JD.; ''Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling.''; PubMedEurope PMCScholia
Penzo-Mendèz A, Umbhauer M, Djiane A, Boucaut JC, Riou JF.; ''Activation of Gbetagamma signaling downstream of Wnt-11/Xfz7 regulates Cdc42 activity during Xenopus gastrulation.''; PubMedEurope PMCScholia
Liu X, Liu T, Slusarski DC, Yang-Snyder J, Malbon CC, Moon RT, Wang H.; ''Activation of a frizzled-2/beta-adrenergic receptor chimera promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via Galphao and Galphat.''; PubMedEurope PMCScholia
Dejmek J, Säfholm A, Kamp Nielsen C, Andersson T, Leandersson K.; ''Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells.''; PubMedEurope PMCScholia
Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W.; ''Functional interaction of beta-catenin with the transcription factor LEF-1.''; PubMedEurope PMCScholia
Wang K, Wang X, Zou J, Zhang A, Wan Y, Pu P, Song Z, Qian C, Chen Y, Yang S, Wang Y.; ''miR-92b controls glioma proliferation and invasion through regulating Wnt/beta-catenin signaling via Nemo-like kinase.''; PubMedEurope PMCScholia
Sagot I, Rodal AA, Moseley J, Goode BL, Pellman D.; ''An actin nucleation mechanism mediated by Bni1 and profilin.''; PubMedEurope PMCScholia
Sheldahl LC, Park M, Malbon CC, Moon RT.; ''Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner.''; PubMedEurope PMCScholia
Ma L, Wang HY.; ''Mitogen-activated protein kinase p38 regulates the Wnt/cyclic GMP/Ca2+ non-canonical pathway.''; PubMedEurope PMCScholia
Habas R, Kato Y, He X.; ''Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1.''; PubMedEurope PMCScholia
Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y.; ''The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway.''; PubMedEurope PMCScholia
Chen W, ten Berge D, Brown J, Ahn S, Hu LA, Miller WE, Caron MG, Barak LS, Nusse R, Lefkowitz RJ.; ''Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4.''; PubMedEurope PMCScholia
Bonacci TM, Ghosh M, Malik S, Smrcka AV.; ''Regulatory interactions between the amino terminus of G-protein betagamma subunits and the catalytic domain of phospholipase Cbeta2.''; PubMedEurope PMCScholia
Dai L, Aye Thu C, Liu XY, Xi J, Cheung PC.; ''TAK1, more than just innate immunity.''; PubMedEurope PMCScholia
Montcouquiol M, Rachel RA, Lanford PJ, Copeland NG, Jenkins NA, Kelley MW.; ''Identification of Vangl2 and Scrb1 as planar polarity genes in mammals.''; PubMedEurope PMCScholia
Yamanaka H, Moriguchi T, Masuyama N, Kusakabe M, Hanafusa H, Takada R, Takada S, Nishida E.; ''JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates.''; PubMedEurope PMCScholia
Schmitt AM, Shi J, Wolf AM, Lu CC, King LA, Zou Y.; ''Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping.''; PubMedEurope PMCScholia
Omer CA, Miller PJ, Diehl RE, Kral AM.; ''Identification of Tcf4 residues involved in high-affinity beta-catenin binding.''; PubMedEurope PMCScholia
MacDonald BT, Tamai K, He X.; ''Wnt/beta-catenin signaling: components, mechanisms, and diseases.''; PubMedEurope PMCScholia
Birbach A.; ''Profilin, a multi-modal regulator of neuronal plasticity.''; PubMedEurope PMCScholia
Wang HY, Malbon CC.; ''Wnt-frizzled signaling to G-protein-coupled effectors.''; PubMedEurope PMCScholia
Shin TH, Yasuda J, Rocheleau CE, Lin R, Soto M, Bei Y, Davis RJ, Mello CC.; ''MOM-4, a MAP kinase kinase kinase-related protein, activates WRM-1/LIT-1 kinase to transduce anterior/posterior polarity signals in C. elegans.''; PubMedEurope PMCScholia
Jenny A, Reynolds-Kenneally J, Das G, Burnett M, Mlodzik M.; ''Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding.''; PubMedEurope PMCScholia
Saneyoshi T, Kume S, Amasaki Y, Mikoshiba K.; ''The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos.''; PubMedEurope PMCScholia
Sato A, Khadka DK, Liu W, Bharti R, Runnels LW, Dawid IB, Habas R.; ''Profilin is an effector for Daam1 in non-canonical Wnt signaling and is required for vertebrate gastrulation.''; PubMedEurope PMCScholia
Rocheleau CE, Yasuda J, Shin TH, Lin R, Sawa H, Okano H, Priess JR, Davis RJ, Mello CC.; ''WRM-1 activates the LIT-1 protein kinase to transduce anterior/posterior polarity signals in C. elegans.''; PubMedEurope PMCScholia
Boutros M, Paricio N, Strutt DI, Mlodzik M.; ''Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling.''; PubMedEurope PMCScholia
Ishitani S, Inaba K, Matsumoto K, Ishitani T.; ''Homodimerization of Nemo-like kinase is essential for activation and nuclear localization.''; PubMedEurope PMCScholia
Dissanayake SK, Wade M, Johnson CE, O'Connell MP, Leotlela PD, French AD, Shah KV, Hewitt KJ, Rosenthal DT, Indig FE, Jiang Y, Nickoloff BJ, Taub DD, Trent JM, Moon RT, Bittner M, Weeraratna AT.; ''The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition.''; PubMedEurope PMCScholia
Sato A, Yamamoto H, Sakane H, Koyama H, Kikuchi A.; ''Wnt5a regulates distinct signalling pathways by binding to Frizzled2.''; PubMedEurope PMCScholia
Li C, Chen H, Hu L, Xing Y, Sasaki T, Villosis MF, Li J, Nishita M, Minami Y, Minoo P.; ''Ror2 modulates the canonical Wnt signaling in lung epithelial cells through cooperation with Fzd2.''; PubMedEurope PMCScholia
Mikels AJ, Nusse R.; ''Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Lai SL, Chien AJ, Moon RT.; ''Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Tree DR, Shulman JM, Rousset R, Scott MP, Gubb D, Axelrod JD.; ''Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A.; ''Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling.''; PubMedEurope PMCScholia
Habas R, Dawid IB, He X.; ''Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation.''; PubMedEurope PMCScholia
Rebecchi MJ, Pentyala SN.; ''Structure, function, and control of phosphoinositide-specific phospholipase C.''; PubMedEurope PMCScholia
Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E.; ''The way Wnt works: components and mechanism.''; PubMedEurope PMCScholia
Dutil EM, Toker A, Newton AC.; ''Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1).''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Keranen LM, Dutil EM, Newton AC.; ''Protein kinase C is regulated in vivo by three functionally distinct phosphorylations.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Malbon CC.; ''Frizzleds: new members of the superfamily of G-protein-coupled receptors.''; PubMedEurope PMCScholia
Ma L, Wang HY.; ''Suppression of cyclic GMP-dependent protein kinase is essential to the Wnt/cGMP/Ca2+ pathway.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC.; ''Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMedEurope PMCScholia
Fradkin LG, Dura JM, Noordermeer JN.; ''Ryks: new partners for Wnts in the developing and regenerating nervous system.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Watanabe N, Higashida C.; ''Formins: processive cappers of growing actin filaments.''; PubMedEurope PMCScholia
Hogan PG, Chen L, Nardone J, Rao A.; ''Transcriptional regulation by calcium, calcineurin, and NFAT.''; PubMedEurope PMCScholia
Poy F, Lepourcelet M, Shivdasani RA, Eck MJ.; ''Structure of a human Tcf4-beta-catenin complex.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Amano M, Nakayama M, Kaibuchi K.; ''Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity.''; PubMedEurope PMCScholia
Kühl M, Sheldahl LC, Park M, Miller JR, Moon RT.; ''The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape.''; PubMedEurope PMCScholia
Guo N, Hawkins C, Nathans J.; ''Frizzled6 controls hair patterning in mice.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Li X, Roszko I, Sepich DS, Ni M, Hamm HE, Marlow FL, Solnica-Krezel L.; ''Gpr125 modulates Dishevelled distribution and planar cell polarity signaling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Yamamoto H, Kitadai Y, Yamamoto H, Oue N, Ohdan H, Yasui W, Kikuchi A.; ''Laminin gamma2 mediates Wnt5a-induced invasion of gastric cancer cells.''; PubMedEurope PMCScholia
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Chen J, Zhang M.; ''The Par3/Par6/aPKC complex and epithelial cell polarity.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kim W, Kim M, Jho EH.; ''Wnt/β-catenin signalling: from plasma membrane to nucleus.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Heasman SJ, Ridley AJ.; ''Mammalian Rho GTPases: new insights into their functions from in vivo studies.''; PubMedEurope PMCScholia
Hofmann F.; ''The biology of cyclic GMP-dependent protein kinases.''; PubMedEurope PMCScholia
Park TJ, Gray RS, Sato A, Habas R, Wallingford JB.; ''Subcellular localization and signaling properties of dishevelled in developing vertebrate embryos.''; PubMedEurope PMCScholia
Wang H, Lee Y, Malbon CC.; ''PDE6 is an effector for the Wnt/Ca2+/cGMP-signalling pathway in development.''; PubMedEurope PMCScholia
May-Simera H, Kelley MW.; ''Planar cell polarity in the inner ear.''; PubMedEurope PMCScholia
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).
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.
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).
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)
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).
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).
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).
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).
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).
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)
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).
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.
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).
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.
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).
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).
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).
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).
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).
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).
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).
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)
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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)
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.
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).
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).
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.
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)
WNT5A stimulation of FZD4-expressing HEK293 cells promotes internalization of the receptor, suggesting a receptor-ligand interaction (Chen et al, 2003).
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).
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).
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).
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).
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).
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).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
WNT target
genes:TCF/LEF:CTNNB1target gene
transcriptskinase C (alpha, beta, gamma
isoforms)beta-gamma:PLC beta
1/2/3G-protein (o/t2)
(inactive)signaling in
response to WNTAnnotated Interactions
WNT target
genes:TCF/LEF:CTNNB1WNT target
genes:TCF/LEF:CTNNB1target gene
transcriptskinase C (alpha, beta, gamma
isoforms)beta-gamma:PLC beta
1/2/3beta-gamma:PLC beta
1/2/3G-protein (o/t2)
(inactive)