updated august 2007

The Wnt pathway is increasingly becoming more complex and new participants are still being uncovered. One example is the RNAi screen by DasGupta et al. (2005) identifying a further 237 components. It becomes hard to include all of these new components and the list below is selective. See the simplified map for a further selection.

Note: Santos et al (2005) have analyzed the Wnt pathway by a natural language processing (NLP) system.

Frp, WIF, Dkk, Kremen, Wise	Links
In the extracellular space, several secreted proteins can bind directly to Wnts, to modulate Wnt activity. The secreted Frps (Rattner, 1997) resemble the ligand binding domains of the Frizzled receptor. WIFs form another group of secreted Wnt binding factors (Hsieh 1999). Dickkopf (Dkk) in Xenopus antagonizes Wnt action (Glinka1998 Fedi, 1999) by binding to LRP (Mao et al,2001, Bafico et al, 2001; Semenov et al, 2001). Dkk also binds to Kremen to downregulate LRP on the cell surface (Mao, 2002). Wise and the related protein SOST/Sclerostin can also bind to LRP, to either inhibit or stimulate Wnt signaling (Itasaki, 2003; Semenov 2005, Li 2005) Surprisingly, none of these Wnt inhibitors have been detected in the Drosophila or C. elegans genome (R. Nusse, unpublished)	FRPs
	Frp alignment
	Dickkopf
	model
	2 state model
	Wnt Frontpage

Frizzled, G, LRP/Arrow, CK1g, Boca/Mesd, Shisa, PG, Norrin, Drl/RYK	Links
Wnts interact genetically and biochemically with a complex of receptors.The specificity between Wnts and receptor complexes is determined by the Frizzled class of receptors (Bhanot, 1996), of which the CRD (cysteine-rich domain) is the primary ligand binding domain (Dann et al, 2001). In vertebrates, the secreted protein norrin (nor) is another ligand that can bind to Frizzled (Xu et al, 2004). There are several lines of evidence for Fz coupling to G proteins when activated (Malbon 2001; Katanaev, 2005). Shisa can inhibit Frizzled maturation (Yamamoto, 2005) In Drosophila as well as in vertebrates, LRP (or arrow) is required for Wnt signaling as well, and can bind to Wnt-Frizzled to form a ternary complex (Wehrli et al, 2000: Tamai et al, 2000; Pinson et al, 2000). The cytoplasmic tail of LRP can bind to Axin, in a Wnt and phosphorylation dependent manner (Mao et al., 2001, Tolwinsky, 2003, Tamai et al, 2004). Phosphorylation of the tail of LRP is regulated by two protein kinases: GSK3 and CK1gamma (Zeng, 2005; Davidson 2005; reviewed by Nusse, 2005 . Zeng et al (2008)propose a role for Dsh and Fz in this process as well. The boca/mesd protein in specifically involved in LRP5/6 transport and mutations in this gene in Drosophila and mice have Wnt specific phenotypes (Hsieh, 2003, Culi, 2003).In Drosophila (Derailed, Yoshikawa 2003), C.elegans (Lin-18, Inoue 2004) and in mammals (RYK, Lu et al 2004), receptors of the tyrosine kinase class are also implicated in binding to Wnt and promoting signaling. RYK can interact with Dsh ( Lu et al 2004). The interactions between Wnts and receptors are regulated by Proteoglycans (PG) (reviewed in Baeg, 2000) for which Wnt proteins have a high affinity. (Bradley 1990).	Frizzleds
	Frizzled alignment
	LRP/Arrow
	model
	2 state model
	Wnt Frontpage

Dsh, Par-1, CK1, CK2, PP2C, GBP, Naked, PR72, Dpr/Fr, Dab2, LKB	Links
The Wnt signal leads, through its receptor to activation of Dishevelled (Dsh). While the mechanism of action of Dsh is not known, it can interact with a large number of other molecules, including Casein Kinase 1 (CK1e); Peters 1999, Sakanaka, 1999, Klein et al, 2006) Casein Kinase 2 (CK2; Willert 1997 Song, 2003, Dominguez 2004) and GBP/Frat1 (Li L1999, Salic, 2000; Farr 2000). CK1 appears to be important for Wnt signaling, both in Xenopus and in C. elegans ( Peters 1999). It should be noted that CK1 and CK2 are unrelated kinases. A third kinase interacting with Dsh is Par-1 (Sun et al, 2001). This kinase acts as a positive regaulator of Wnt signaling in Drosophila and in other systems; and can phosphorylate Dsh directly. Ossipova et al. (2005) have suggested that PAR-1A and PAR-1BX are essential for canonical signaling to b-catenin Dsh can also bind to the Phosphatase PP2C (PP2C) which is able to dephosphorylate Axin (Strovel, 1999). The KLHL12-Cullin-3 ubiquitin ligase can leaqd to degradation of Dsh (Angers, 2006) In Drosophila, the naked cuticle gene (naked) acts as an inducible inhibitor of Wingless signaling (Zeng et al, 2000) The naked protein can directly bind to the Dsh protein (Rousset et al, 2001) and to the protein phosphatase PR72 (Creyghton 2005). PR130 modulates Wntsignaling by counteracting repression of Naked cuticle (Creyghton, 2006) Dsh can also bind to GBP (Yost 1998) and to Axin (Smalley, 1999, Salic, 2000), an interaction that may lead to the next step in Wnt signaling, the activation of b-catenin. Dapper and the closely related Frodo (Dpr/Fr) molecules can also bind to Dsh, to regulate its activity (Cheyette, 2002, Gloy, 2002). Finally, Disabled-2 (Dab-2) can interact with Dsh and other Wnt signaling components (Hocevar, 2003) LKB1 (XEEK1) regulates Wnt signalling by binding to GSK (Ossipova, 2003)	Dishevelled
	Dsh alignment
	Naked
	model
	2 state model
	Wnt Frontpage

b-catenin , GSK3, Axin, WTX, PP2A, APC, bTrCP GBP Diversin, MACF1	Links
Armadillo/b-catenin is the key mediator of the Wnt signal. In cells not exposed to the signal, b-catenin levels are kept low through interactions with the protein kinase zw3/GSK-3b, CK1a, APC and Axin (Behrens, 1998 Itoh 1998., Hamada, 1999.) Another player in this complex is the Wilms tumor suppressor gene WTX (Major, 2007, Rivera, 2007) b-catenin is degraded, after phosphorylation by GSK-3 and CK1 alpha (Yanagawa 2002, Liu 2002, Amit 2002), through the ubiquitin pathway (Aberle 1997.), involving interactions with Slimb/ß-TrCP (Jiang 1998, Marikawa 1998,; reviewed in Maniatis 1999) Axin also binds to the phosphatase PP2A. (Hsu 1999), an enzyme that may dephosphorylate APC and b-catenin as well (Xing et al, 2003) According to Li, 2001, PP2A activity inhibits Wnt signaling. The binding between Axin and Diversin brings CK1epsilon to this complex (Schwarz-Romond 2002) In a current model, Wnt signaling initially leads to a complex between Dsh, GBP/Frat1, Axin and Zw3/GSK, which may be the regulatory step in the inactivation of Zw3/GSK (Salic, 2000; Farr 2000). The DIX domain in Axin is similar to the NH2 terminus in Dsh, and promotes interactions between Dsh and Axin (Hsu 1999, Smalley, 1999). As a consequence, GSK does not phosphorylate b-catenin anymore, releasing it from the Axin complex and accumulation (Salic, 2000).The stabilized b-catenin then enters the nucleus (Tolwinski and Wieschaus, 2004) to interact with TCF. Binding of Axin to the cytoplasmic tail of LRP in a Wnt dependent manner (Mao et al., 2001, Tolwinski 2003, Tamai et al, 2004) may also play a role in rearranging this complex. Chen et al (2006) have described a role for MACF1 in the beta-catenin-Axin complex. Loss of APC in mammalian cells can also lead to a critical loss over Arm control, leading to cell transformation (reviewed in Polakis, 2000). APC has a specific function in keeping b-catenin out of the nucleus (Henderson, 2000; Rosin-Arbesfeld, 2000) There are many other proteins binding to APC.	Axin
	b-cat alignment
	Axin alignment
	model
	2 state model
	Wnt Frontpage

TCF, Groucho, HDAC, CBP, Pontin52, Reptin52, Brg-1, Jun, Lgs, Pygo, Pitx2, Chibby, Hyx	Links
In the nucleus, in the absence of the Wnt signal,TCF acts as a repressor of Wnt/Wg target genes (Brannon 1997, Bienz 1998 . Riese 1997; also in C. elegans Lin 1998). TCF can form a complex with Groucho (Cavallo 1998). The repressing effect of Groucho is mediated by interactions with Histone Deacetylases (HDAC, Chen 1999). b-catenin can convert TCF into a transcriptional activator of the same genes that are repressed by TCF alone (reviewed in Nusse, 1999). Daniels and Weis (2005) have shown that b-catenin displaces Groucho from TCF. Two other key players in this complex are Legless (Bcl9) and Pygopos (Kramps 2002, Thompson 2002, Parker 2002). In mammalian cells and in the Zebrafish, Bcl9-2 regulates binding of b-catenin to the adhesion complex or its presence in the nucleus, by interacting with the tyrosine phosphorylated form of b-catenin (Brembeck, 2004). Townsley et al (2004) have also provided evidence for a role for Legless (Bcl9) and Pygopus to transport b-catenin to the nucleus but this model was challenged by Hoffmans et al, 2005. TCF4 can bind to cJun in a JNK dependent manner and activate the Jun promoter (Nateri, 2005). Nuclear export of b-catenin is regulated by RanBP3 (Hendriksen, 2005). Hyrax (Hyx) and its human ortholog, Parafibromin are required for nuclear transduction of the Wnt/Wg signal and bind directly to the C-terminal region of beta-catenin/Armadillo (Mosiman, 2006) Chibby is a nuclear antagonist of b-catenin (Takemura, 2003) In Drosophila, TCF interacts with CBP (P300, Histone acetylase, Waltzer 1998.) repressing gene transcription when Wnt signaling is inactive. In mammalian cells, CBP/P300 can however behave as a co-activator of TCF-b-catenin (Hecht, 2000, Takemaru, 2000). There is also evidence for b-catenin directly acting on another DNA binding protein, Pitx2, converting that into an active transcription factor (Kioussi, 2002) and to the Androgen Receptor (Yang et al, 2002). MED12 a subunit in Mediator has been implicated in b-catenin function (Kim, 2006) Brg-1 is a mammalian SWI/SNF and Rsc chromatin-remodelling complex protein binding to b-catenin and promoting activity (Barker, 2001) Pontin52 and Reptin52 are proteins that are related to each other and interact with b-catenin (Bauer, 2000) . These proteins bind in turn to the histidine triad protein Hint1 (Heiske, 2005) There are many target genes of this pathway, listed in a separate table.	TCF
	table target genes
	model
	2 state model
	Wnt Frontpage

XSox17, Smad4, Lines, CtBP, HBP1	Links
b-catenin activity in the nucleus may also be regulated by interactions with other members of the HMG-box family (to which TCF belongs) including XSox17 (Zorn et al, 1999). Specificity of activation of target genes can be achieved by interaction with other factors, for example the Smad4 protein which mediates TGF-beta signaling (Nishita et al, 2000). he Drosophila segment polarity gene lines is a stage specific modulator of wingless signaling, acting in the nucleus (Hatini, 2000) CtBP acts as another co-repressor binding to TCF (Brannon, 1999) and so does the HMG box protein HBP1 (Sampson, 2001)
	model
	2 state model
	Wnt Frontpage