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Wnt signaling pathway diagram

updated June 2010 The Wnt pathway is increasingly becoming more complex and new participants are still being uncovered. It becomes hard to include all of these new components and the list below is selective. See the simplified map for a further selection.

Wnt, Porc, Wls/Evi

Wnt genes can be expressed in many different cell types; their expression is not restricted to dedicated cells. There is control over the secretion and processing of the Wnt protein. Wnt proteins are modified by palmitoylation (Willert 2003) and glycosylation (Mason, 1992). A special form of monounsaturated palmitoylation has been detected on a serine residue in the Wnt protein (Takada 2006) The Porcupine (Porc) protein may be involved in secretion or ER transport, as Wingless is retained in the ER in porcupinemutant Drosophila embryos (Kadowaki 1996, van den Heuvel 1993). In C. elegans, the porcupine homolog mom-1has a similar function in promoting secretion of the Wnt protein Mom-2 (Rocheleau 1997). Porcupine has some homology to a family of o-acyl transferases and may be involved in lipid modification of Wnt proteins (Hofmann, 2000, Willert 2003, Zhai, 2004, Takada 2006). In addition to porcupine, several other proteins, including the transmembrane Wls/Evi are specifically involved in Wnt secretion (Banziger, 2006; Bartscherer, 2006).Even though there is control over Wnt secretion, there is no evidence that the function of genes like porcupine and Wls/Evi is restricted to particular cells implying that once Wnt genes are expressed, their proteins will be made in any cell type.

Frp, WIF, Dkk

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 (Glinka1998Fedi, 1999) by binding to LRP (Mao et al,2001, Bafico et al, 2001; Semenov et al, 2001).

Frizzled, LRP/Arrow, Dsh

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 Drosophila as well as in vertebrates,LRP (or arrow) is required for Wnt signaling as well, and can bind to WntFrizzled 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 Wnt signal leads, through its receptor to activation of Dishevelled (Dsh). Wnt signaling at the level of receptor interactions and activity may be associated with intracellular compartments such as vacuoles, given the role of the pre-renon receptor as an adaptor between Wnt receptors and the vacuolar H+adenosine triphosphatase (V-ATPase) complex (Cruciat, 2010).

beta-catenin , GSK3, Axin, WTX, APC, beta-TrCP

Armadillo/beta-catenin is the key mediator of the Wnt signal. In cells not exposed to the signal, beta-catenin levels are kept low through interactions with the protein kinase 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) beta-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 beta-TrCP(Jiang 1998, Marikawa 1998,; reviewed inManiatis 1999) 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 phosphorylatebeta-catenin anymore, releasing it from the Axin complex and accumulation (Salic, 2000).The stabilizedbeta-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. Goentero and Kirschner (2009) have shown that abolute levels of beta-catenin are less important than fold-changes in determining activity of Wnt signaling in target cells (reviewed by Ferrell, 2009). Loss of APC in mammalian cells can also lead to a critical loss over beta-catenin control, leading to cell transformation (reviewed in Polakis, 2000).

TCF, Groucho, Brg-1, Lgs, Pygo, Hyx

In the nucleus, in the absence of the Wnt signal,TCFacts 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).beta-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 beta-catenin displaces Groucho from TCF. Two other key players in this complex are Legless (Bcl9)and Pygopos (Kramps 2002, Thompson 2002,Parker 2002). Brg-1 is a mammalian SWI/SNF and Rsc chromatin-remodelling complex protein binding tobeta-catenin and promoting activity (Barker, 2001) There are many target genes of the Wnt pathway, listed in a separate table.

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Mouse Wnt genes

Updated December 2009

There are 19 Wnt genes in the mouse genome. Most genes linked to MGI, Mouse Genome Informatics. See thecomparative table of all vertebrate Wnt genes for an explanation of the numbering/nomenclature. There is a separate table for syntenic linkage groups.

Also, see alignments of many Wnt proteins

gene

natural allele

Phenotype of Knockouts or other functions

loss midbrain, loss cerebellum McMahon 1990 Thomas KR, 1990, McMahon 1992

Wnt1 (previously called int-1)

swaying Thomas, 1991

deficiency in neural crest derivatives, reduction in dorsolateral neural precursors in the neural tube together with Wnt-3A KO Ikeya M, et al.

decrease in the number of thymocytes (with Wnt-4 deletion;Mulroy 2002)

Wnt2 (previously called irp)

placental defects Monkley, 1996 Defective lung development (with Wnt2b; Goss, 2009)

Wnt2b/13

retinal cell differentiation Kubo, 2003, Kubo, 2005 Defective lung development (with Wnt2b; Goss, 2009)

Wnt3

early gastrulation defect; Axis formation (Liu P, 1999; M. Capecchi; personal communication) Hair growth Kishimoto 2000, Millar 1999 Defect in establishing the AER (Barrow, 2003) medial-lateral retinotectal topography (Schmitt, 2005) hippocampal neurogenesis (Lie, 2005)

somites, tailbud defects (Takada, 1994 Greco 1996 Yoshikawa Y, 1997 ) through loss expression Brachyury (Yamaguchi et al, 1999) This is mediated by Lef-1 (Galceran, 2001)

vestigial Wnt3a tail Greco 1996

deficiency in neural crest derivatives, reduction in dorsolateral neural precursors in the neural tube together with Wnt-1 KO Ikeya M, et al.

Loss hippocampus (Lee et al, 2000) Segmentation oscillation clock (Aulehla 2003) Left right asymmetry (Nakaya 2005) HSC self-renewal defect (Luis, 2008)

kidney defects Stark K, 1994, renal vesicle induction Park, 2007 Sex determination (Kim 2006) defects in female development; absence Mullerian Duct. Ectopic Testosterone synthesis in females. Vainio S, et al 1999

Wnt4

side-branching in mammary gland (Brisken, 2000) decrease in the number of thymocytes (with Wnt-1 deletion; Mulroy 2002) Repression of the migration of steroidogenic adrenal precursors into the gonad Jeays-Ward 2003 Anterior-posterior guidance of commissural axons (not tested in Wnt4 mutant; Lyuksyutova et al, 2003).

truncated limbs, truncated AP axis, reduced number proliferating cells Yamaguchi 1999 Distal lung morphogenesis (Li, 2002) Chondrocyte differentiation, longitudinal skeletal outgrowth (Yang, 2003) Inhibits B cell proliferation and functions as a tumor suppressor (Liang 2003)

Wnt5a

Defects in posterior growth of the female reproductuve tract (Mericskay et al, 2004) shortened and widened cochlea (planar polarity) Qian 2007 Mammary gland phenotype (Roarty, 2007) prostate gland development Huang 2009 intestinal elongation Cervantes, 2009 endothelial differentiation of ES cells Yang, 2009

Wnt5b Wnt6

postaxial Wnt7a hemimelia Parr 1998

limb polarity (Parr 1995) female infertility; failure regression of the Mullerian duct because the receptor for Mullerian-inhibiting substance is not expressed.Parr 1998

maintenance appropriate uterine patterning during

the development of the mouse female reproductive tract (Miller 1998)

Delayed maturation synapses in Cerebellum (Hall, 2000) High levels cell death in response to DES in the Female Reproductive Tract (Carta L, Sassoon D, 2004)

Wnt7b

May promote neuronal differentiation (Hirabayashi 2004) CNS vasculature (with Wnt7b, Stenman 2008)

Placental developmental defects (Parr, 2001) Respiratory failure; defects in early mesenchymal proliferation leading to lung hypoplasia (Shu, 2002) macrophage-induced programmed cell death (Lobov, 2005) also in LRP5 and LEF1 mutants)

Lung development (Rajagopal 2008) CNS vasculature (with Wnt7a, Stenman 2008, Liebner 2008) cortico-medullary axis in the kidney (Yu et al, 2009)

Wnt8a

Wnt8b

Loss of function mutant: no effect on neural development, but changes in gene expression. (Fotaki, 2009)

Wnt9a

(prev. Wnt14)

Loss of function mutant: Joint integrity (Spater 2006)

Wnt9b

regulation of mesenchymal to epithelial transitions (Carroll, 2005)

(prev. Wnt15)

renal vesicle induction Park, 2007 planar cell polarity of the kidney epithelium (Karner, 2009)

Wnt10a


Wnt10b

Taste Papilla Development (Iwatsuki, 2007) Loss of function mutant: decreased trabecular bone (Bennett 2005)

Loss gene promotes Coexpression of Myogenic and Adipogenic program (Vertino, 2005) Overexpression inhibits adipogenesis Ross, 2000

Ureteric branching defects (Majumdar, 2003) Kispert A 1996

Wnt11

Cardiogenesis Pandur 2002

Wnt16

Activated by E2A-Pbx1 fusion protein in Pre-B ALL McWhirter 1999

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Vertebrate Wnt genes

Comparative table of all vertebrate Wnt genes (upd. April , 2003)
In the following table, the red diamond indicates that the particular Wnt gene has been identified. There are additional tables for each species and a separate table for syntenic linkage groups for mouse and human genes. See the footnotes for more info. See alignments Wnts

Wnt genes in Vertebrates

gene
Wnt1

Mouse

Human

Xenopus Chicken Zebrafish

Wnt2 Wnt2B Wnt3 Wnt3A Wnt4 Wnt4B Wnt5A Wnt5B Wnt6 Wnt7A Wnt7B Wnt7C

gene
Wnt8A Wnt8B Wnt9A Wnt9B Wnt10A Wnt10B Wnt11

Mouse

Human

Xenopus Chicken Zebrafish

Wnt12, Wnt13, Wnt14, Wnt15 have all been renamed, see below Wnt-16

notes

1. A gene called Wnt-12 identified by Adamson et al is the same as reported by Lee et al, Hardiman et al, and Wang and Shackleford; and called Wnt-10B. As this mouse Wnt gene is indeed very similar to Wnt-10 genes cloned from Xenopus and Zebrafish (Wolda, S. L. and Moon, R. T. (1992) and it should be called Wnt-10B. 2. The gene called human Wnt-13 (Katoh et al, 1996) is very similar to the human Wnt-2 and is better named Wnt-2B. The first Wnt-2 cloned from Xenopus is called XWnt-2 Wolda, S. L. and Moon, R. T. (1992) but it is the ortholog of Wnt-2B/Wnt13. A Xenopus Wnt-2 cloned by Landesman Y and Sokol SY (1997) is called XWnt-2B, but is actually the ortholog of the human and mouse Wnt-2. 3. The chicken Wnt-8C is probably the true ortholog of Xenopus Wnt-8A, as these genes are very similar. In addition, there are no other chicken Wnt-8 genes yet, nor have separate orthologs of CWnt-8C been cloned from the mouse and the human. 4. Wnt9 was initially only isolated from Hagfisch (Eptatretus stouti) and Thresher Shark (Alopius vulpinus) Sidow 1992. It was realized byQian et al (2003) that the genes first called Wnt14 and Wnt15 are orthologs of Wnt9. Wnt14 and Wnt15 have therefore been renamed into Wnt9A and Wnt9B.

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Human Wnt genes (updated, links restored October 2009)

Note: there are 19 human Wnt genes altogether There is a separate table for syntenic linkage groups. See the comparative table of all vertebrate Wnt genes for and explanation of the numbering/nomenclature. Also, see alignments of Wnt proteins
Linked to HUGO WNT1 WNT2 WNT2B/13 WNT3 WNT3A Mullerian-duct regression and virilization (Biason-Lauber 2004) Tetra-Amelia (Niemann 2004) Disease

WNT4

SERKAL syndrome (Mandel, 2008)

WNT5A Associated with Susceptibility to type 2 diabetes (Kanazawa 2004)

WNT5B

WNT6 WNT7A WNT7B Fuhrmann syndrome

WNT8A WNT8B WNT9A

(previously WNT14)
WNT9B

Previously WNT15)
Odonto-onychodermal dysplasia Adaimy, 2007 , Bohring, 2009 Mutations in Obesity patients Christodoulides 2006

WNT10A

WNT10B

Split-Hand/Foot Malformation (Ugur 2008)

WNT11 WNT16