Summary: wnt family
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "Wnt signaling pathway". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at firstname.lastname@example.org and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Wnt signaling pathway Edit Wikipedia article
The Wnt signaling pathway is a network of proteins that passes signals from receptors on the surface of the cell through the cytoplasm and ultimately to the cell's nucleus where the signaling cascade leads to the expression of target genes. It controls cell-cell communication in the embryo and adult (ie, cell proliferation and differentiation during development and healing). The Wnt signalling pathway is an example of paracrine signalling.
It was identified first for its role in cancer development, and separately in creating normal patterns of embryonic development. Its role in embryonic patterning was discovered when genetic mutations in critical players in this pathway produced abnormal fruit fly embryos. Later research found that the two genes responsible for this type of breast cancer in the mouse and the abnormal patterning in the fruit fly were in the same family and part of the Wnt signaling pathway.
The Wnt signaling pathway is evolutionarily conserved, and functions across species ranging from the fruit fly to humans. It is also required for adult tissue maintenance in bone, heart, muscle, and elsewhere. Mutations in this pathway in adults contribute to degenerative diseases and cancers.
The discovery of Wnt signaling is due largely to several lines of research that led to a better understanding of oncogenic retroviruses. Specifically, a shift in focus to the cancer-causing properties of these viruses led to the discovery of specific cancer-causing genes known as proto-oncogenes. This discovery encouraged the research of Roel Nusse and Harold Vamus in 1982, where they infected mice with the oncogenic retrovirus MMTV (mouse mammary tumor virus) to see which mouse genes would produce breast tumors upon mutation. Using a method known as proviral tagging, they were able to use this research to identify a new mouse proto-oncogene that they named int1 (integration 1).
However, due to other major mutation discoveries in human tumors at that time, int1 was mostly overshadowed. Its importance was not fully appreciated until researchers noted that it had a high degree of conservation across several species, including humans and Drosophila. Its presence in Drosophila melanogaster was particularly important because in 1987, researchers were able to determine that the int1 gene in Drosophila was actually the already characterized Drosophila gene known as Wingless (Wg). This meant that the mammalian int1 was the homologue of Wg.
The uncovering of this shared homology was an exciting discovery due to the fact that previous research by Christiane Nüsslein-Volhard and Eric Wieschaus, which would later win the 1995 Nobel Prize in Physiology or Medicine, had already elucidated the function of Wg as a segment polarity gene involved in embryonic development. Research in int1 and its signaling pathways increased because abnormalities in embryonic development mechanisms have long been implicated in cancer. Consequently, this increase in research would lead to the discovery of further genes related to int1. Since all those genes had not been activated via proviral integration, it quickly became clear that the int gene nomenclature was no longer adequate. Thus, the int/Wingless family was renamed the Wnt family and int1 became Wnt1. The name Wnt was chosen because it is a portmanteau of int and Wg and stands for Wingless-related integration site.
 Wnt signaling proteins
The Wnt proteins are a diverse family of secreted lipid-modified signaling glycoproteins that are 350-400 amino acids in length. The type of lipid modification that occurs on these proteins is palmitoylation of cysteines in a conserved pattern of 23-24 cysteine residues. In Wnt signaling, these proteins act as ligands to activate the different Wnt pathways.
|Homo sapiens||Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt9A, Wnt9B, Wnt10A, Wnt10B, Wnt11, Wnt16|
|Mus musculus||Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt9A, Wnt9B, Wnt10A, Wnt10B, Wnt11, Wnt16|
|Xenopus||Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt10A, Wnt10B, Wnt11, Wnt11R|
|Danio rerio||Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt10A, Wnt10B, Wnt11, Wnt16|
|Drosophila||Wg, DWnt2, DWnt3/5, DWnt 4, DWnt6, WntD/DWnt8, DWnt10|
 Foundation of Wnt signaling
Wnt signaling begins when one of the Wnt proteins binds the N-terminal extra-cellular cysteine-rich domain of a Frizzled (Fz) family receptor. These receptors span the plasma membrane seven times and constitute a distinct family of G-protein coupled receptors (GPCRs). However, to facilitate Wnt signaling, co-receptors may also be required alongside the interaction between the Wnt protein and Fz receptor. Examples include lipoprotein receptor-related protein (LRP)-5/6, receptor tyrosine kinase (Ryk), and ROR2. Upon activation of the receptor and co-receptors, a signal is sent to the phosphoprotein Dishevelled (Dsh), which is located in the cytoplasm. This signal is transmitted via a direct interaction between Fz and Dsh. Dsh are present in all organisms and they all share the following highly conserved protein domains: an amino-terminal DIX domain, a central PDZ domain, and a carboxy-terminal DEP domain. These different domains are important because after Dsh, the Wnt signal can branch off into several different pathways and each pathway interacts with a different combination of the three domains.
 Canonical and noncanonical pathways
The three best characterized Wnt signaling pathways are the canonical Wnt pathway, the noncanonical Planar Cell Polarity pathway, and the noncanonical Wnt/Ca2+ pathway. As their names suggest, these pathways belong to one of two categories: canonical or noncanonical. The difference between these two categories is the presence or absence of β-catenin. The canonical Wnt pathway involves β-catenin, while the noncanonical pathways operate independently of it.
 The canonical Wnt pathway
The canonical Wnt pathway (or Wnt/β-catenin pathway) is the Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family. Without Wnt signaling, the β-catenin would not accumulate in the cytoplasm since a destruction complex would normally degrade it. This destruction complex includes the following proteins: Axin, adenomatosis polyposis coli (APC), protein phosphatase 2A (PP2A), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α). It degrades β-catenin by targeting it for ubiquitination, which subsequently sends it to the proteasome to be digested. However, as soon as Wnt binds Fz and LRP-5/6, the destruction complex function becomes disrupted. This is due to Wnt causing the translocation of both a negative regulator of Axin and the destruction complex to the plasma membrane. This negative regulator becomes localized to the cytoplasmic tail of LRP-5/6. Phosphorylation by other proteins in the destruction complex subsequently binds Axin to this tail as well. Axin becomes de-phosphorylated and its stability and levels are decreased. Dsh then becomes activated via phosphorylation and its DIX and PDZ domains inhibit the GSK3 activity of the destruction complex. This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside the TCF/LEF transcription factors.
 The noncanonical Planar Cell Polarity pathway
The noncanonical Planar Cell Polarity (PCP) pathway is one of the two Wnt pathways that does not involve β-catenin. It does not use LRP-5/6 as its co-receptor and is thought to use NRH1, Ryk, PTK7, or ROR2. As in the canonical Wnt pathway, the PCP pathway is activated via the binding of Wnt to Fz and its co-receptor. The receptor then recruits Dsh, which uses its PDZ and DEP domains to form a complex with Dishevelled-associated activator of morphogenesis 1 (DAAM1). Daam1 then activates the small G-protein Rho through a guanine exchange factor. Rho activates Rho-associated kinase (ROCK), which is one of the major regulators of the cytoskeleton. Dsh also forms a complex with rac1 and mediates profilin binding to actin. Rac1 activates JNK and can also lead to actin polymerization. Profilin binding to actin can result in restructuring of the cytoskeleton and gastrulation.
 The noncanonical Wnt/calcium pathway
The noncanonical Wnt/calcium pathway is the other Wnt pathway that does not stimulate accumulation of β-catenin. Its role is to help regulate calcium release from the endoplasmic reticulum (ER) in order to control intracellular calcium levels. Like other Wnt pathways, upon ligand binding, the activated Fz receptor directly interacts with Dsh and activates specific Dsh-protein domains. The domains involved in Wnt/calcium signaling are the PDZ and DEP domains. However, unlike other Wnt pathways, the Fz receptor also directly interfaces with a trimeric G-protein. This co-stimulation of Dsh and the G-protein can lead to the activation of either PLC or cGMP-specific PDE. If PLC is activated, the plasma membrane component PIP2 is cleaved into DAG and IP3. When IP3 binds its receptor on the ER, calcium is released. Increased concentrations of calcium and DAG can activate Cdc42 through PKC. Cdc42 is an important regulator of cell adhesion, migration, and tissue separation. Increased calcium also activates calcineurin and CaMKII. Calcineurin induces activation of the transcription factor NFAT, which regulates ventral patterning. CamKII activates TAK1 and NLK kinase, which can interfere with TCF/ß-Catenin signaling in the canonical Wnt pathway. However, if PDE is activated, calcium release from the ER is inhibited. PDE mediates this through the inhibition of PKG, which subsequently causes the inhibition of calcium release.
 Other pathways
Along with the three pathways, Wnt signaling also regulates a number of other signaling pathways that have not been as extensively elucidated. One such pathway includes the interaction between Wnt and GSK3. During cell growth, Wnt can inhibit GSK3 in order to activate mTOR in the absence of β-catenin. However, Wnt can also serve as a negative regulator of mTOR via activation of the tumor suppressor TSC2, which is upregulated via Dsh and GSK3 interaction. During myogenesis, Wnt has been shown to use PKA and CREB to activate the genes MyoD and Myf5. Wnt has also been seen to act in conjunction with Ryk and Src to allow for regulation of neuron repulsion during axonal guidance. Wnt regulates gastrulation when CK1 serves as an inhibitor of Rap1-GTPase in order to modulate the cytoskeleton during gastrulation. Further regulation of gastrulation is achieved when Wnt uses ROR2 along with the CDC42 and JNK pathway to regulate the expression of PAPC. Dsh can also interact with aPKC, Par3, Par6, and LGl in order to control cell polarity and microtubule cytoskeleton development. While these pathways overlap with components associated with PCP and Wnt/Calcium signaling, they are considered distinct pathways because they produce entirely different responses.
In order to insure proper functioning, Wnt signaling is constantly regulated at several points along its signaling pathways. For instance, as previously mentioned, Wnt proteins are palmitoylated. The protein porcupine has been shown to be involved in this palmitoylation process, which means that it helps regulate when the Wnt ligand is secreted by determining when it is fully formed. Secretion of Wnt protein is further controlled with proteins such as wntless and evenness interrupted and complexes such as the retromer complex. Upon secretion, the ligand can also be prevented from reaching its receptor through the binding of certain proteins such as the stabilizers Dally and glypican 3, which inhibit diffusion. At the Fz receptor, the binding of proteins other than Wnt can antagonize signaling. Specific antagonists include Dickkopf (Dkk), Wnt inhibitory factor 1 (WIF-1), secreted Frizzled-related proteins (SFRP), Cerebrus, Frzb, Wise, and SOST. All of these constitute inhibitors of Wnt signaling; however, other molecules have been shown to act as activators as well. For example, Norrin and R-Spondin2 have been shown to activate Wnt signaling in the absence of Wnt ligand. Interactions with between signaling pathway has also been seen to regulate the different Wnt pathways. As previously mentioned, this has been seen in the case of the Wnt/calcium pathway, which inhibits the TCF/β-catenin signaling of the canonical Wnt pathway.
 Wnt-induced cell responses
 Embryonic development
 Neural tube patterning
In vertebrates, dorso-ventral patterning of the developing neural tube is achieved by the counteracting activities of morphogenetic signaling gradients set up by Sonic Hedgehog (Shh) in the ventral floor plate and notochord and the canonical Wnt/β-catenin pathway acting in the roof plate, which is the dorsal most region of the neural tube. While evidence that Wnt and Shh are direct antagonists of one another remains to be seen, the role of Wnt in patterning the neural tube is thought to work in an indirectly inhibitory manner towards Shh via the canonical Wnt pathway.
Studies in early neural tube development have shown that the Wnt/β-catenin pathway is largely responsible for regulating Shh expression in the dorsal region of the neural tube. Addition of the GSK3 inhibitor LiCl, which stabilizes β-catenin by preventing its destruction, has been shown to attenuate Shh response in neural tube explants in chicks. Chick electroporation assays have shown that ectopic activation of the Wnt/β-catenin pathway components results in an expansion of the dorsal genes Pax7 and Pax6 into the more ventral regions of the neural tube. These regions become dorsalized due to the ectopic presence of the active Wnt components, which are thought to inhibit the expression of genes such as Olig2 and Nkx2.2 that are normally found there. Furthermore, misexpression of activated canonical Wnt pathway components β-catenin and TCF/LEF results in complete dorsalization of the neural tube. Inhibition of Wnt signaling in the neural tube by introduction of a dominant-negative inactive form of TCF, the transcription factor activated by the Wnt/β-catenin pathway, results in shift of ventral genes into more dorsal regions of the neural tube.
Wnt signaling in the dorsal region of the neural tube also controls the expression of a transcription factor Gli3, one of the main inhibitors of the Shh/Gli pathway. It is by signaling through the canonical Wnt/β-catenin pathway that Wnt is able to activate and control the expression of the Gli3 transcription factor to repress transcriptional activity of Shh/Gli in the dorsal region of the neural tube and elicit dorsal cell fates.
In addition to Wnt and Shh signaling, studies have shown that bone morphogenetic proteins (Bmp) are also necessary for Shh regulation in the dorsal neural tube and since cross-talk exists between the Bmp and Wnt pathways, it was thought that Bmps were regulating the activities of Wnt. Recent studies have shown that Wnt may not be mediated by Bmps, but rather that Bmps may be mediated by Wnts. However, the interactions of the Wnt and Bmp pathways remain unclear and further research needs to be done to identify exactly how Bmps and Wnts work together to elicit dorsal cell fates in the developing neural tube.
 Planar cell polarity
An example of the control of planar cell polarity in insects like Drosophila is determining which direction the tiny hairs on the wings of a fly are aligned. Planar cell polarity is distinct from and perpendicular to apical/basal polarity. The signaling pathway that is involved in planar cell polarity includes frizzled and dishevelled but not the axin complex proteins. The non-classical cadherins Fat, Dachsous, and Flamingo appear to modulate frizzled function. Other proteins including prickle, strabismus, rhoA, and rho-kinase act downstream of frizzled and dishevelled to regulate the cytoskeleton and planar cell polarity.
Some of the proteins involved in planar cell patterning of the Drosophila wing are used in vertebrates during regulation of cell movements during events such as gastrulation. A common feature of both hair patterning in Drosophila and cell movements such as vertebrate gastrulation is control of actin filaments by G proteins such as Rho and Rac.
 Axon guidance
Wnt has some diverse roles in axon guidance. For example, the Wnt receptor Ryk is required for Wnt mediated axon guidance on the contralateral side of the corpus callosum. Another example is in the growing spinal cord commissural neurons: after their extending axons cross the midplate of the spinal cord, they are guided by a Wnt gradient, which is active through the Frizzled receptors in this case.
 Stem cell differentiation
Traditionally, it is assumed that Wnt proteins can act as Stem Cell Growth Factors, promoting the maintenance and proliferation of stem cells.
However, a recent study revealed that Wnt appears to block proper communication, with the Wnt signaling pathway having a negative effect on stem cell function. Thus, in the case of muscle tissue, the misdirected stem cells, instead of generating new muscle cells (myoblasts), differentiated into scar-tissue-producing cells called fibroblasts. The stem cells failed to respond to instructions, actually creating wrong cell types.
Understanding the mechanisms by which pluripotency, self-renewal, and subsequent differentiation are controlled in embryonic stem cells is crucial to utilizing them therapeutically. In addition, control of Wnt signaling may allow for minimizing the use of animal products, which can introduce unwanted pathogens, in stem cell cultures. Wnt signaling was first identified as a potential component to differentiation because of its established role in development. Recent research has supported this hypothesis. There are data to suggest that Wnt signaling induces differentiation of pluripotent stem cells into mesoderm and endoderm progenitor cells.
There are several pieces of evidence to suggest that Wnt signaling is important in stem cell differentiation. TCF3, a transcription factor regulated by Wnt signaling, has been shown to repress nanog, a gene required for stem cell pluripotency and self-renewal. Over expression of another gene associated with pluripotency, OCT4 leads to increased beta-catenin activity, suggesting Wnt involvement.
Studies of embryoid bodies have led to new insights regarding the role of Wnt signaling in human embryonic stem cells. Researchers at Stanford School of Medicine observed that embryoid bodies spontaneously begin gastrulation. They determined that gastrulation in embryoid bodies mimics the in vivo process in human embryos; in vivo gastrulation has been previously linked to the Wnt pathway. Formation of the primitive streak in particular was associated with localized Wnt activation in the embryoid bodies. Once the Wnt pathway is activated, it is self-reinforcing. It is unclear, however, what induces the initial Wnt signaling that begins gastrulation.
Research published in the Journal of Biological Chemistry has suggested that activation of the Wnt pathway in mouse embryonic stem cells induces differentiation into multipotent mesoderm and endoderm cells. This study showed that upon inducing Wnt signaling in mono-layer embryonic stem cell cultures, the cells express high levels of markers associated with mesoderm development, particularly T-brachyury and Flk-1. The cells also expressed high levels of Foxa2, Lhx1, and AFP, which are associated with endoderm development. The progenitor cells created via Wnt activation seemed to have particularly high potential to differentiate into bone and cartilage. The researchers suggested that beta-catenin plays an important role in skeletal development. They demonstrated that the progenitor cells could also develop into endothelial, cardiac, and vascular smooth muscle lineages.
A publication from the American Society of Hematology extended the previous study to human embryonic stem cells (hESCs) by demonstrating that Wnt signaling can induce hematoendothelial cell development from hESCs. This study showed that Wnt3 leads to mesoderm committed cells with hematopoietic potential. Overexpression of Wnt1 led to faster, more efficient hematoendothelial differentiation than Wnt3 overexpression. Wnt1 has also been shown to antagonize neural differentiation; this observation suggests a variety of roles for the Wnt pathway in stem cell activity. In contrast to Wnt3, which is associated with mesoderm and endoderm differentiation, Wnt1 serves the opposite function in neural stem cells. Wnt1 appears to be a major factor in self-renewal of neural stem cells. Wnt stimulation is also associated with regeneration of nervous system cells, which is further evidence of a role in promoting neural stem cell proliferation.
 Environmental enrichment
Changes in Wnt signaling mimic in adult mice the effects of environmental enrichment upon synapses in the hippocampus with regard to reversible increase in their numbers, and spine plus synapse densities at large mossy fiber terminals It seems that Wnt signaling might be part of the means by which experience regulates synapse numbers and hippocampal network structure.
 Clinical implications
Ever since its initial discovery, Wnt signaling has had an association with cancer. When Wnt1 was discovered, it was first identified as a proto-oncogene in a mouse model for breast cancer. Furthermore, the fact that Wnt1 is a homolog of Wg shows that it is involved in embryonic development, which often calls for rapid cell division and migration. Thus, misregulation of these processes can cause unwanted cell growth and movement, which can lead to tumor development.
Activity of the canonical Wnt pathway has been directly measured in the development of benign and malignant breast tumors. Its presence is indicated with elevated levels of β-catenin in the nucleus and/or cytoplasm, which can be detected with immunohistochemical staining and Western blotting. Furthermore, increased β-catenin expression has been strongly correlated with poor prognosis in breast cancer patients. This accumulation may be due to several factors such as mutations in β-catenin, deficiencies in the β-catenin destruction complex, overexpression of Wnt ligands, loss of inhibitors, and/or decreased activity of regulatory pathways (such as the Wnt/calcium pathway). Breast tumors have also been seen to metastasize due to Wnt involvement in the epithelial-mesenchymal transition (EMT). Research looking at metastasis of basal-like breast cancer to the lungs has shown that repression of Wnt/β-catenin signaling can prevent EMT, which can inhibit metastasis.
Wnt signaling has also been implicated in the development of more than just breast-type cancers. Changes in CTNNB1 expression, which is the gene that encodes β-catenin, has been seen in not just breast cancer, but also colorectal cancer, melanoma, prostate cancer, lung cancer, and several other cancer types. Increased expression of Wnt ligand-proteins such as Wnt 1, Wnt2, and Wnt7A have been observed in the development of glioblastoma, oesophageal cancer, and ovarian cancer respectively. Other proteins known to cause multiple types of cancer in the absence of proper functioning include ROR1, ROR2, SFRP4, Wnt5A, WIF1, and those of the TCF/LEF family.
 Type II diabetes
 See also
- Signal transduction
- Developmental biology
- Wingless localisation element 3 (WLE3)
- Baldness treatments
- Mouse Wnt proteins from Signaling Gateway Molecule Pages
- Mouse Frizzled proteins from Signaling Gateway Molecule Pages
- The Wnt Homepage from Nusse Lab, Stanford
- Wnt pathways, their relationship, disease, and therapies by healthvalue.net
- Drosophila Wnt pathway from KEGG
- mouse Wnt pathway from KEGG
- humanα Wnt pathway from KEGG
- Homo sapiens (human) Wnt pathway from KEGG
- video of grey hair reversal
- Netpath - A curated resource of signal transduction pathways in humans
- Wnt Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
- Wnt game
- Logan C.W., Nusse R. (2004). "The Wnt signaling pathway in development and disease". Cell Dev. Bio. 20: 781–810. doi:10.1146/annurev.cellbio.20.010403.113126. PMID 15473860.
- Lie DC, Colamarino SA, Song HJ, Désiré L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (October 2005). "Wnt signalling regulates adult hippocampal neurogenesis". Nature 437 (7063): 1370–5. doi:10.1038/nature04108. PMID 16251967.
- Nusse, Roel; Varmus, Harold (22 May 2012). "Three decades of Wnts: a personal perspective on how a scientific field developed". The EMBO Journal 31 (12): 2670–2684. doi:10.1038/emboj.2012.146.
- Klaus A., Birchmeier W. (2008). "Wnt signaling and its impact on development and cancer". Nature Reviews Cancer 8 (5): 387–398. doi:10.1038/nrc2389. PMID 18432252.
- Cadigan K.M., Nusse R. (1997). "Wnt signaling: a common theme is animal development". Genes & Development 11 (24): 3286–3305. doi:10.1101/gad.11.24.3286.
- Komiya, Y; Habas, R (2008 Apr). "Wnt signal transduction pathways.". Organogenesis 4 (2): 68–75. PMID 19279717.
- Nusse, Roel. "The Wnt Homepage". Retrieved 15 April 2013.
- Rao, Tata; Kühl, Michael (2010). "An Updated Overview on Wnt Signaling Pathways : A Prelude for More". Circulation Research 106: 1798–1806. doi:10.1161/CIRCRESAHA.110.219840.
- Schulte, Gunnar; Bryja, Vítězslav (1 October 2007). "The Frizzled family of unconventional G-protein-coupled receptors". Trends in Pharmacological Sciences 28 (10): 518–525. doi:10.1016/j.tips.2007.09.001.
- Habas, Raymond; Dawid, Igor B (1 January 2005). "Dishevelled and Wnt signaling: is the nucleus the final frontier?". Journal of Biology 4 (1): 2. doi:10.1186/jbiol22.
- Sugimura, Ryohichi, and Linheng Li. "Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases." Birth Defects Research Part C: Embryo Today: Reviews 90.4 (2010) : 243-256. Print.
- Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2010). "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell (journal) 126 (5): 955–968. doi:10.1016/j.cell.2006.06.055. PMID 16959574.
- Malinauskas T, Aricescu AR, Lu W, Siebold C, Jones EY (July 2011). "Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1". Nature Structural & Molecular Biology 18 (8): 886–893. doi:10.1038/nsmb.2081. PMC 3430870. PMID 21743455.
- Malinauskas T (2008). "Docking of fatty acids into the WIF domain of the human Wnt inhibitory factor-1". Lipids 43 (3): 227–30. doi:10.1007/s11745-007-3144-3. PMID 18256869.
- Alvarez-Medina R, Cayuso J, Okubo T, Takada S, Marti E (December 2008). "Wnt canonical pathway restricts graded Shh/Gli patterning activity through the regulation of Gli3 expression". Development 135 (2): 237–247. doi:10.1242/dev.012054. PMID 18057099.
- Robertson CP, Braun MM, Roelink H (March 2004). "Sonic Hedgehog Patterning in Chick Neural Plate is Antagonized by a Wnt3-Like Signal". Developmental Dynamics 229 (3): 510–519. doi:10.1002/dvdy.10501. PMID 14991707.
- Ulloa F, Marti E (August 2009). "Wnt Won the War: Antagonistic Role of Wnt over Shh Controls Dorso-Ventral Patterning of the Vertebrate Neural Tube". Developmental Dynamics 239 (1): 69–79. doi:10.1002/dvdy.22058. PMID 19681160.
- Fanto M, McNeill H (February 2004). "Planar polarity from flies to vertebrates". J. Cell. Sci. 117 (Pt 4): 527–33. doi:10.1242/jcs.00973. PMID 14730010.
- Povelones M, Howes R, Fish M, Nusse R (December 2005). "Genetic Evidence That Drosophila frizzled Controls Planar Cell Polarity and Armadillo Signaling by a Common Mechanism". Genetics 171 (4): 1643–54. doi:10.1534/genetics.105.045245. PMC 1456092. PMID 16085697.
- Habas R, Dawid IB, He X (January 2003). "Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation". Genes Dev. 17 (2): 295–309. doi:10.1101/gad.1022203. PMC 195976. PMID 12533515.
- Keeble TR, Halford MM, Seaman C, Kee N, Macheda M, Anderson RB, Stacker SA, Cooper HM (May 2006). "The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum". J. Neurosci. 26 (21): 5840–8. doi:10.1523/JNEUROSCI.1175-06.2006. PMID 16723543.
- Lyuksyutova, AI, Lu, CC, Milanesio, N, King, LA, Guo, N, Wang, Y, Nathans, J, Tessier-Lavigne, M, Zou, Y (December 2003). "Anterior-Posterior Guidance of Commissural Axons by Wnt-Frizzled Signaling". Science 302 (5652): 1984–1988. doi:10.1126/science.1089610. PMID 14671310.
- Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR 3rd, Nusse R (May 2003). "Wnt proteins are lipid-modified and can act as stem cell growth factors". Nature 423 (6938): 448–52. doi:10.1038/nature01611. PMID 12717451.
- Stanford researchers find culprit in aging muscles that heal poorly - Standford.edu. Retrieved: August 10th, 2007.
- Nusse R (May 2008). "Wnt signaling and stem cell control". Cell Res. 18 (5): 523–7. doi:10.1038/cr.2008.47. PMID 18392048.
- Pereira L, Yi F, Merrill BJ (October 2006). "Repression of Nanog Gene Transcription by Tcf3 Limits Embryonic Stem Cell Self-Renewal". Mol. Cell. Biol. 26 (20): 7479–91. doi:10.1128/MCB.00368-06. PMC 1636872. PMID 16894029.
- Hochedlinger K, Yamada Y, Beard C, Jaenisch R (May 2005). "Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues". Cell 121 (3): 465–77. doi:10.1016/j.cell.2005.02.018. PMID 15882627.
- Embryoid Bodies Get Organized - Nature.com Retrieved: May 30, 2009
- Bakre MM, Hoi A, Mong JC, Koh YY, Wong KY, Stanton LW (October 2007). "Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation". J. Biol. Chem. 282 (43): 31703–12. doi:10.1074/jbc.M704287200. PMID 17711862.
- Woll PS, Morris JK, Painschab MS et al. (January 2008). "Wnt signaling promotes hematoendothelial cell development from human embryonic stem cells". Blood 111 (1): 122–31. doi:10.1182/blood-2007-04-084186. PMC 2200802. PMID 17875805.
- Gogolla N, Galimberti I, Deguchi Y, Caroni P (May 2009). "Wnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus". Neuron 62 (4): 510–25. doi:10.1016/j.neuron.2009.04.022. PMID 19477153.
- Howe, Louise; Brown, Anthony (2004). "Wnt Signaling and Breast Cancer". Cancer Biology and Therapy 3 (1): 36–41. doi:10.4161/cbt.3.1.561.
- Taketo, M Mark. "Shutting down Wnt signal-activated cancer." Nature Genetics 36. (2004): 320-22. Web. 17 Apr 2011.
- DiMeo, T. A.; Anderson, K.; Phadke, P.; Feng, C.; Perou, C. M.; Naber, S.; Kuperwasser, C. (1 July 2009). "A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer". Cancer Research 69 (13): 5364–5373. doi:10.1158/0008-5472.CAN-08-4135.
- Anastas, Jamie N.; Moon, Randall T. (21 December 2012). "WNT signalling pathways as therapeutic targets in cancer". Nature Reviews Cancer 13 (1): 11–26. doi:10.1038/nrc3419.
- Dinasarapu A.R, Saunders B, Ozerlat I, Azam K and Subramaniam S (2010). "Signaling Gateway Molecule Pages - a data model perspective". Bioinformatics 27 (12): 1736–1738. doi:10.1093/bioinformatics/btr190. PMC 3106186. PMID 21505029.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
wnt family Provide feedback
Wnt genes have been identified in vertebrates and invertebrates but not in plants, unicellular eukaryotes or prokaryotes. In humans, 19 WNT proteins are known. Because of their insolubility little is known about Wnt protein structure, but all have 23 or 24 Cys residues whose spacing is highly conserved. Signal transduction by Wnt proteins (including the Wnt/beta-catenin, the Wnt/Ca++, and the Wnt/polarity pathway) is mediated by receptors of the Frizzled and LDL-receptor-related protein (LRP) families .
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR005817
Wnt proteins constitute a large family of secreted molecules that are involved in intercellular signalling during development. The name derives from the first 2 members of the family to be discovered: int-1 (mouse) and wingless (Drosophila) [PUBMED:9891778]. It is now recognised that Wnt signalling controls many cell fate decisions in a variety of different organisms, including mammals [PUBMED:10508601]. Wnt signalling has been implicated in tumourigenesis, early mesodermal patterning of the embryo, morphogenesis of the brain and kidneys, regulation of mammary gland proliferation and Alzheimer's disease [PUBMED:10967351, PUBMED:9192851].
Wnt-mediated signalling is believed to proceed initially through binding to cell surface receptors of the frizzled family; the signal is subsequently transduced through several cytoplasmic components to B-catenin, which enters the nucleus and activates the transcription of several genes important in development [PUBMED:10733430]. Several non-canonical Wnt signalling pathways have also been elucidated that act independently of B-catenin. Canonical and noncanonical Wnt signaling branches are highly interconnected, and cross-regulate each other [PUBMED:21536746].
Members of the Wnt gene family are defined by their sequence similarity to mouse Wnt-1 and Wingless in Drosophila. They encode proteins of ~350-400 residues in length, with orthologues identified in several, mostly vertebrate, species. Very little is known about the structure of Wnts as they are notoriously insoluble, but they share the following features characteristics of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines [PUBMED:9891778] that are probably involved in disulphide bonds. The Wnt proteins seem to adhere to the plasma membrane of the secreting cells and are therefore likely to signal over only few cell diameters. Fifteen major Wnt gene families have been identified in vertebrates, with multiple subtypes within some classes.
In humans, 19 Wnt proteins have been identified that share 27% to 83% amino-acid sequence identity and a conserved pattern of 23 or 24 cysteine residues [PUBMED:11806834]. Wnt genes are highly conserved between vertebrate species sharing overall sequence identity and gene structure, and are slightly less conserved between vertebrates and invertebrates.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||extracellular region (GO:0005576)|
|Molecular function||receptor binding (GO:0005102)|
|Biological process||multicellular organismal development (GO:0007275)|
|Wnt receptor signaling pathway (GO:0016055)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||104|
|Number in full:||10329|
|Average length of the domain:||159.90 aa|
|Average identity of full alignment:||55 %|
|Average coverage of the sequence by the domain:||94.96 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the wnt domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...