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Family: wnt (PF00110)

Summary: wnt family

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Wnt signaling pathway Edit Wikipedia article

The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. All three Wnt signaling pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled inside the cell. The canonical Wnt pathway leads to regulation of gene transcription, the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell, and the noncanonical Wnt/calcium pathway regulates calcium inside the cell. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved, meaning they are similar across many species from fruit flies to humans.[1][2]

Wnt signaling was first identified for its role in carcinogenesis, but has since been recognized for its function in embryonic development. The embryonic processes it controls include body axis patterning, cell fate specification, cell proliferation, and cell migration. These processes are necessary for proper formation of important tissues including bone, heart, and muscle. Its role in embryonic development was discovered when genetic mutations in proteins in the Wnt pathway produced abnormal fruit fly embryos. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice.

The clinical importance of this pathway has been demonstrated by mutations that lead to a variety of diseases, including breast and prostate cancer, glioblastoma, type II diabetes, and others.[3][4]

Background and etymology[edit]

The discovery of Wnt signaling was influenced by research on oncogenic (cancer-causing) retroviruses. In 1982, Roel Nusse and Harold Varmus infected mice with mouse mammary tumor virus in order to mutate mouse genes to see which genes could cause breast tumors when mutated. They identified a new mouse proto-oncogene that they named int1 (integration 1).[2][5]

It was determined that int1 has a high degree of conservation across several species, including humans and Drosophila. Its presence in Drosophila melanogaster led researchers to discover in 1987 that the int1 gene in Drosophila was actually the already known and characterized Drosophila gene known as Wingless (Wg).[2] Since previous research by Christiane Nüsslein-Volhard and Eric Wieschaus (which won them the Nobel Prize in Physiology or Medicine in 1995) had already established the function of Wg as a segment polarity gene involved in the formation of the body axis during embryonic development, researchers determined that the mammalian int1 discovered in mice is also involved in embryonic development.[6]

Since int1's discovery in 1982, continued research would lead to the discovery of further genes related to int1; however, since all those genes had not been identified in the same manner as int1, it quickly became clear that the int gene nomenclature, or naming system, 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 combination, or portmanteau, of int and Wg and stands for Wingless-related integration site.[2]

Proteins[edit]

Crystal protein structure of Wnt8 and the cysteine-rich domain of Frizzled 8.

The Wnt proteins are a diverse family of secreted lipid-modified signaling glycoproteins that are 350–400 amino acids in length.[7] The type of lipid modification that occurs on these proteins is palmitoylation of cysteines in a conserved pattern of 23–24 cysteine residues.[3] Palmitoylation is necessary because it initiates targeting of the Wnt protein to the plasma membrane for secretion and it allows the Wnt protein to bind its receptor due to the covalent attachment of fatty acids. Wnt proteins also undergo glycosylation, which attaches a carbohydrate in order to insure proper secretion.[8] In Wnt signaling, these proteins act as ligands to activate the different Wnt pathways via paracrine and autocrine routes.[1][4]

These proteins are also highly conserved across species.[2] They can be found in mice, humans, Xenopus, Zebrafish, Drosophila, and many others.[9]

Species Wnt proteins
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

Mechanism[edit]

Figure 2. Wnt binds to (activates) the receptor. Axin is removed from the "destruction complex." β-Cat moves into the nucleus, binds to a transcription factor on DNA, and activates transcription of a protein. "P" represents phosphate.
Figure 1. Wnt doesn't bind to the receptor. Axin, GSK and APC form a "destruction complex," and β-Cat is destroyed.

Foundation[edit]

Wnt signaling begins when one of the Wnt proteins binds the N-terminal extra-cellular cysteine-rich domain of a Frizzled (Fz) family receptor.[10] These receptors span the plasma membrane seven times and constitute a distinct family of G-protein coupled receptors (GPCRs).[11] 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.[4] Upon activation of the receptor, 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 proteins 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.[12]

Canonical and noncanonical pathways[edit]

The three best characterized Wnt signaling pathways are the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. As their names suggest, these pathways belong to one of two categories: canonical or noncanonical. The difference between the categories is that a canonical pathway involves the protein β-catenin while a noncanonical pathway operates independently of it.[10]

Alt
Canonical Wnt pathway

The canonical Wnt pathway[edit]

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).[13] It degrades β-catenin by targeting it for ubiquitination, which subsequently sends it to the proteasome to be digested.[10][14] 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.[4] 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.[4][14]

Noncanonical PCP pathway

The noncanonical planar cell polarity pathway[edit]

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.[4][15]

Noncanonical Wnt/calcium pathway

The noncanonical Wnt/calcium pathway[edit]

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.[4] 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.[4] CamKII activates TAK1 and NLK kinase, which can interfere with TCF/ß-Catenin signaling in the canonical Wnt pathway.[16] 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.[4]

Integrated, convergent, Wnt signaling pathway[edit]

The binary distinction of canonical and non-canonical Wnt signaling pathways has come under scrutiny and an integrated Wnt pathway has been proposed;[17] some evidence for this was found for one Wnt ligand (Wnt5A).[18] Very recently, evidence for a convergent Wnt signaling pathway, that shows integrated activation of Wnt/Ca2+ and Wnt/ß-catenin signaling, for multiple Wnt ligands, was described in mammalian cell lines.[19]

Other pathways[edit]

Along with the pathways, described above, 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.[20] During myogenesis, Wnt uses PKA and CREB to activate the genes MyoD and Myf5.[21] 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.[4]

Regulation[edit]

In order to ensure 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 mediates 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.[4][14] 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), Cerberus, 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 between different Wnt signaling pathways also regulate Wnt signling. As previously mentioned, the Wnt/calcium pathway can inhibit TCF/β-catenin in order to prevent canonical Wnt pathway signaling.[4][14]

Induced cell responses[edit]

Embryonic development[edit]

Wnt signaling plays a critical role in the embryonic development of a variety of organisms. It is detected in both vertebrates and invertebrates, including humans, frogs, zebrafish, C. elegans, Drosophila, and numerous others. It was first known to be involved in the segment polarity of Drosophila, where it helps to establish anterior and posterior polarities; however, it has since then been implicated in numerous other developmental processes. As its function in Drosophila suggests, it plays a key role in body axis formation, particularly the formation of the anteroposterior and dorsoventral axes. It is also involved in the induction of cell differentiation to prompt formation of important organs such as the lungs and ovaries. Wnt further insures the development of these specific tissues through proper regulation of cell proliferation and migration. These are just a few Wnt functions, but they demonstrate that the numerous functions of Wnt signaling can be divided into one of the following categories: axis patterning, cell fate specification, cell proliferation, and cell migration.[22]

Axis patterning[edit]

In early embryonic development, the formation of the primary body axes is a crucial step in establishing the overall body plan of each particular organism. The different axes include the anteroposterior axis, dorsoventral axis, and right-left axis. Wnt signaling can be implicated in the formation of the anteroposterior and dorsoventral axes. Wnt signaling activity in anterior-posterior development can be seen in several organisms including mammals, fish, and frogs. In mammals, the primitive streak and other surrounding tissues produce the morphogenic compounds Wnts, BMPs, FGFs, Nodal, and retinoic acid to establish the posterior region during late gastrula. These proteins form concentration gradients and the areas of their highest concentration establish the posterior region and the areas of their lowest concentration indicate the anterior region. In fish and frogs, β-catenin produced by canonical Wnt signaling causes the formation of organizing centers, which, alongside BMPs, elicits posterior formation. Wnt involvement in dorsoventral axis formation can be seen in the activity of the formation of the Spemann organizer, which establishes the dorsal region. Canonical Wnt signaling production β-catenin induces the formation of this organizer via the activation of the genes twin and siamois.[17][22] Similarly, in avian gastrulation, cells of the Koller's sickle express different mesodermal marker genes that allow for the differential movement of cells during the formation of the primitive streak. Wnt signaling activated by FGFs is responsible for this movement.[23][24]

Wnt signaling is also involved in the axis formation of specific body parts and organ systems that are a part of later development. In vertebrates, sonic hedgehog (Shh) and Wnt morphogenetic signaling gradients establish the dorsoventral axis of the central nervous system during neural tube axial patterning. High Wnt signaling establishes the dorsal region while high Shh signaling indicates in the ventral region.[25] Wnt is also involved in the dorsal-ventral formation of the central nervous system through its involvement in axon guidance. Wnt proteins guide the axons of the spinal cord in an anterior-posterior direction.[26] Wnt is also involved in the formation of the limb dorsal-ventral axis. Specifically, Wnt7a helps produce the dorsal patterning of the developing limb.[17][22]

Cell fate specification[edit]

Cell fate specification, or cell differentiation, is a cellular process where undifferentiated cells can become a more specialized cell type. Wnt signaling induces differentiation of pluripotent stem cells into mesoderm and endoderm progenitor cells.[27] These progenitor cells are then further induced to differentiate into more specific cell types such as endothelial, cardiac, and vascular smooth muscle lineages.[28] Wnt signaling can also induce blood formation from stem cells. Specifically, Wnt3 leads to mesoderm committed cells with hematopoietic potential.[29] Wnt1 has also been shown to antagonize neural differentiation and is a major factor in self-renewal of neural stem cells. This allows for regeneration of nervous system cells, which is further evidence of a role in promoting neural stem cell proliferation.[27] Wnt signaling has also been shown to be involved in germ cell determination, gut tissue specification, hair follicle development, lung tissue development, trunk neural crest cell differentiation, nephron development, ovary development, and sex determination.[22]

Cell proliferation[edit]

In order to have the mass differentiation of cells needed to form the specified cell tissues of different organisms, a proliferation, or cell growth, of embryonic stem cells must take place. This process is mediated through canonical Wnt signaling, which increases nuclear and cytoplasmic level of β-catenin. Increased levels of β-catenin can initiate transcriptional activation of proteins such as cyclin D1 and c-myc, which control the G1 to S phase transition in the cell cycle. Entry into the S phase causes DNA replication and ultimately mitosis, which are responsible for cell proliferation.[30] This increase in proliferation is directly paired with cell differentiation because as the stem cells proliferate, they are differentiated into the specific tissues that are induced to become. This allows for overall growth and development of specific tissue systems during embryonic development. This is apparent in systems such as the circulatory system where Wnt3a leads to proliferation and expansion of hematopoietic stem cells needed for red blood cell formation.[31]

Cell migration[edit]

Diagram illustrating the epithelial-mesenchymal transition.

Cell migration during embryonic development allows for the establishment of body axes, tissue formation, limb induction, and several other processes. Wnt signaling helps mediate this process, particularly during convergent extension. Research has shown that signaling from both the Wnt PCP pathway and canonical Wnt pathway is required for proper convergent extension during gastrulation. Convergent extension is further regulated by the Wnt/calcium pathway, which blocks convergent extension when activated. Wnt signaling also induces cell migration in later stages of development through the control of the migration behavior of neuroblasts, neural crest cells, myocytes, and tracheal cells.[32]

Wnt signaling is also involved in another key migration process known as the epithelial-mesenchymal transition (EMT). This process is what allows epithelial cells to transform into mesenchymal cells so that they are no longer held in place at the laminin. It involves a down-regulation of cadherins so that cells can detach from laminin and migrate. Wnt signaling is an inducer of EMT, particularly in mammary development.[33]

Insulin sensitivity[edit]

Diagram illustrating the interaction between the Wnt and insulin signaling pathways.

Insulin is a peptide hormone involved in glucose homeostasis within certain organisms. Specifically, it leads to upregulation of glucose transporters in the cell membrane in order to increase glucose uptake from the bloodstream. This process is partially mediated by activation of Wnt/β-catenin signaling, which can increase a cell's sensitivity to insulin. In particular, Wnt10b is a Wnt protein shown to increase this sensitivity in skeletal muscle cells.[34]

Clinical implications[edit]

Cancer[edit]

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. 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. Misregulation of these processes can cause unwanted cell growth and movement, which can lead to tumor development.[2]

Activity of the canonical Wnt pathway is involved 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. Increased β-catenin expression is 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, most frequently by mutations in structurally disordered regions of APC, overexpression of Wnt ligands, loss of inhibitors, and/or decreased activity of regulatory pathways (such as the Wnt/calcium pathway).[35][36][37] 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.[38]

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, can be measured 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.[39]

Type II diabetes[edit]

Type II diabetes, or diabetes mellitus type 2, is a common disease that causes reduced insulin secretion and increased insulin resistance in the periphery. It results in increased blood glucose levels, or hyperglycemia, which can be fatal if left untreated. Since Wnt signaling is involved in insulin sensitivity, malfunctioning of its pathway could be involved in the development of type II diabetes. Overexpression of Wnt5b, for instance, may increase susceptibility to type II diabetes due to its role in adipogenesis, or fat production, since obesity and type II diabetes have a high comorbidity.[40] Wnt signaling is also a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS) known to cause DNA and cellular damage.[41] This ROS-induced damage is significant because it can cause the development of acute hepatic insulin resistance, or injury-induced insulin resistance.[42] Mutations in Wnt signaling-associated transcription factors, such as TCF7L2, are also linked to increased susceptibility to type II diabetes.[43]

See also[edit]

External links[edit]

References[edit]

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  37. ^ Minde DP, Radli M, Forneris F, Maurice MM, Rüdiger SG (2013). "Large Extent of Disorder in Adenomatous Polyposis Coli Offers a Strategy to Guard Wnt Signalling against Point Mutations". PLOS ONE. doi:10.1371/journal.pone.0077257. 
  38. ^ 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. 
  39. ^ 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. 
  40. ^ Welters, HJ; RN Kulkarni (2008). "Wnt signaling: relevance to beta-cell biology and diabetes". Trends in Endocrinology & Metabolism 19 (10): 349–355. doi:10.1016/j.tem.2008.08.004. PMID 18926717. 
  41. ^ Yoon, J. C.; Ng, A.; Kim, B. H.; Bianco, A.; Xavier, R. J.; Elledge, S. J. (15 July 2010). "Wnt signaling regulates mitochondrial physiology and insulin sensitivity". Genes & Development 24 (14): 1507–1518. doi:10.1101/gad.1924910. 
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  43. ^ Grant, Struan F A; Thorleifsson, Gudmar; Reynisdottir, Inga; Benediktsson, Rafn; Manolescu, Andrei; Sainz, Jesus; Helgason, Agnar; Stefansson, Hreinn; Emilsson, Valur; Helgadottir, Anna; Styrkarsdottir, Unnur; Magnusson, Kristinn P; Walters, G Bragi; Palsdottir, Ebba; Jonsdottir, Thorbjorg; Gudmundsdottir, Thorunn; Gylfason, Arnaldur; Saemundsdottir, Jona; Wilensky, Robert L; Reilly, Muredach P; Rader, Daniel J; Bagger, Yu; Christiansen, Claus; Gudnason, Vilmundur; Sigurdsson, Gunnar; Thorsteinsdottir, Unnur; Gulcher, Jeffrey R; Kong, Augustine; Stefansson, Kari (15 January 2006). "Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes". Nature Genetics 38 (3): 320–323. doi:10.1038/ng1732. 
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This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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 [1].

Literature references

  1. Miller JR; , Genome Biol 2002;3:REVIEWS3001.: The Wnts. PUBMED:11806834 EPMC:11806834


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.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

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...

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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.

  Seed
(104)
Full
(10329)
Representative proteomes NCBI
(7789)
Meta
(0)
RP15
(210)
RP35
(287)
RP55
(607)
RP75
(979)
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Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(104)
Full
(10329)
Representative proteomes NCBI
(7789)
Meta
(0)
RP15
(210)
RP35
(287)
RP55
(607)
RP75
(979)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

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.

  Seed
(104)
Full
(10329)
Representative proteomes NCBI
(7789)
Meta
(0)
RP15
(210)
RP35
(287)
RP55
(607)
RP75
(979)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

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.

Pfam alignments:

HMM logo

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...

Trees

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.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Family
Author: Sonnhammer ELL
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 information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 19.4 19.4
Trusted cut-off 19.6 19.6
Noise cut-off 17.7 17.9
Model length: 310
Family (HMM) version: 14
Download: download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Structures

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.

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