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 into a cell through cell surface receptors. 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 pathways are activated by binding a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the Dishevelled protein inside the cell. The canonical Wnt pathway leads to regulation of gene transcription, and is thought to be negatively regulated in part by the SPATS1 gene. The noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell. 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 in animals, which means they are similar across animal species from fruit flies to humans.
Wnt signaling was first identified for its role in carcinogenesis, then 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 Wnt pathway proteins produced abnormal fruit fly embryos. Wnt signaling also controls tissue regeneration in adult bone marrow, skin and intestine. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice.
This pathway's clinical importance was demonstrated by mutations that lead to various diseases, including breast and prostate cancer, glioblastoma, type II diabetes and others. Encouragingly, in recent years researchers reported first successful use of Wnt pathway inhibitors in mouse models of disease.
- 1 History and Etymology
- 2 Proteins
- 3 Mechanism
- 4 Induced cell responses
- 5 Clinical implications
- 6 See also
- 7 References
- 8 External links
History and Etymology
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 mutated genes could cause breast tumors. They identified a new mouse proto-oncogene that they named int1 (integration 1).
Int1 is highly conserved across multiple species, including humans and Drosophila. Its presence in D. 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). 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.
Continued research led to the discovery of further int1-related genes; however, because those genes were not identified in the same manner as int1, the int gene nomenclature was inadequate. Thus, the int/Wingless family became the Wnt family and int1 became Wnt1. The name Wnt is a portmanteau of int and Wg and stands for "Wingless-related integration site".
Wnt comprises 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. 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 ensure proper secretion. In Wnt signaling, these proteins act as ligands to activate the different Wnt pathways via paracrine and autocrine routes.
|Homo sapiens||WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16|
|Mus musculus (Identical proteins as in H. sapiens)||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|
|Hydra||hywnt1, hywnt5a, hywnt8, hywnt7, hywnt9/10a, hywnt9/10b, hywnt9/10c, hywnt11, hywnt16|
|C. elegans||mom-2, lin-44, egl-20, cwn-1, cwn-2 |
Wnt signaling begins when a Wnt protein binds to 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 be required alongside the interaction between the Wnt protein and Fz receptor. Examples include lipoprotein receptor-related protein (LRP)-5/6, receptor tyrosine kinase (RTK), and ROR2. 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 multiple 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/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.
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, 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 LRP5/6, the destruction complex function becomes disrupted. This is due to Wnt causing the translocation of the negative Wnt regulator, Axin, and the destruction complex to the plasma membrane. Phosphorylation by other proteins in the destruction complex subsequently binds Axin to the cytoplasmic tail of LRP5/6. Axin becomes de-phosphorylated and its stability and levels decrease. 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 (T-cell factor/lymphoid enhancing factor) transcription factors. β-catenin recruits other transcriptional coactivators, such as BCL9, Pygopus and Parafibromin/Hyrax. The complexity of the transcriptional complex assembled by β-catenin is beginning to emerge thanks to new high-throughput proteomics studies. The promiscuity of the β-catenin interacting proteins complicates our understanding: BCL9 and Pygopus have been reported, in fact, to possess several β-catenin-independent functions (therefore, likely, Wnt signaling-independent).
The noncanonical planar cell polarity (PCP) pathway 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. 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 DIX 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 also does not involve 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 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 ventral patterning. Increased calcium also activates calcineurin and CaMKII. CaMKII induces activation of the transcription factor NFAT, which regulates cell adhesion, migration and tissue separation. Calcineurin 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.
Integrated Wnt pathway
The binary distinction of canonical and non-canonical Wnt signaling pathways has come under scrutiny and an integrated, convergent Wnt pathway has been proposed. Some evidence for this was found for one Wnt ligand (Wnt5A). 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.
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 uses PA and CREB to activate MyoD and Myf5 genes. Wnt also acts 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-ATPase 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, Pa3, 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 different responses.
In order to ensure proper functioning, Wnt signaling is constantly regulated at several points along its signaling pathways. For example, Wnt proteins are palmitoylated. The protein porcupine mediates this process, which means that it helps regulate when the Wnt ligand is secreted by determining when it is fully formed. Secretion is further controlled with proteins such as wntless and evenness interrupted and complexes such as the retromer complex. Upon secretion, the ligand can be prevented from reaching its receptor through the binding of 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, SOST, and Naked cuticle. These constitute inhibitors of Wnt signaling. However, other molecules also act as activators. Norrin and R-Spondin2 activate Wnt signaling in the absence of Wnt ligand. Interactions between Wnt signaling pathways also regulate Wnt signaling. As previously mentioned, the Wnt/calcium pathway can inhibit TCF/β-catenin, preventing canonical Wnt pathway signaling. Prostaglandin E2 is an essential activator of the canonical Wnt signaling pathway. Interaction of PGE2 with its receptors E2/E4 stabilizes β-catenin through cAMP/PKA mediated phosphorylation. The synthesis of PGE2 is necessary for Wnt signaling mediated processes such as tissue regeneration and control of stem cell population in zebrafish and mouse. Intriguingly, the unstructured regions of several oversized Intrinsically disordered proteins play crucial roles in regulating Wnt signaling.
Induced cell responses
Wnt signaling plays a critical role in embryonic development. It operates in both vertebrates and invertebrates, including humans, frogs, zebrafish, C. elegans, Drosophila and others. It was first found in the segment polarity of Drosophila, where it helps to establish anterior and posterior polarities. It is implicated in 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 involved in the induction of cell differentiation to prompt formation of important organs such as lungs and ovaries. Wnt further ensures the development of these tissues through proper regulation of cell proliferation and migration. Wnt signaling functions can be divided into axis patterning, cell fate specification, cell proliferation and cell migration.
In early embryo development, the formation of the primary body axes is a crucial step in establishing the organism's overall body plan. The axes include the anteroposterior axis, dorsoventral axis, and right-left axis. Wnt signaling is implicated in the formation of the anteroposterior and dorsoventral (DV) axes. Wnt signaling activity in anterior-posterior development can be seen in 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. Areas of highest concentration establish the posterior region while areas of 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, elicit posterior formation. Wnt involvement in DV axis formation can be seen in the activity of the formation of the Spemann organizer, which establishes the dorsal region. Canonical Wnt signaling β-catenin production induces the formation of this organizer via the activation of the genes twin and siamois. 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.
Wnt signaling is also involved in the axis formation of specific body parts and organ systems later in 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 the ventral region. Wnt is involved in the DV 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. Wnt is also involved in the formation of the limb DV axis. Specifically, Wnt7a helps produce the dorsal patterning of the developing limb.
In the embryonic differentiation waves model of development Wnt plays a critical role as part a signalling complex in competent cells ready to differentiate. Wnt reacts to the activity of the cytoskeleton, stabilizing the initial change created by a passing wave of contraction or expansion and simultaneously signals the nucleus through the use of its different signalling pathways as to which wave the individual cell has participated in. Wnt activity thereby amplifies mechanical signalling that occurs during development.
Cell fate specification
Cell fate specification or cell differentiation is a 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. These progenitor cells further differentiate into cell types such as endothelial, cardiac and vascular smooth muscle lineages. Wnt signaling induces blood formation from stem cells. Specifically, Wnt3 leads to mesoderm committed cells with hematopoietic potential. Wnt1 antagonizes 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. Wnt signaling is 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. Wnt signaling also antagonizes heart formation, and Wnt inhibition was shown to be a critical inducer of heart tissue during development, and small molecule Wnt inhibitors are routinely used to produce cardiomyocytes from pluripotent stem cells .
In order to have the mass differentiation of cells needed to form the specified cell tissues of different organisms, proliferation and growth of embryonic stem cells must take place. This process is mediated through canonical Wnt signaling, which increases nuclear and cytoplasmic β-catenin. Increased 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. This proliferation increase is directly paired with cell differentiation because as the stem cells proliferate, they also differentiate. 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.
The biochemistry of cancer stem cells is subtly different than that of other tumor cells. These so-called Wnt-addicted cells hijack and depend on constant stimulation of the Wnt pathway to promote their uncontrolled growth, survival and migration. In cancer, Wnt signaling can become independent of regular stimuli, through mutations in downstream oncogenes and tumor suppressor genes that become permanently activated even though the normal receptor has not received a signal. β-catenin binds to transcription factors such as the protein TCF4 and in combination the molecules activate the necessary genes. LF3 strongly inhibits this binding in vitro, in cell lines and reduced tumor growth in mouse models. It prevented replication and reduced their ability to migrate, all without affecting healthy cells. No cancer stem cells remained after treatment. The discovery was the product of "rational drug design", involving AlphaScreens and ELISA technologies.
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. 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.
Wnt signaling is involved in another key migration process known as the epithelial-mesenchymal transition (EMT). This process allows epithelial cells to transform into mesenchymal cells so that they are no longer held in place at the laminin. It involves cadherin down-regulation so that cells can detach from laminin and migrate. Wnt signaling is an inducer of EMT, particularly in mammary development.
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 insulin sensitivity. In particular, Wnt10b is a Wnt protein that increases this sensitivity in skeletal muscle cells.
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 lead to tumor development via excess cell proliferation.
Canonical Wnt pathway activity is involved in the development of benign and malignant breast tumors. Its presence is revealed by 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 correlated with poor prognosis in breast cancer patients. This accumulation may be due to 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). Breast tumors can metastasize due to Wnt involvement in EMT. Research looking at metastasis of basal-like breast cancer to the lungs showed that repression of Wnt/β-catenin signaling can prevent EMT, which can inhibit metastasis.
Wnt signaling has been implicated in the development of other cancers. Changes in CTNNB1 expression, which is the gene that encodes β-catenin, can be measured in breast colorectal, melanoma, prostate, lung, and other cancers. Increased expression of Wnt ligand-proteins such as Wnt 1, Wnt2 and Wnt7A were observed in the development of glioblastoma, oesophageal cancer and ovarian cancer respectively. Other proteins that cause multiple cancer types in the absence of proper functioning include ROR1, ROR2, SFRP4, Wnt5A, WIF1 and those of the TCF/LEF family.
Type II diabetes
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 untreated. Since Wnt signaling is involved in insulin sensitivity, malfunctioning of its pathway could be involved. Overexpression of Wnt5b, for instance, may increase susceptibility due to its role in adipogenesis, since obesity and type II diabetes have high comorbidity. Wnt signaling is a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS) known to cause DNA and cellular damage. This ROS-induced damage is significant because it can cause acute hepatic insulin resistance, or injury-induced insulin resistance. Mutations in Wnt signaling-associated transcription factors, such as TCF7L2, are linked to increased susceptibility.
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- van Amerongen R, Nusse R (Oct 2009). "Towards an integrated view of Wnt signaling in development". Development. 136 (19): 3205–14. doi:10.1242/dev.033910. PMID 19736321.
- van Amerongen R, Fuerer C, Mizutani M, Nusse R (Sep 2012). "Wnt5a can both activate and repress Wnt/β-catenin signaling during mouse embryonic development". Developmental Biology. 369 (1): 101–14. doi:10.1016/j.ydbio.2012.06.020. PMC . PMID 22771246.
- Thrasivoulou C, Millar M, Ahmed A (Dec 2013). "Activation of intracellular calcium by multiple Wnt ligands and translocation of β-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/β-catenin pathways". The Journal of Biological Chemistry. 288 (50): 35651–9. doi:10.1074/jbc.M112.437913. PMC . PMID 24158438.
- 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 (Sep 2006). "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell. 126 (5): 955–68. doi:10.1016/j.cell.2006.06.055. PMID 16959574.
- Kuroda K, Kuang S, Taketo MM, Rudnicki MA (2013). "Canonical Wnt signaling induces BMP-4 to specify slow myofibrogenesis of fetal myoblasts". Skeletal Muscle. 3 (1): 5. doi:10.1186/2044-5040-3-5. PMC . PMID 23497616.
- Malinauskas T, Jones EY (Dec 2014). "Extracellular modulators of Wnt signalling". Current Opinion in Structural Biology. 29: 77–84. doi:10.1016/j.sbi.2014.10.003. PMID 25460271.
- 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 . 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.
- 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. 8 (10): e77257. Bibcode:2013PLoSO...877257M. doi:10.1371/journal.pone.0077257. PMC . PMID 24130866.
- Gilbert, Scott F. (2010). Developmental biology (9th ed.). Sunderland, Mass.: Sinauer Associates. ISBN 9780878933846.
- Vasiev, Bakhtier; Balter, Ariel; Chaplain, Mark; Glazier, James A.; Weijer, Cornelis J. (2010-05-11). "Modeling Gastrulation in the Chick Embryo: Formation of the Primitive Streak". PLoS ONE. 5 (5): e10571. Bibcode:2010PLoSO...510571V. doi:10.1371/journal.pone.0010571. PMC . PMID 20485500.
- Gilbert SF. Developmental Biology. 10th edition. Sunderland (MA): Sinauer Associates; 2014. Early Development in Birds. Print
- Ulloa F, Martí E (Jan 2010). "Wnt won the war: antagonistic role of Wnt over Shh controls dorso-ventral patterning of the vertebrate neural tube". Developmental Dynamics. 239 (1): 69–76. doi:10.1002/dvdy.22058. PMID 19681160.
- Zou Y (Sep 2004). "Wnt signaling in axon guidance". Trends in Neurosciences. 27 (9): 528–32. doi:10.1016/j.tins.2004.06.015. PMID 15331234.
- Gordon, NK, Gordon R The organelle of differentiation in embryos: the cell state splitter Theor Biol Med Model (2016) 13: 11. https://doi.org/10.1186/s12976-016-0037-2
- Gordon, N. Gordon, R.Embryogenesis Explained World Scientific Publishing, Singapore, 2016, pg 580-591
- Nusse R (May 2008). "Wnt signaling and stem cell control". Cell Research. 18 (5): 523–7. doi:10.1038/cr.2008.47. PMID 18392048.
- Bakre MM, Hoi A, Mong JC, Koh YY, Wong KY, Stanton LW (Oct 2007). "Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation". The Journal of Biological Chemistry. 282 (43): 31703–12. doi:10.1074/jbc.M704287200. PMID 17711862.
- Woll PS, Morris JK, Painschab MS, Marcus RK, Kohn AD, Biechele TL, Moon RT, Kaufman DS (Jan 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 . PMID 17875805.
- Schneider, V. A. (1 February 2001). "Wnt antagonism initiates cardiogenesis in Xenopus laevis". Genes & Development. 15 (3): 304–315. doi:10.1101/gad.855601. PMC .
- Marvin, M. J. (1 February 2001). "Inhibition of Wnt activity induces heart formation from posterior mesoderm". Genes & Development. 15 (3): 316–327. doi:10.1101/gad.855501. PMC .
- Ueno, S.; Weidinger, G.; Osugi, T.; Kohn, A. D.; Golob, J. L.; Pabon, L.; Reinecke, H.; Moon, R. T.; Murry, C. E. (23 May 2007). "Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells". Proceedings of the National Academy of Sciences. 104 (23): 9685–9690. Bibcode:2007PNAS..104.9685U. doi:10.1073/pnas.0702859104. PMC .
- Willems, E.; Spiering, S.; Davidovics, H.; Lanier, M.; Xia, Z.; Dawson, M.; Cashman, J.; Mercola, M. (7 July 2011). "Small-Molecule Inhibitors of the Wnt Pathway Potently Promote Cardiomyocytes From Human Embryonic Stem Cell-Derived Mesoderm". Circulation Research. 109 (4): 360–364. doi:10.1161/CIRCRESAHA.111.249540. PMC .
- Burridge, Paul W; Matsa, Elena; Shukla, Praveen; Lin, Ziliang C; Churko, Jared M; Ebert, Antje D; Lan, Feng; Diecke, Sebastian; Huber, Bruno; Mordwinkin, Nicholas M; Plews, Jordan R; Abilez, Oscar J; Cui, Bianxiao; Gold, Joseph D; Wu, Joseph C (15 June 2014). "Chemically defined generation of human cardiomyocytes". Nature Methods. 11 (8): 855–860. doi:10.1038/nmeth.2999.
- Kaldis P, Pagano M (Dec 2009). "Wnt signaling in mitosis". Developmental Cell. 17 (6): 749–50. doi:10.1016/j.devcel.2009.12.001. PMID 20059944.
- Willert K, Jones KA (Jun 2006). "Wnt signaling: is the party in the nucleus?". Genes & Development. 20 (11): 1394–404. doi:10.1101/gad.1424006. PMID 16751178.
- Hodge, Russ (2016-01-25). "Hacking the programs of cancer stem cells". medicalxpress.com. Medical Express. Retrieved 2016-02-12.
- Schambony A, Wedlich D. "Wnt Signaling and Cell Migration". Madame Curie Bioscience Database. Landes Bioscience. Retrieved 7 May 2013.
- Micalizzi DS, Farabaugh SM, Ford HL (Jun 2010). "Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression". Journal of Mammary Gland Biology and Neoplasia. 15 (2): 117–34. doi:10.1007/s10911-010-9178-9. PMC . PMID 20490631.
- Abiola M, Favier M, Christodoulou-Vafeiadou E, Pichard AL, Martelly I, Guillet-Deniau I (Dec 30, 2009). "Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells". PLoS ONE. 4 (12): e8509. Bibcode:2009PLoSO...4.8509A. doi:10.1371/journal.pone.0008509. PMC . PMID 20041157.
- Howe LR, Brown AM (Jan 2004). "Wnt signaling and breast cancer". Cancer Biology & Therapy. 3 (1): 36–41. doi:10.4161/cbt.3.1.561. PMID 14739782.
- Taketo MM (Apr 2004). "Shutting down Wnt signal-activated cancer". Nature Genetics. 36 (4): 320–2. doi:10.1038/ng0404-320. PMID 15054482.
- DiMeo TA, Anderson K, Phadke P, Fan C, Feng C, Perou CM, Naber S, Kuperwasser C (Jul 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): 5364–73. doi:10.1158/0008-5472.CAN-08-4135. PMC . PMID 19549913.
- Anastas JN, Moon RT (Jan 2013). "WNT signalling pathways as therapeutic targets in cancer". Nature Reviews. Cancer. 13 (1): 11–26. doi:10.1038/nrc3419. PMID 23258168.
- Welters HJ, Kulkarni RN (Dec 2008). "Wnt signaling: relevance to beta-cell biology and diabetes". Trends in Endocrinology and Metabolism. 19 (10): 349–55. doi:10.1016/j.tem.2008.08.004. PMID 18926717.
- Yoon JC, Ng A, Kim BH, Bianco A, Xavier RJ, Elledge SJ (Jul 2010). "Wnt signaling regulates mitochondrial physiology and insulin sensitivity". Genes & Development. 24 (14): 1507–18. doi:10.1101/gad.1924910. PMC . PMID 20634317.
- Zhai L, Ballinger SW, Messina JL (Mar 2011). "Role of reactive oxygen species in injury-induced insulin resistance". Molecular Endocrinology. 25 (3): 492–502. doi:10.1210/me.2010-0224. PMC . PMID 21239612.
- Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (Mar 2006). "Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes". Nature Genetics. 38 (3): 320–3. doi:10.1038/ng1732. PMID 16415884.
- Mouse Wnt proteins from Signaling Gateway Molecule Pages
- Dinasarapu AR, Saunders B, Ozerlat I, Azam K, Subramaniam S (Jun 2011). "Signaling gateway molecule pages--a data model perspective". Bioinformatics. 27 (12): 1736–8. doi:10.1093/bioinformatics/btr190. PMC . PMID 21505029.
- "Search Molecule Pages - Signaling Gateway".
- "The Wnt Homepage".
- "KEGG PATHWAY: dme04310".
- mouse Wnt pathway from KEGG
- "KEGG PATHWAY: hsa04310".
- "KEGG PATHWAY: Wnt signaling pathway - Homo sapiens (human)".
- ABC News. "Can Grey Hair Be Reversed? Video - ABC News". ABC News.
- Netpath - A curated resource of signal transduction pathways in humans
- Wnt Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
- filip. "EPSF homepage".
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||signaling receptor binding (GO:0005102)|
|Biological process||multicellular organism development (GO:0007275)|
|Wnt 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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, 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 UniProtKB sequence database using the family HMM
- 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.
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.
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:||213|
|Number in full:||4410|
|Average length of the domain:||261.20 aa|
|Average identity of full alignment:||35 %|
|Average coverage of the sequence by the domain:||82.37 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|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.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 2 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 sequence.
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