Wnt signaling pathway

The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.[1]

Contents

Discovery

The first Wnt gene was discovered by Roeland Nusse and Harold Varmus in 1982 when they observed activation of Int1 (integration 1) in the breast tumors of mice infected with mouse mammary tumor virus (MMTV), in which Int was identified as a vertebrate gene near several integration sites of MMTV.[2] The origin of the name Wnt comes from a hybrid of Int and Wg (wingless) in Drosophila, which is the best characterized Wnt gene.[3] Although the wingless gene was originally identified as a recessive mutation affecting wing and haltere development in Drosophila melanogaster,[4] wingless has been important towards understanding the Wnt signaling system in other organisms, and its function as a segment polarity gene was discovered by Christiane Nüsslein-Volhard and Eric Wieschaus through their work on Drosophila mutants with phenotypes related to mutations in the Wg signaling pathway. As a result of their work, they later went on to win the Nobel Prize in Physiology and Medicine in 1995. It was not until 1987 that researchers found that Wg was the homologue to mammalian Int1 due to a common evolutionary origin evidenced by similar amino acid sequences of their encoded proteins.[3]

Mutations of the wingless gene in the fruit fly were found in wingless flies, while tumors caused by MMTV were found to have copies of the virus integrated into the genome forcing overproduction of one of several Wnt genes. The ensuing effort to understand how similar genes produce such different effects has revealed that Wnt proteins are a major class of secreted morphogenic ligands of profound importance in establishing the pattern of development in the bodies of all multicellular organisms studied.

Members

The following is a list of human genes that encode WNT signaling proteins:[5]

The following is a list of receptors that are acted upon by various WNT signaling proteins:

Wnt signaling proteins

The Wnt proteins are a group of secreted lipid-modified (palmitoylation) signaling proteins of 350-400 amino acids in length.[6] Following the signal sequence, they carry a conserved pattern of 23-24 cysteine residues, on which palmitoylation occurs on a cysteine residue.[7] These proteins activate various pathways in the cell that can be categorized into the canonical and noncanonical Wnt pathways.[8] Through these signaling pathways, Wnt proteins play a variety of important roles in embryonic development, cell differentiation, and cell polarity generation.[7]

Mechanism

The Wnt pathway involves a large number of proteins that can regulate the production of Wnt signaling molecules, their interactions with receptors on target cells and the physiological responses of target cells that result from the exposure of cells to the extracellular Wnt ligands. Although the presence and strength of any given effect depends on the Wnt ligand, cell type, and organism, some components of the signaling pathway are remarkably conserved in a wide variety of organisms, from Caenorhabditis elegans to humans. Protein homology suggests that several distinct Wnt ligands were present in the common ancestor of all bilaterian life, and certain aspects of Wnt signaling are present in sponges and even in slime molds.

The canonical Wnt pathway describes a series of events that occur when Wnt proteins bind to cell-surface receptors of the Frizzled family, causing the receptors to activate Dishevelled family proteins and ultimately resulting in a change in the amount of β-catenin that reaches the nucleus (Figure 2). Dishevelled (DSH) is a key component of a membrane-associated Wnt receptor complex (Figure 2), which, when activated by Wnt binding, inhibits a second complex of proteins that includes axin, GSK-3, and the protein APC (Figure 1). The axin/GSK-3/APC complex normally promotes the proteolytic degradation of the β-catenin intracellular signaling molecule. After this "β-catenin destruction complex" is inhibited, a pool of cytoplasmic β-catenin stabilizes, and some β-catenin, is able to enter the nucleus and interact with TCF/LEF family transcription factors to promote specific gene expression (interaction 2, Figure 2).

Cell surface Frizzled (FRZ) proteins usually interact with a transmembrane protein called LRP (Figure 2).[9] LRP binds Frizzled, Wnt and axin and may stabilize a Wnt/Frizzled/LRP/Dishevelled/axin complex at the cell surface ("receptor complex" in Figure 2).

In vertebrates, several secreted proteins have been described that can modulate Wnt signaling by either binding to Wnts[10] or binding to a Wnt receptor protein. For example, Sclerostin (not shown in a figure) can bind to LRP and inhibit Wnt signaling.[11]

The part of the pathway linking the cell surface Wnt-activated Wnt receptor complex to the prevention of β-catenin degradation is still under investigation. There is evidence that trimeric G proteins (G in Figure 2) can function downstream from Frizzled.[12] It has been suggested that Wnt-activated G proteins participate in the disassembly of the axin/GSK3 complex.[13]

Several protein kinases and protein phosphatases have been associated with the ability of the cell surface Wnt-activated Wnt receptor complex to bind axin and disassemble the axin/GSK3 complex.[14] Phosphorylation of the cytoplasmic domain of LRP by CK1 and GSK3 can regulate axin binding to LRP (interaction 1 in Figure 2). The protein kinase activity of GSK3 appears to be important for both the formation of the membrane-associated Wnt/FRZ/LRP/DSH/Axin complex and the function of the Axin/APC/GSK3/β-catenin complex. Phosphorylation of β-catenin by GSK3 leads to the destruction of β-catenin (Figure 1).

Feedback regulation of canonical Wnt signaling occurs via a variety of mechanisms, including induction or repression of Wnt signaling components themselves, including AXIN2 and Naked cuticle.

Ligands that act on Wnt signaling

Wnt-induced cell responses

Several important effects of the canonical Wnt pathway include:

Wnt and patterning the neural tube

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, the dorsal most region of the neural tube. While evidence that Wnt and Sonic hedgehog 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 Sonic Hedgehog via the canonical Wnt pathway.[17][18][19]

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 Sonic Hedgehog response in neural tube explants in chicks.[18] Chick electroporation assays have shown that ectopic activation of the Wnt/β-catenin pathway components results in an expansion of dorsal genes, Pax7 and Pax6, into 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.[17] 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.[17]

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.[17] 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.[17][19]

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, because of cross-talk 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.[19]

Non-canonical Wnt signaling

There are many non-canonical pathways, but the two best-studied pathways are the Planar Cell Polarity (PCP) and Wnt/Calcium Pathways. The most distinctive differences between the canonical and non-canonical pathways include the specific ligands activating each pathway, ß-Catenin, LRP5/6 co-receptor, and Dsh-DEP domain independence, and the ability of the non-canonical pathway to inhibit the canonical pathway. Ligands that activate the non-canonical pathways are Wnt4, Wnt5a, and Wnt11.[20] [21] Expression of Wnt5a was shown to be increased in prostate cancer [22]; the mechanism of this increase in Wnt5a protein expression was proposed to be increase in Wnt5a gene transcription due to hypomethylation of Wnt5a promotor region. [23] [24]

In the PCP pathway, ligand binding to the receptor recruits Dishevelled (Dsh), which forms a complex with Daam1. Daam1 then activates the small G-protein Rho through guanine exchange factor. Rho activates ROCK ( Rho-associated kinase), 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.

In the Wnt/Calcium pathway, Wnt5a and Frizzled regulate intracellular calcium levels. Ligand binding causes the coupled G-protein to activate PLC, leading to the generation of DAG and IP3. When IP3 binds to its receptor on the ER, intracellular calcium concentration increases. Ligand binding also activates cGMP-specific phosphodiesterase (PDE), which depletes cGMP and further increases calcium concentration. Increased concentrations of calcium and DAG can activate Cdc42 (cell division control protein 42) through PKC. Cdc42 is an important regulator of cell adhesion, migration, and tissue separation.[21] Increased calcium also activates calcineurin and CamKII (calcium/calmodulin-dependent kinase). Calcineurin induces activation of transcription factor NFAT, which regulates ventral patterning.[21] CamKII activates TAK1 and NLK kinase, which can interfere with TCF/ß-Catenin signaling in the canonical pathway.[25]

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.[26] 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.[26][27]

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.[28]

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.[29] 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.[30]

Stem cells

Traditionally, it is assumed that Wnt proteins can act as Stem Cell Growth Factors, promoting the maintenance and proliferation of stem cells.[31]

However, a recent study conducted by the Stanford University School of Medicine 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.[32]

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.[33] 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.[33] TCF3, a transcription factor regulated by Wnt signaling, has been shown to repress nanog, a gene required for stem cell pluripotency and self-renewal.[34] Over expression of another gene associated with pluripotency, OCT4 leads to increased beta-catenin activity, suggesting Wnt involvement.[35]

Studies of embryoid bodies (see embryoid body) 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.[36] 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.[37] 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.[38] 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.[33]

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[39] It seems that Wnt signaling might be part of the means by which experience regulates synapse numbers and hippocampal network structure.[39]

Wnt pathway in cancer stem cells

The canonical and non-canonical pathways show that the Wnt pathway is strictly regulated by many different elements. Thus, it can be expected that misregulation of these various components can have drastic effects throughout an organism. One interesting aspect of the Wnt pathway in particular is its involvement in the fate of stem cells[40] and its role as a regulator of stem cell choice to proliferate or self-renew. Given these properties, it is not surprising that a strong correlation between Wnt signaling and the onset of cancer exists. In the normal pathway, APC and Axin prevent β-catenin from traveling to the nucleus by engaging it in the destruction complex. However, an APC deficiency or mutations to β-catenin that prevent its degradation can lead to excessive stem cell renewal and proliferation, predisposing the cells to the formation of tumors.[41] Alteration of Wnt5a, a tumor suppressor gene, could also lead to tumor formation.

One of the potential ways to treat cancer is to affect β-catenin, a central component of the canonical Wnt pathway. Non-steroidal anti-inflammatory drugs (NSAIDs) that interfere β-catenin signaling have been shown to be promising for the prevention of colorectal cancer. NSAIDs inhibit prostaglandin production, which interferes with β-catenin/TCF-dependent transcription.[42] Another suggested method of treatment is to use natural antagonists of the Wnt pathway, such as secreted frizzled-related proteins (sFRPs) or Dkk. Furthermore, using small molecules to block the interaction between β-catenin and TCF could stop the proliferation of cancer. Researchers have also developed a recombinant adenovirus (Ad-CBR) that constitutively expresses the β-catenin binding domain of APC.[43] This enables the tumor suppressor activity of APC, thus preventing β-catenin translocation to the nucleus. Scientists are also using monoclonal antibodies against Wnt proteins to induce apoptosis in cancer cells.[43] Currently, there are many investigations underway to target various components of the Wnt pathway as a means of finding more effective treatments for cancer.

See also

External links

References

  1. ^ 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. 
  2. ^ Nusse R, van Ooyen A, Cox D, Fung YK, Varmus H (1984). "Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15". Nature 307 (5947): 131–6. doi:10.1038/307131a0. PMID 6318122. 
  3. ^ a b Klaus A., Birchmeier W. (2008). "Wnt signaling and its impact on development and cancer". Nature Reviews Cancer 8: 387–398. doi:10.1038/nrc2389. 
  4. ^ Sharma R P, Chopra V L (February 1976). "Effect of the Wingless (wg1) Mutation on Wing and Haltere Development in Drosophila melanogaster". Developmental Biology 48 (2): 461–465. doi:10.1016/0012-1606(76)90108-1. PMID 815114. 
  5. ^ Katoh Y, Katoh M (March 2005). "Identification and characterization of rat Wnt6 and Wnt10a genes in silico". Int. J. Mol. Med. 15 (3): 527–31. PMID 15702249. 
  6. ^ Cadigan K.M., Nusse R. (1997). "Wnt signaling: a common theme is animal development". Genes & Development 11: 3286–3305. 
  7. ^ a b Logan C.W., Nusse R. (2004). "The Wnt signaling pathway in development and disease". Cell Dev. Bio. 20: 781–810. 
  8. ^ Nelson W.J., Nusse R. (2004). "Convergence of Wnt, ß-Catenin, and Cadherin Pathways". Science 303: 1483–1487. 
  9. ^ Wehrli M, Dougan ST, Caldwell K, O'Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S (September 2000). "arrow encodes an LDL-receptor-related protein essential for Wingless signalling". Nature 407 (6803): 527–30. doi:10.1038/35035110. PMID 11029006. 
  10. ^ Kawano Y, Kypta R (July 2003). "Secreted antagonists of the Wnt signalling pathway". J. Cell. Sci. 116 (Pt 13): 2627–34. doi:10.1242/jcs.00623. PMID 12775774. 
  11. ^ Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (May 2005). "Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling". J. Biol. Chem. 280 (20): 19883–7. doi:10.1074/jbc.M413274200. PMID 15778503. 
  12. ^ Katanaev VL, Ponzielli R, Sémériva M, Tomlinson A (January 2005). "Trimeric G protein-dependent frizzled signaling in Drosophila". Cell 120 (1): 111–22. doi:10.1016/j.cell.2004.11.014. PMID 15652486. http://linkinghub.elsevier.com/retrieve/pii/S0092867404010876. 
  13. ^ Liu X, Rubin JS, Kimmel AR (November 2005). "Rapid, Wnt-induced changes in GSK3beta associations that regulate beta-catenin stabilization are mediated by Galpha proteins". Curr. Biol. 15 (22): 1989–97. doi:10.1016/j.cub.2005.10.050. PMID 16303557. 
  14. ^ Nusse R (December 2005). "Cell biology: relays at the membrane" (PDF). Nature 438 (7069): 747–9. doi:10.1038/438747a. PMID 16340998. http://www.stanford.edu/~rnusse/reviews/NaVReviewFinal438747a.pdf. 
  15. ^ Liu J, Wu X, Mitchell B, Kintner C, Ding S, Schultz PG (March 2005). "A small-molecule agonist of the Wnt signaling pathway". Angew. Chem. Int. Ed. Engl. 44 (13): 1987–90. doi:10.1002/anie.200462552. PMID 15724259. 
  16. ^ Kawano, Y.; Kypta, R. (2003). "Secreted antagonists of the Wnt signalling pathway". Journal of Cell Science 116 (13): 2627–2634. doi:10.1242/jcs.00623. PMID 12775774.  edit
  17. ^ a b c d e 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. 
  18. ^ a b 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. 
  19. ^ a b c 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. 
  20. ^ Michael Kuehl (2005). "Wnt11". Signaling Gateway Molecule Pages. doi:10.1038/mp.a002376.01. http://www.signaling-gateway.org/molecule/query?afcsid=A002385. 
  21. ^ a b c Komiya, Yuko, and Raymond Habas. “Wnt signal transduction pathways.” Organogenesis 4.2 (2008) : 68-75. Print.
  22. ^ Wang Q, Symes AJ, Kane CA, Freeman A, Nariculam J, et al. (2010). Hotchin, Neil A.. ed. "A Novel Role for Wnt/Ca2+ Signaling in Actin Cytoskeleton Remodeling and Cell Motility in Prostate Cancer". PLoS ONE 5 (5): e10456. doi:10.1371/journal.pone.0010456. PMC 2864254. PMID 20454608. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2864254. 
  23. ^ Michael Kuehl (2005). "Wnt5a". Signaling Gateway Molecule Pages. doi:10.1038/mp.a002385.01. http://www.signaling-gateway.org/molecule/query?afcsid=A002385. 
  24. ^ Wang Q, Symes AJ, Kane CA, Freeman A, Nariculam J, et al. (2007). "Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer". Oncogene 26 (45): 6560–5. doi:10.1038/sj.onc.1210472. PMID 17486081. 
  25. ^ 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.
  26. ^ a b 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. 
  27. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1456092. 
  28. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=195976. 
  29. ^ 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. 
  30. ^ 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. 
  31. ^ 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. 
  32. ^ Stanford researchers find culprit in aging muscles that heal poorly - Standford.edu. Retrieved: August 10th, 2007.
  33. ^ a b c Nusse R (May 2008). "Wnt signaling and stem cell control". Cell Res. 18 (5): 523–7. doi:10.1038/cr.2008.47. PMID 18392048. http://www.nature.com/cr/journal/v18/n5/full/cr200847a.html. 
  34. ^ 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. http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=16894029. 
  35. ^ 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. http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(05)00163-7. 
  36. ^ Embryoid Bodies Get Organized - Nature.com Retrieved: May 30, 2009
  37. ^ 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. http://www.jbc.org/cgi/content/full/282/43/31703. 
  38. ^ 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. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=17875805. 
  39. ^ a b 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. http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(09)00346-8. 
  40. ^ Nusse, Roel. "Wnt Signaling in Disease and Development." Cell Research 15. (2005): 28-32. Web. 17 Apr 2011.
  41. ^ Taketo, M Mark. "Shutting down Wnt signal-activated cancer." Nature Genetics 36. (2004): 320-22. Web. 17 Apr 2011.
  42. ^ Macdonald, Bryan. "Wnt/β-catenin Signaling: Components, Mechanisms, and Diseases." Developmental Cell 17.1 (2009): 9-26. Web. 17 Apr 2011.
  43. ^ a b Luu, Hue. "Wnt/β-catenin Signaling Pathway as Novel Cancer Drug Targets." Current Cancer Drug Targets 4. (2004): 653-71. Web. 17 Apr 2011.
  44. ^ 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. PMID 21505029. http://bioinformatics.oxfordjournals.org/content/27/12/1736.abstract. 
Signaling pathways
Agents
By location
Other concepts
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
Signaling pathway: Wnt signaling pathway
Ligand
WNT1 · WNT2 · WNT2B · WNT3 · WNT3A · WNT4 · WNT5A · WNT5B · WNT6 · WNT7A · WNT7B · WNT8A, WNT8B · WNT9A · WNT9B · WNT10A · WNT10B · WNT11 · WNT16
Receptor
Second messenger
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)