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Wnt Signaling Pathway

Figure 1. The Wnt/β-catenin signaling pathway

What is Wnt?
The term “Wnt” is derived from the terms wingless and int. The Int oncogenes, including Int1, were first identified in the mouse mammary tumor. In 1987, investigators sequenced wingless in Drosophila and found it was the homolog of int-1. 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". Wnts are secreted factors that regulate cell growth, motility, and differentiation during embryonic development. Wnts act in a paracrine fashion by activating diverse signaling cascades inside the target cells.
Wnt gene family
The Wnt family consists of a number of highly conserved genes that regulate gene expression, cell behavior, cell adhesion, and cell polarity, including 19 genes in humans and mice, 7 in Drosophila, and 5 in C. elegans. Wnt-1 is one member of a gene family whose additional members were isolated either as a target for MMTV insertion (Wnt-3, Wnt-3A was subsequently isolated by homology to Wnt-3), fortuitously from a chromosomal walk directed around the cystic fibrosis gene (Wnt-2), or from mouse embryo RNA using the polymerase chain reaction (Wnt-4, -5A, -5B, -6, -7A,and -7B) . There are now at least 10 known members of the Wnt family in the mouse; all of which are expressed during development, many in the developing nervous system with some expressed in adult brain as well. In addition, five members of the Wnt family are expressed in the normal mammary gland in the mouse and are differentially regulated during pregnancy and lactation. This family has been remarkably well conserved throughout evolution, with homologues present in both invertebrates and vertebrates. In addition to the predicted amino acid sequence similarities among family members, a role in cell signaling has also been documented for several Wnt family members. For example, wingless, the Drosophila homologue of Wnt-1, is necessary for proper segmental patterning of the embryo and is proposed to function locally via cell-cell interactions.
Wnt signaling pathway
The Wnt signaling pathway is a conserved pathway. The Wnt family of signaling proteins participates in multiple developmental events during embryogenesis and has also been implicated in adult tissue homeostasis. Wnt signals are pleiotropic, with effects that include mitogenic stimulation, cell fate specification, and differentiation. The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. The Wnts are secreted glycoproteins and comprise a large family of nineteen proteins in humans hinting to a daunting complexity of signaling regulation, function and biological output.
Wnt proteins are secreted glycoproteins that bind to the N-terminal extra-cellular cysteine-rich domain of the Frizzled (Fz) receptor family of which there is ten Fz in humans. The extra-cellular Wnt signal stimulates several intra-cellular signal transduction cascades. In this article, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway).

1. The Wnt/β-catenin signaling cascade

A simple outline of the current model of Wnt signal transduction is presented in Figure 1. Wnt proteins released from or presented on the surface of signaling cells act on target cells by binding to the Frizzled (Fz)/low density lipoprotein (LDL) receptor-related protein (LRP) complex at the cell surface. These receptors transduce a signal to several intracellular proteins that include Dishevelled(Dsh), glycogen synthase kinase-3β (GSK-3), Axin, Adenomatous Polyposis Coli(APC), and the transcriptional regulator, β-catenin, after phosphorylation, β-catenin is ubiquitinated by β-trcp and subsequently degraded by the proteasome. Cytoplasmic β-catenin levels are normally kept low through continuous proteasome-mediated degradation, which is controlled by a complex containing GSK-3/APC/Axin. When cells receive Wnt signals, the degradation pathway is inhibited, and consequently β-catenin accumulates in the cytoplasm and nucleus. Nuclear β-catenin interacts with transcription factors such as lymphoid enhancer-binding factor 1/T cell-specific transcription factor (LEF/TCF) to affect transcription. A large number of Wnt targets have been identified that include members of the Wnt signal transduction pathway itself, which provide feedback control during Wnt signaling.

2. The Wnt-PCP signaling cascade

Wnt Signaling Pathway
Figure 2. The planar cell polarity transduction cascade
The planar cell polarity pathway involves RhoA and Jun Kinase (JNK) and controls cytoskeletal rear-rangements. Its main role is the temporal and spatial control of embryonic development, as exemplified in the polar arrangement of cuticular hairs in Drosophila or the convergent-extension movements in Xenopus embryos. On a cellular level, this pathway regulates the polarity of cells through effects on their cytoskeletal organization. Cells in the epithelia are known to possess a defined apical-basolateral polarity but in addition they are also polarized along the plane of the epithe-lial layer. The defining feature of this pathway is its regulation of the actin cytoskeleton for such polarized organization of structures and directed migration.
Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh. Dsh through Daam1 mediates activation of Rho which in turn activates Rho kinase (ROCK). Daam1 also mediates actin polymerization through the actin binding protein Profilin. Dsh also mediates activation of Rac, which in turn activates JNK. The signaling from Rock, JNK and Profilin are integrated for cytoskeletal changes for cell polarization and motility during gastrulation.

3. The Wnt-Ca2+ signaling cascade

Wnt Signaling Pathway
Figure 3. The Wnt/Ca2+ signal transduction cascade
The Wnt/Ca2+ pathway is stimulated by Wnt 5a and Wnt 11 and involves an increase in intracellular Ca2+ and activation of Ca2+-sensitive signalling components, such as calmodulin-dependent kinase, the phosphatase calcineurin, and the transcription factor NF-AT. The Wnt/Ca2+ pathway can counteract the canonical Wnt pathway; however, it is not clear whether this pathway is conserved in mammals and whether it is implicated in tumorigenesis.
Wnt signaling via Fz mediates activation of Dsh via activation of G-proteins. Dishevelled activates the phosphodiesterase PDE which inhibits PKG and in turn inhibits Ca2+ release. Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin. Calcineurin activate NF-AT to regulate ventral cell fates. CamK11 activates TAK and NLK, which inhibit  β-catenin/TCF function to negatively regulate dorsal axis formation. DAG through PKC activates CDC42 to mediate tissue separation and cell movements during gastrulation.

4. Pathway regulation

One key level of regulation of Wnt signaling occurs in the extra-cellular milieu with the presence of a diverse number of secreted Wnt antagonists. After binding of Wnt to the receptor complex, the signal is transduced to cytoplasmic phosphoprotein Dishevelled (Dsh/Dvl), and studies have uncovered that Dsh can directly interact with Fz. At the level of Dsh, the Wnt signal branches into at least three major cascades, canonical, Planar Cell Polarity and Wnt/Ca2+. Dsh is an important downstream component of this transduction pathway and is the first cytoplasmic protein that is pivotally involved in all three major branches of Wnt signaling.  The Wnt ligands are secreted glycoproteins that are heavily modified prior to transport and release into the extra-cellular milieu.
The porcupine protein has been shown to play an important role in the palmitolation of the Wnt proteins, and their secretion is regulated by the wntless or evenness interrupted proteins and the retromer complex. In the extra-cellular matrix, the Wnt proteins may be bound to and stabilized by heparan sulfate proteoglycans including Dally and glypican 3 which further limits their diffusion and modulate their signaling abilities. In the extra-cellular matrix, a number of secreted proteins that bind to Wnts and prevent their interaction with either Fz or LRP5/6 to antagonize Wnt signaling have been identified. These include Dickkopf (Dkk) proteins, Wnt-inhibitor protein (WIF), soluble Frizzled-related proteins (SFRP), Cerebrus, Frzb and the context dependent Wnt inhibitor Wise. Each of these secreted inhibitors are tightly regulated during embryogenesis and serve to limit or likely create a gradient of Wnt signaling for pattern formation. An interesting recent finding is the identification of factors including Norrin and R-Spondin2, which can bind to the LRP5/6 receptor and may activate Wnt signaling independent of a Wnt ligand. The SOST protein can also bind to LRP5/6 where it can antagonize Wnt signaling.

5. Downstream signaling

Once in the nucleus, β-catenin is thought to convert the TCF repressor complex into a transcriptional activator complex. This may occur through displacement of Groucho from TCF/LEF and recruitment of the histone acetylase CBP/p300 (cyclic AMP response element-binding protein). CBP may bind to the β-catenin/TCF complex as a coactivator, a hypothesis that remains to be tested directly. Another activator, Brg-1, is a component of the SWI/SNF (switching-defective and sucrose nonfermenting) chromatin remodeling complex, which, with CBP, may induce chromatin remodeling that favors target gene transcription. Further interactions between the TCF-β-catenin complex and chromatin could bemediated by Legless (Bcl9) and Pygopos. Mutations in either of these genes result in wingless-like phenotypes in Drosophila, and both genes promote Wnt signaling in mammalian cell culture experiments.

Wnt Signaling Pathway

Figure 4. Nuclear factors in Wnt signaling

6. Relationship with diseases

In adults, mis-regulation of the Wnt pathway also leads to a variety of abnormalities and degenerative diseases (Table1).

Table1. Human genetic diseases and Wnt signaling components

Gene Disease
WNT3 Tetra-amelia
LRP5 Bone density defects
Vascular defects in the eye (osteoperosis-pseudoglioma syndrome, OPPG; familial exudative vitreoretinopathy, FEVR)
FZD4 Retinal angiogenesis defects (familial exudative vitreoretinopathy, FEVR)
Axin2 Tooth agenesis; Predisposition to colorectal cancer
APC Polyposis coli, colon cancer

Tetra-amelia, also called autosomal recessive tetraamelia, is an extremely rare autosomal recessive congenital disorder characterized by the absence of all four limbs. Other areas of the body are also affected by malformations, such as the face, skull, reproductive organs, anus and pelvis. The disorder has been proposed to result from WNT3 loss-of-function mutations.
An LRP mutation has been identified that causes increased bone density at defined locations such as the jaw and palate. The mutation is a single amino-acid substitution that makes LRP5 insensitive to Dkk-mediated Wnt pathway inhibition, indicating that the phenotype results from overactive Wnt signaling in the bone. LRP5 mutations can also be accompanied by vasculature defects in the eye (osteoperosis-pseudoglioma syndrome or OPPG). In addition, a hereditary disorder, called familial exudative vitreopathy (FEVR), is caused by mutations in both LRP5 and the Fz4 receptor, which results in defective vasculogenesis in the peripheral retina.
A nonsense mutation in Axin2 has been shown to produce severe tooth agenesis, or oligodontia, a condition inwhichmultiple permanent teeth aremissing. In addition to tooth defects, individuals with Axin2 mutations display a prediposition to colon cancer. Moreover, the best-known example of a disease involving a Wnt pathway mutation that produces tumors is familial adenomatous polyposis (FAP), an autosomal, dominantly inherited disease in which patients display hundreds or thousands of polyps in the colon and rectum.
Moreover, the best-known example of a disease involving a Wnt pathway mutation that produces tumors is familial adenomatous polyposis (FAP), an autosomal, dominantly inherited disease in which patients display hundreds or thousands of polyps in the colon and rectum. This disease is caused most frequently by truncations in APC, which promote aberrant activation of the Wnt pathway leading to adenomatous lesions owing to increased cell proliferation. Mutations in β-catenin and APC have also been found in sporadic colon cancers and a large variety of other tumor types.

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2. Beverly D. Smolich, Jill A. McMahon, Andrew P. McMahon.Wnt family proteins are secreted and associated with the cell surface.Molecular Biology of the Cell,1993,4, 1267-1275.
3. Yiping Wang, Yi-Ping Li, Christie Paulson.Wnt and the Wnt signaling pathway in bone development and disease [J].NIH Public Access, 2014,19: 379–407.
4. Catriona Y. Logan, Roel Nusse.The Wnt signaling pathway in development and disease.Annu. Rev. Cell Dev. Biol. 2004. 20:781–810.
5. B. Lustig, J. Behrens. The Wnt signaling pathway and its role in tumor development [J]. Cancer Res Clin Oncol (2003) 129: 199–221
6. B. Sumithra, Urmila Saxena, Asim Bikas Das. Alternative splicing within the Wnt signaling pathway: role in cancer development [J]. Cell Oncol. 2015.

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