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Wnt Family

Overview

The Wnt protein family includes a large number of cysteine-rich glycoproteins. The Wnt proteins activate signal transduction cascades via three different pathways, the canonical Wnt pathway, the noncanonical planar cell polarity (PCP) pathway, and the noncanonical Wnt/Ca2+ pathway.

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.

These proteins are highly conserved across species. They can be found in mice, humans, xenopus, zebrafish, drosophila and many others.

Wnt Family

Figure 1. Crystal protein structure of Wnt8

Members of Wnt Family

Table 1. Wnt family related products

Wnt Family Ligands WNT1 WNT2 WNT2B
WNT3 WNT3A WNT4
WNT5A WNT5B WNT6
WNT7A WNT7B WNT8A
WNT8B WNT9A WNT9B
WNT10A WNT10B WNT11
WNT16    
 


Frizzled Receptors

FZD1 FZD2 FZD3
FZD4 FZD5 FZD6
FZD7 FZD8 FZD9
FZD10    

Table 2. Wnt family members.

WNT1 Proto-oncogene protein WNT1 is a protein that in humans is encoded by the WNT1 gene. This gene is a member of the WNT gene family. It is conserved in evolution, and the protein encoded by this gene is known to be 98% identical to the mouse Wnt1 protein at the amino acid level. The studies in mouse indicate that the Wnt1 protein functions in the induction of the mesencephalon and cerebellum. This gene was originally considered as a candidate gene for Joubert syndrome, an autosomal recessive disorder with cerebellar hypoplasia as a leading feature.
WNT2 WNT2 is a protein that in humans is encoded by the WNT2 gene. WNT2 have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. Alternatively spliced transcript variants have been identified for this gene.
WNT2B Protein Wnt-2b (formerly Wnt13) is a protein that in humans is encoded by the WNT2B gene. This gene encodes a member of the wingless-type MMTV integration site (WNT) family of highly conserved, secreted signaling factors. WNT family members function in a variety of developmental processes including regulation of cell growth and differentiation and are characterized by a WNT-core domain. This gene may play a role in human development as well as human carcinogenesis. This gene produces two alternative transcript variants.
WNT3 Proto-oncogene protein Wnt-3 is a protein that in humans is encoded by the WNT3 gene. It encodes a protein showing 98% amino acid identity to mouse Wnt3 protein, and 84% to human WNT3A protein, another WNT gene product.
WNT4 WNT4 is a secreted protein that in humans is encoded by the Wnt4 gene, found on chromosome 1. It promotes female sex development and represses male sex development. Loss of function can have serious consequences, such as female to male sex reversal.
WNT5A Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene. The WNT5A is highly expressed in the dermal papilla of depilated skin. It encodes a protein showing 98%, 98%, and 87% amino acid identity to the mouse, rat and the xenopus Wnt5a protein, respectively.
WNT5B Protein Wnt-5b is a protein that in humans is encoded by the WNT5B gene. It encodes a protein showing 94% and 80% amino acid identity to the mouse Wnt5b protein and the human WNT5A protein, respectively. Alternative splicing of this gene generates two transcript variants.
WNT6 Wingless-type MMTV integration site family, member 6, also known as WNT6, is a human gene. It is overexpressed in cervical cancer cell line and strongly coexpressed with another family member, WNT10A, in colorectal cancer cell line. The gene overexpression may play key roles in carcinogenesis. This gene and the WNT10A gene are clustered in the chromosome 2q35 region. The protein encoded by this gene is 97% identical to the mouse Wnt6 protein at the amino acid level.
WNT7A Protein Wnt-7a is a protein that in humans is encoded by the WNT7A gene. It encodes a protein showing 99% amino acid identity to the mouse Wnt7A protein. Decreased expression of this gene in human uterine leiomyoma is found to be inversely associated with the expression of estrogen receptor alpha.
WNT7B Protein Wnt-7b is a protein that in humans is encoded by the WNT7B gene. It encodes a protein showing 99% and 91% amino acid identity to the mouse and xenopus Wnt7A proteins, respectively. Among members of the human WNT family, this protein is most similar to WNT7A protein (77.1% total amino acid identity).
WNT8A Protein Wnt-8a is a protein that in humans is encoded by the WNT8A gene. Wnt8a may be involved in development of early embryos as well as germ cell tumors.
WNT8B Protein Wnt-8b is a protein that in humans is encoded by the WNT8B gene. It encodes a protein showing 95%, 86%, and 71% amino acid identity to the mouse, zebrafish and xenopus Wnt8B proteins, respectively. The expression patterns of the human and mouse genes appear identical and are restricted to the developing brain. The chromosomal location of this gene to 10q24 suggests it as a candidate gene for partial epilepsy.
WNT9A Protein Wnt-9a (formerly Wnt14) is a protein that in humans is encoded by the WNT9A gene. It is expressed in gastric cancer cell lines. The protein encoded by this gene shows 75% amino acid identity to chicken Wnt14, which has been shown to play a central role in initiating synovial joint formation in the chick limb. This gene is clustered with another family member, WNT3A, in the chromosome 1q42 region.
WNT9B Protein Wnt-9b (formerly Wnt15) is a protein that in humans is encoded by the WNT9B gene.
WNT10A Wnt-10a is a protein that in humans is encoded by the WNT10A gene. WNT10A is strongly expressed in the cell lines of promyelocytic leukemia and burkitt's lymphoma. This gene and the WNT6 gene are clustered in the chromosome 2q35 region.
WNT10B Protein Wnt-10b (formerly Wnt12) is a protein that in humans is encoded by the WNT10B gene. This protein is 96% identical to the mouse Wnt10b protein at the amino acid level. This gene is clustered with another family member, WNT1, in the chromosome 12q13 region.
WNT11 Protein Wnt-11 is a protein that in humans is encoded by the WNT11 gene. It encodes a protein showing 97%, 85%, and 63% amino acid identity with mouse, chicken, and xenopus Wnt11 protein, respectively. This gene may play roles in the development of skeleton, kidney, and lung, and is considered to be a plausible candidate gene for High Bone Mass Syndrome.
WNT16 Protein Wnt-16 is a protein that in humans is encoded by the WNT16 gene. It has been proposed that stimulation of WNT16 expression in nearby normal cells is responsible for the development of chemotherapy-resistance in cancer cells.

Cellular functions

WNT4 is involved in a couple features of pregnancy as a downstream target of BMP2. For example, it regulates endometrial stromal cell proliferation, survival, and differentiation. These processes are all necessary for the development of an embryo. Ablation in female mice results in subfertility, with defects in implantation and decidualization. For instance, there is a decrease in responsiveness to progesterone signaling. Furthermore, postnatal uterine differentiation is characterized by a reduction in gland numbers and the stratification of the luminal epithelium.

Non-canonical Wnt5a has also been shown to bind to Ror1/2, RYK, and RTK depending on cell and receptor context to mediate a variety of functions ranging from cell proliferation, polarity, differentiation and apoptosis.

WNT6 plays a role in the formation and maturation of different embryonic structures, namely the fetal heart, ventral body wall, and somite derived structures. Wnt6, through the canonical Wnt signaling pathway, inhibits the induction of cardiogenic mesoderm. For this reason, Wnt6 inhibitors like Cerberus must be present to allow the cells to be induced.

WNT7A gene not only guides the development of the anterior-posterior axis in the female reproductive tract but also plays a critical role in uterine smooth muscle pattering and maintenance of adult uterine function. It is also responsive to changes in the levels of sex steroid hormone in the female reproductive tract.

WNT10A and another family member, the WNT6 gene, are strongly coexpressed in colorectal cancer cell lines. The gene overexpression may play key roles in carcinogenesis through activation of the WNT-beta-catenin-TCF signaling pathway.

Role in disease

WNT1 gene was originally considered as a candidate gene for joubert syndrome, an autosomal recessive disorder with cerebellar hypoplasia as a leading feature.

WNT2 has been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis.

The mouse studies show the requirement of Wnt3 in primary axis formation in the mouse. Studies of the gene expression suggest that this gene may play a key role in some cases of human breast, rectal, lung, and gastric cancer through activation of the WNT-beta-catenin-TCF signaling pathway.

WNT4 is essential for nephrogenesis. It regulates kidney tubule induction and the mesenchymal to epithelial transformation in the cortical region. WNT4 contributes to the formation of the neuromuscular junction in vertebrates. Expression is high during the creation of first synaptic contacts, but subsequently downregulated. WNT4 is also associated with lung formation and has a role in the formation of the respiratory system. When WNT4 is knocked out, there are many problems that occur in lung development. It has been shown that when WNT4 is knocked out, the lung buds formed are reduced in size and proliferation has greatly diminished which causes underdeveloped or incomplete development of the lungs. It also causes tracheal abnormalities because it affects the tracheal cartilage ring formation. Lastly, the absence of WNT4 also affects the expression of other genes that function in lung development such as Sox9 and FGF9.

Wnts, specifically Wnt5a, have also been positively correlated and implicated in inflammatory diseases such as rheumatoid arthritis, tuberculosis, and atherosclerosis. A central player and active secretor of Wnt5a in both cancer and these inflammatory diseases are macrophages.

Knockout models show that without Wnt6 the fetus develops an enlarged heart, while upregulating Wnt6 results in the heart being underdeveloped. Several Wnts, including Wnt6, have shown to be involved in the formation of the ventral body wall and result in birth defects such as failure of the wall to close, hypoplasia of the musculature, and other defects.

Mutations in the WNT10A gene are associated with Schöpf–Schulz–Passarge syndrome and hypodontia.

WNT10B may be involved in breast cancer, and its protein signaling is, it is presumed, a molecular switch that governs adipogenesis. Gain-of-function of Wnt10b in mouse hearts has shown to improve cardiac tissue repair after myocardial injury, by promoting coronary vessel formation and attenuating pathological fibrosis.

References:

1. Logan CY, Nusse R. "The Wnt signaling pathway in development and disease". Annual Review of Cell and Developmental Biology. 2004, 20: 781–810.
2. Cadigan KM, Nusse R. "Wnt signaling: a common theme in animal development". Genes & Development. 1997, 11 (24): 3286–305.
3. Rao TP, Kühl M. "An updated overview on Wnt signaling pathways: a prelude for more". Circulation Research. 2010,106 (12): 1798–806.
4. Howe LR, Brown AM. "Wnt signaling and breast cancer". Cancer Biology & Therapy. 2004, 3 (1): 36–41.
5. Anastas JN, Moon RT. "WNT signaling pathways as therapeutic targets in cancer". Nature Reviews. Cancer. 2013, 13 (1): 11–26.
6. Welters HJ, Kulkarni RN. "Wnt signaling: relevance to beta-cell biology and diabetes". Trends in Endocrinology and Metabolism. 2008, 19 (10): 349–55.

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