Wnt signal pathway and Wnt protein
As a highly conserved signaling pathway in evolution, Wnt signaling pathway plays an important role in many biological processes such as growth, development, metabolism and stem cell maintenance. The loss control of Wnt pathway is closely related to the occurrence of diseases such as cancer, obesity and diabetes. The regulation of classical Wnt pathway mainly revolves around two key regulators, beta-Catenin and TCF, which affect the expression of a large number of target genes related to growth and metabolism at the transcriptional level.
Figure 1. Wnt signaling pathways and the intervention targets of Wnt pathway inhibitors. (Fu W B,st al. 2019)
The opening and closing of Wnt signal transduction pathway directly control the expression level of a large number of genes related to growth and metabolism. At the same time, this signal pathway indirectly affects the genes downstream of these pathways through complex interactions with other signal pathways (such as TGFbeta/BMP, Hedgehog, PI3K, RTK, etc.). Therefore, Wnt signal transduction pathway is involved in the regulation of a variety of biological processes, including embryonic growth and morphological development, tissue stability, energy metabolism balance and stem cell maintenance. The disorder of Wnt pathway is closely related to major human diseases. The excessive activation of Wnt pathway is closely related to the occurrence of a variety of cancers (including colon cancer, gastric cancer, breast cancer, etc.), but also can promote the metastasis of cancer cells. In addition, disorders of the Wnt pathway can also lead to metabolic diseases. Wnt signal pathway can inhibit adipocyte differentiation. Therefore, the inhibition of this signal pathway can lead to obesity, which in turn leads to metabolic disorders. Through the investigation of different ethnic groups, it is found that the genetic diversity of TCF7L7 gene, a key regulator in the Wnt pathway, is most closely related to the incidence of type 2 diabetes, but so far there is still a lack of sufficient understanding of its mechanism. In recent years, it has been found that Wnt signaling pathway plays an important role in the maintenance of epidermal stem cells, intestinal stem cells, hematopoietic stem cells, neural stem cells, embryonic stem cells and tumor stem cells.
Figure 2. Beta-Catenin regulates transcription of its target genes in nucleus (Yin DZ, et al. 2011)
There are 19 subtypes of Wnt protein in mammals. Wnt protein induces a series of downstream signal transduction by binding to the receptor on the cell membrane, and it has a production-modification-secretion- transport pathway. Wnt protein is a kind of highly insoluble protein, which is mainly due to its lipophilic modification. There are two main modifications of Wnt protein: glycosylation and palmitoylation. In vivo, adipose modified Wnt protein binds to cell surface and cell matrix, which reduces its diffusivity. During development, Wnt acts as a morphogenetic factor, which requires Wnt protein to spread far away. Wnt protein enhances its diffusivity by forming polymers or binding to lipoprotein particles.
Figure 3. Coop and ISWI are newly discovered factors that regulate the Wnt pathway ( Yin DZ, et al. 2011)
What is PTC protein?
Protein patched homolog 1 is also known as PTC, PTCH1, This gene encodes a member of the patched gene family. The encoded protein is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis, as well as the desert hedgehog and indian hedgehog proteins. This gene functions as a tumor suppressor. Mutations of this gene have been associated with basal cell nevus syndrome, esophageal squamous cell carcinoma, trichoepitheliomas, transitional cell carcinomas of the bladder, as well as holoprosencephaly. Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described, but their full-length sequences and biological determined currently. PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgehog binds PTCH1, smoothened is released and signals cell proliferation. Mutations in this gene are associated with nevoid basal cell carcinoma syndrome, trichoepitheliomas and holoprosencephaly. Alternative splicing results in multiple transcriptional variants that encode different isotypes. Other splicing variants have been described, but their full-length sequences and biological validity cannot be determined. Mutations in PTCH1 can cause Goering syndrome and have been found in patients with panencephalic preencephalopathy. Some of these patients showed cleft lip in the precursors of the whole brain, and missense mutations of PTCH1 were also found in sequencing screening of patients with nonsyndromic cleft lip and pa cleft lip. Mutations in PTCH1 are also associated with medulloblastoma.
Figure 4. Hedgehog pathway. PTCH1/2 constitutively inhibits smoothened. Inhibition of PTCH1, either through Hh ligand binding or inactivating mutations in PTCH1, promotes Smo activation. Smo activation, in turn, leads to GLi1 transcriptional activation and upregulation of Smo-dependent genes. Oral smoothened inhibitors inhibit Smo activation, leading to a downregulation of GLi1-dependent transcriptional activity. (Doan H Q, et al. 2016)
What is the relationship between tumor and tumor?
One of the characteristics of cancer cells is abnormal proliferation and out of control of cell cycle. The regulation of Wnt pathway on stem cell self-renewal is also used by cancer cells. Most colon cancers start with a difference in the Wnt pathway.Often caused by activation, familial colonic polyposis is a hereditary disease. FAP is caused by the inactivation of APC, which leads to the increase of nuclear beta-Catenin level and cell proliferation. With the continuous proliferation of APC mutant cells, other oncogenes or tumor suppressor genes may also mutate, resulting in tumorigenesis. In other colon cancer cases, there are mutations of other genes in Wnt pathway. It is generally believed that the mechanism of colon cancer caused by abnormal activation of Wnt pathway is similar to that of Wnt in maintaining crypt stem cells and proliferative precursor cells. By regulating the expression of cyclinD and c-myc genes, cells remain in a proliferative state similar to precursor cells for a long time, which also provides a window for other carcinogenic mutations. In addition to colon cancer, mutations in the Wnt signaling pathway can also cause others.The occurrence of tumor at the site. For example, most hairy parent tumors are accompanied by mutations in beta-Catenin. Functional deletion mutations of Axin were found in some cases of hepatocellular carcinoma.
Figure 5. Wnt signaling in cancer. ( Polakis P. 2000 )
As a transmembrane protein receptor downstream of the Hh signal pathway, transmembrane protein receptors are distributed on the target cell membrane. Ptch is encoded by tumor suppressor gene Patched and consists of a single peptide chain of 12 transmembrane regions. It has two functions of binding Hh ligand and inhibiting Smo, and plays a negative role in regulating Hh signaling pathway. Two Ptch homologous genes, Ptch1 and Ptch2, have been found in human genome. In tumor cells, the Hh signal pathway is abnormally activated. It has been found that blocking Hh signal pathway with cyclopamine can promote the apoptosis of SNU16 gastric cancer cells, which is related to the down-regulation of the expression of anti-apoptotic protein Bcl 2. Glioma cells can be stagnated in G0/G1 phase by inhibiting Hh signal pathway. In addition, epithelial-mesenchymal transformation can be induced to promote the invasive ability of pancreatic cancer cells by up-regulating Snail and E-terminal cadherin,Hh signal transduction pathway. In summary, Hh signaling pathway plays a role in tumor proliferation, cell cycle regulation, tumor invasion and metastasis, stem cell stem cell maintenance and so on.
Figure 6. Inhibition of components of the Shh Pathway in cancer. Inactive signaling (left) occurs in the absence of Shh ligand wherein PTCH1 inhibits SMO resulting in GLI1 sequestration in the cytoplasm by SUFU. In the presence of Shh (right), PTCH1 suppression of SMO is abrogated resulting in the nuclear accumulation of GLI1 and activation of target genes that promote several oncogenic properties to tumor cells. (Rimkus T, st al. 2016）
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