Wnt Signaling Pathway

Introduction

The Wnt signaling pathway is a highly evolutionarily conserved signaling pathway that is widely present in multicellular organisms. This pathway has an effect on cell proliferation, differentiation, apoptosis, cell polarity, cell migration and invasion, and plays an important role in the development and formation of various organs and pathophysiological processes in adulthood. Numerous studies have shown that changes in the Wnt signaling pathway are closely related to formation and development of tumor, development of degenerative diseases, and changes in stem cell function. More new studies have shown that this pathway is also potentially linked to inflammation, neovascularization, maintenance of immune function, wound healing and tissue regeneration. This pathway is being used as a key hotspot in basic applications and drug development research in each of these areas.

Wnt family member

Members of the Wnt family are promoters of the Wnt signaling pathway, which are widely expressed in a variety of tissues and are highly conserved in evolution, with high homology from lower organisms to higher mammals. The 19 Wnt proteins in mammals are divided into Wnt-1 and Wnt-5a families according to the different Wnt pathways involved. The Wnt-1 family is involved in the classical Wnt/β-catenin pathway, including Wnt1, Wnt2, Wnt3, Wnt8a, Wnt8b, Wntl0a, and Wntl0b. The Wnt-5a family is associated with non-canonical Wnt signaling pathways, including Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, and Wnt11.

Wnt signaling pathway

The Wnt signaling pathway includes the canonical Wnt pathway (β-catenin-dependent pathway) and the non-canonical Wnt pathway (β-catenin-independent pathway). As a highly conserved signaling pathway in evolution, the Wnt signaling pathway plays an important role in many biological processes such as growth, development, metabolism, and stem cell maintenance. Loss of control of the Wnt pathway is closely related to the development of diseases such as cancer, bone-related diseases, obesity, and diabetes.

β-catenin-dependent pathway

At present, the research on the classical Wnt / β-catenin signaling pathway is relatively thorough, and its core molecule is β-catenin. This pathway plays an important regulatory role in cell proliferation, migration, differentiation, and apoptosis. In the Wnt / β-catenin signaling pathway, auto-secretory or paracrine Wnt proteins bind to cell surface receptor frizzled (Frz), synergistically with lipoprotein receptor-related proteins 5 and 6 (LDL-receptor- Related protein 5/6, LRP5/6) together activates dishevelled (Dsh), triggering intracellular signal transduction. Further, a protein degradation complex composed of glycogen synthase kinase-3 (GSK-3β), adenomatous polyposis coli (APC), and axin (axin) is inhibited. The protein degradation complex can be degraded by phosphorylating β-catenin.

Figure 1 Wnt canonical signaling pathway

β-catenin-independent pathway

The initiation of the Wnt signal is that the Wnt ligand binds to a specific receptor on the target cell, transducing a specific signaling pathway, resulting in a series of physiological responses in the target cell. This process is related to the type of Wnt ligand and the type of cell, ie tissue specificity. In addition to the classical Wnt/β-catenin pathway, Wnt activates non-canonical signaling pathways through different receptors. These signaling pathways are more complex than the classical Wnt pathway and include a wide variety of signaling pathways, such as the Wnt/Ca2+ pathway and the Wnt/JNK pathway. In recent years, research on non-canonical Wnt signaling pathways has begun to increase.

Figure 2 Wnt non-canonical signaling pathway

The relationship between the Wnt signaling pathway and other signaling pathways

Wnt signal pathway and Notch signal pathway

The Notch signaling pathway is a highly conserved set of intercellular communication mechanisms. The Wnt and Notch signaling pathways interact and coordinate development in embryonic development, tissue regeneration, and tumor formation. The notch can bind to β-catenin to inhibit the Wnt signaling pathway, induce cycle arrest and apoptosis in human tongue cancer cells; Wnt activates Dvl against Notch signaling pathway. GSK-3β in the Wnt signaling pathway also interacts with the Notch pathway to affect Notch pathway activity. However, studies have also found that the Wnt and Notch pathways play a synergistic role in certain cells. For example, activation of the Notch signaling pathway in APC-mutant mice activates the Wnt signaling pathway to promote adenocarcinoma development.

Figure 3 Schematic representation of the role of Wnt, Notch, TGF- β and Hif-1 α signaling

Wnt signaling pathway and TGF-β/BMP signaling pathway

The transforming growth factor β (transformation growth factor-β, TGF-β) superfamily consists of TGF-β, activin, and bone morphogenetic protein (BMP). The TGF-β superfamily and its receptors (TGF-βRI and TGF-βII), intracellular signal transduction molecules (mainly the Smad protein family) constitute a signaling pathway that affects tumorigenesis and development, namely the TGF/BMP signaling pathway. The Wnt signaling pathway and the TGF-β/BMP signaling pathway can mutually regulate the activity of each other pathway. The expression of BMP4 in colon cancer cells is dependent on the expression of β-catenin. BMP2/4 of the TGF-β/BMP pathway also regulates Wnt8 expression in the Wnt pathway. Smad7 combined with β-catenin or directly linked to Axin can cause accumulation of β-catenin in cells.

Wnt signaling pathway and Hippo pathway

The Hippo pathway is a highly conserved growth-growth signaling pathway that regulates cell proliferation and differentiation as well as cell death. In the nucleus, the two pathways play a synergistic role, and YAP and β-catenin interact to induce expression of the target gene in the canonical Wnt pathway. When there is a Wnt signal, YAP /TAZ can detach from the β-catenin degradation complex, causing nuclear aggregation and activation of WNT /YAP /TAZ-dependent biological effects. In the absence of Wnt, YAP/TAZ plays a role in the recruitment of β-transduction repeat containing protein, leading to the non-activation of β-catenin.

Wnt signaling pathway and fibrotic disease

Fibrosis refers to an increase in fibrous connective tissue in organ tissues and a decrease in parenchymal cells. Recent studies have confirmed that abnormalities in the Wnt signaling pathway are closely related to the occurrence and progression of various organizing fibrotic diseases such as liver, lung, and kidney.

Figure 4 The TGF-β, WNT, and YAP/TAZ signaling pathways converge

Abnormal activation of the Wnt/β-catenin signaling pathway is closely related to the formation of idiopathic pulmonary fibrosis (IPF). In the lung tissues of patients with pulmonary fibrosis, the expressions of Fz2, Fz3, Wnt1, Wnt17b, Wnt10b, β-catenin and lymphoid enhancer factor (LEF) were significantly increased. Exogenous Wnt5a promotes the proliferation of hepatic stellate cells (HSC), and Wnt/β-catenin signaling pathway also participates in the formation of hepatic fibrosis by activating HSC. In addition, TGF-β and Wnt11 also play an important role in the development of renal interstitial fibrosis. At the same time, Wnt-induced secreted protein 1 (WISP1) is regulated by the level of β-catenin in Wnt signaling pathway, and the expression of WISP1 is enhanced, which leads to cardiomyocyte hypertrophy, myocardial fibroblast proliferation, and fibrosis formation.

Wnt signal and tumor

Abnormal activation of the Wnt signaling pathway is involved in the induction and regulation of multiple tumors. Wnt1 is associated with colorectal cancer, esophageal cancer, gastric cancer, pancreatic cancer, head and neck cancer, melanoma, sarcoma, leukemia, basal cell carcinoma, lung cancer, mesothelioma, and the like. Wnt2 is highly expressed in the fetal lungs and low in the placenta. Wnt5a is up-regulated in melanoma, odontogenic tumors, non-small cell lung cancer, and squamous cell carcinoma; however, Wnt5a is down-regulated or absent in breast cancer, colorectal cancer, and leukemia. Wnt2, Wnt-5a, and Wnt-7b play important roles in lung maturation. Wnt2, Wnt3, and Wnt5a are expressed in endometrial cancer. Wnt7b is up-regulated in superficial bladder cancer.

The classical Wnt/β-catenin signaling pathway induces liver cancer by activating downstream target genes c-myc, c-jun, CyclinD1, VEGF (vascular endothelial growth factor). In 78% of liver cancer cells, β-catenin was highly expressed, 53% was expressed on the cell membrane, 22% was expressed in the cytoplasm, and 19% was expressed in the cell membrane and nucleus. High expression of β-catenin in the nucleus is more common in moderately and poorly differentiated liver cancer tissues. The high expression of β-catenin in hepatocarcinoma is related to its mutation, and its mutation is a frequent event in liver cancer, which can be as high as 44.1%.

References:

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