The WNT signaling pathway was first discovered in colon cancer research and embryonic development studies of fruit flies (Drosophila melanogaster), frogs (Xenopus laevis), and other animals. Colorectal and other forms of cancers may be caused by abnormal activation of the WNT pathway. The bipartite transcription factor β-catenin/ Tcell factor (β-cat/TCF) is the main effector of the classical WNT pathway. TCF7L2, the primary partner of β-cat in the intestinal epithelia, is generated by heterodimerization of free β-cat with one of the four members of the TCF family (TCF7 [also known as TCF-1], lymphoid enhancer-binding factor 1 [LEF-1], TCF7L1 [also known as TCF-3], and TCF7L2 [also known as TCF-4]).
In the absence of WNT, a ‘destructive complex’ made up of the tumour suppressor adenomatous polyposis coli (APC), axin, the serine threonine kinase glycogen synthase kinase-3 (GSK-3), casein kinase-1 (CK-1), and phosphorylated ERK closely regulates the cellular concentration of free -cat (pERK). β-cat is phosphorylated by this complex after it interacts with it. The proteasome-mediated degradation pathway destroys the phosphorylated β-cat.
The Frizzled receptors and the LDL receptor-related protein 5/6 (LRP5/6) co-receptors are how WNT ligands function. WNT signals are transmitted by the interaction of WNT receptors with Dishevelled (Dvl) protein after receptor binding. This occurrence causes the destructive complex to be disrupted, preventing the phosphorylation-dependent degradation of β-cat, which then reaches the nucleus and forms a complex with a member of the TCF family, stimulating the downstream target genes of β-cat/TCF (or WNT).
Wnt signaling pathway and Diabetes
The Wnt signaling pathway is involved in islet cell proliferation and differentiation in the pancreas. T2DM in humans may be linked to a mutation in the TCF7L2 gene, which is linked to the Wnt pathway. β-cat/TCF, which is made up of free β-catenin and a member of the TCF family, like TCF7L2, is the main effector of Wnt signaling. Given the crucial role that the β-catenin destruction complex plays in Wnt signal transduction and the downstream impact on the diabetes locus TCF7L2, genes involved in this complex may affect susceptibility to type 2 diabetes.
Gene mutations may, in one case, make the β-catenin destruction complex inactive at all times. Except in the absence of Wnt ligands, β-catenin will resist degradation, accumulating in the cytoplasm and nucleus and binding to TCF7L2 and other transcription factors. These transcription factors would then primarily function as transcriptional activators, and excessive expression of any of their target genes could result in diabetes pathology. β-cat/TCF tends to control Gcg expression and GLP-1 activity by acting as an effector of other signaling pathways. The homeostasis of GLP-1 activity is likely to be influenced by bridge between the insulin and WNT pathways.
Roles of Wnt signalling pathway in diabetes
- Islet cell proliferation and differentiation in the pancreas: The Wnt signaling pathway is involved in islet cell proliferation and differentiation in the pancreas, which is important for insulin production and glucose homeostasis.
- TCF7L2 gene mutation: T2DM in humans may be caused by a mutation in the TCF7L2 gene, which is connected to the Wnt pathway.
- β-cat/TCF as the major effector: The main effector of Wnt signaling is β-cat/TCF, which is composed of free -catenin and a member of the TCF family, such as TCF7L2.
- Transcriptional activators: In an instance, gene alterations may render the β-catenin destruction complex inactive at all times. Except in the absence of Wnt ligands, β-catenin will resist degradation, accumulating in the cytoplasm and nucleus and interacting to TCF7L2 and other transcription factors. These transcription factors would thus predominantly work as transcriptional activators, and overexpression of any of their target genes might result in diabetic pathogenesis.
- GLP-1 activity: β-cat/TCF regulates Gcg expression and GLP-1 activity via serving as an effector in other signaling pathways. The bridge between the insulin and WNT pathways is anticipated to have an effect on GLP-1 activity homeostasis.
References:
- Huang, Z., Liao, Y., Huang, R., Chen, J., & Sun, H. (2018). Possible role of TCF7L2 in the pathogenesis of type 2 diabetes mellitus. Biotechnology & Biotechnological Equipment, 2818, 1–5. https://doi.org/10.1080/13102818.2018.1438211
- Jin, T. (2008). The WNT signalling pathway and diabetes mellitus. Diabetologia, 51(10), 1771–1780. https://doi.org/10.1007/s00125-008-1084-y