WNT signaling
Wnts are a class of evolutionarily-conserved, lipid-modified glycoproteins that play a pivotal role in development and homeostasis through a number of different paracrine and autocrine signal-transduction pathways. During early development, Wnt signaling plays a major role in axon guidance, cell polarity, and body axis specification. Extracellular Wnts bind a variety of different receptors, and initiate signaling in several distinct pathways. Receptors include seven-pass transmembrane Frizzleds and receptor tyrosine kinases ROR and Ryk.
Wnt signaling pathways can result in changes to gene transcription. For example, in the canonical β-catenin signaling pathway Wnt signaling prevents destruction of the transcriptional regulator β-catenin. Upon ligation to their receptors, the cytoplasmic protein disheveled (DVL) is recruited, phosphorylated and activated. Activation of DVL induces the dissociation of GSK-3β from Axin and leads to the inhibition of GSK-3β. Next, the phosphorylation and degradation of β-catenin is inhibited as a result of the inactivation of the "destruction complex". Subsequently, stabilized β-catenin translocates into the nucleus leading to changes in different target gene expressions. Wnt signaling can also prompt morphological changes to cellular structure e.g., the non-canonical planar cell polarity pathway induces a kinase cascade that results in reorganization of actin, a core component of the cytoskeleton. The non-canonical Wnt/Ca2+ pathways lead to release of intracellular Ca2+ via G-proteins. Elevated Ca2+ can activate the phosphatase calcineurin, which leads to dephosphorylation of the transcription factor NF-AT and its accumulation in the nucleus.
Genetic and epigenetic deregulation of Wnt/β-catenin signaling contributes to human cancer, which has led to the development of extensive approaches targeting Wnt/β-catenin signaling as cancer therapies. PORCN inhibitors, Wnt ligand antagonists, and FZD antagonists/monoclonal antibodies are beeing examined in clinical trials of various Wnt signaling-associated human cancers. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recent studies have identified several Wnt signaling regulators whose expression is specific to cancer cells. These cancer-specific regulatory processes of Wnt signaling may be druggable vulnerabilities of Wnt signaling-associated cancer.
References:
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- Zimmerli, D et al. (2020): "TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex " Elife [PMID: 32808927]
- Patel, S et al. (2019): "Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights " Front Immunol https://doi.org/10.3389/fimmu.2019.02872doi: 10.4049/jimmunol.1900371
- Zimmerli, D et al. (2017): "Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein–protein interfaces of nuclear factors " Br J Pharmacol 174(24): 4600–4610. doi: 10.1111/bph.13864
- Komiya, Y et al. (2008): "Wnt signal transduction pathways" organogenesis, doi: 10.4161/org.4.2.5851
- Jung, Y et al., (2020): “Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex ” Experimental & Molecular Medicine, 52, pages 183–191 [DOI: nature]
