Wnt Signaling

The Wnt signaling pathway family includes three pathways, all activated by Wnt binding to Frizzled. The canonical Wnt pathway transmits signals from Frizzled to Dishevelled, which propagates the signal to a degradation complex that binds β-catenin. In the inactive state, this complex promotes β-catenin degradation. Upon activation, β-catenin is dephosphorylated and enters the nucleus, promoting cell proliferation, differentiation, and development. The non-canonical/calcium-dependent Wnt pathway regulates calcium levels and adhesion. In this pathway, Dishevelled interacts with G proteins to stimulate calcium release, activating calcineurin and CaMK, which activates NFAT. Lastly, the non-canonical/planar cell polarity pathway transduces signals from Dishevelled to Rho and ROCK, promoting actin polymerization and cytoskeletal remodeling. Several components of this family are implicated in diseases like cancer and type 2 diabetes.

Wnt Signaling Modulators

Figure 1 Chemical structure of Myricetin

Tankyrase Inhibitors

Tankyrase, a member of the PARP family, contains ankyrin repeats, an oligomerization domain, and a PARP domain. It interacts with Axin, a component of the β-catenin degradation complex, promoting its degradation via the ubiquitin-proteasome pathway. Inhibition of Tankyrase stabilizes Axin, leading to β-catenin degradation and preventing activation of downstream processes like differentiation and epithelial-mesenchymal transition.

β-Catenin Inhibitors

β-catenin is a protein that regulates cell adhesion, differentiation, and development. As a component of the cadherin complex, it amplifies signal transduction and activates gene transcription in the Wnt signaling pathway. By binding to transcription factors, β-catenin promotes regional development during early embryogenesis. It also plays a role in maintaining stem cell pluripotency and differentiation. During later development, it facilitates epithelial-mesenchymal transition.

PORCN Inhibitors

PORCN, a member of the membrane-bound O-acyltransferase (MBOAT) family, regulates the Wnt signaling pathway. The palmitoylation reaction mediated by PORCN is crucial for the release of Wnt from the Golgi to the cell surface and its binding to the Frizzled receptor. In the absence of PORCN, Wnt ligands are not secreted, and embryos fail gastrulation. PORCN is essential for embryonic development, but its inhibition can also limit Wnt-driven β-catenin signaling and other proteins involved in the progression of diseases like cancer.

Figure 2 Chemical structure of IWP-2

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