1. Wnt family and signaling pathways
Wnt is a large family of secreted glycoproteins rich in cysteine residues, which
was initially found in mouse breast cancer and is widely expressed in various tissues (8,9). There are 19 kinds of Wnt protein subtypes in mammals, mainly including Wnt1, Wnt2, Wnt3, Wnt4, Wnt5a, Wnt6, Wnt7b, Wnt10b, etc. The Wnt protein signal transduction pathway is a complex protein action network. Most of them can bond to a variety of Frizzled (FZD) receptors, which belong to the G protein-coupled transmembrane protein family (10,11); Part of Wnt protein combines with common receptors, such as low-density lipoprotein receptor-related protein (LRP) 5 and 6, receptor tyrosine kinase-like orphan receptor 2 (Ror2), and receptor tyrosine kinase (Ryk), etc to mediate the signaling pathways of different cells (11,12). Mingyi Li et al. have also shown that FZD receptors are required for Tiki inhibition of cell-surface Wnt signaling. Tiki binds to the Wnt-FZD complex and clears the N-terminus of Wnt3a or Wnt5a, preventing the recruitment and activation of the co-receptors LRP6 or ROR1/2 by the Wnt-FZD complex without affecting the stability of the Wnt-FZD complex (13). Bowin C-F’s team studied the dynamic changes in FZD5-Dishevelled (DVL) 2 interactions induced by Wnt3a and Wnt5a. The discovery of ligand-induced bioluminescent resonance energy transfer changes between FZD5 and DVL2 or the FZD-binding DEP domain isolated by DVL2 shows a complex response in the FZD5-DVL2 complex consisting of DVL2 recruitment and conformational dynamics (14).
Wnt protein subtypes are generally divided into two types: canonical Wnt proteins (such as Wnt3a, Wnt7a) and non-canonical Wnt proteins (such as Wnt5a, Wnt11) (15). They activate different downstream signaling pathways respectively, the canonical Wnt signaling pathway (Wnt/ β-catenin pathway) and the non-canonical Wnt signaling pathway (16). Canonical Wnt/ β-catenin pathway, also known as the β-catenin signaling pathway, mainly refers to a series of reactions after the combination of Wnt protein and the FZD receptor family on the cell surface, so that the ”β-catenin degradation complex” is inhibited and the intracytoplasmic β-catenin is stable. Part of the β-catenin enters the nucleus and interacts with the nuclear transcription factor T-cell factor/lymphoid enhancing factor (TCF/LEF) family to promote the expression of specific genes, which are mainly involved in regulating cell proliferation and differentiation (11,17-19). The other non-canonical Wnt signal pathway, also known as non-dependent on the β-catenin signal pathway, is mainly divided into Wnt/Ca2+ signal transduction pathway and Wnt/Planar cell polarity (PCP) signal transduction pathway. These two pathways bind different receptors, including FZD-3, FZD-4, FZD-5, and receptor tyrosine kinase-like orphan receptor 2 (Ror2), etc (20,21), and are mainly involved in regulating cytoskeletal recombination, cell adhesion, migration, and tissue separation (22). Wnt/Ca2+ signal transduction pathway is activated by Wnt11 or Wnt5a. It can promote the release of intracellular Ca2+ to activate protein kinase C through the action of calmodulin-dependent kinase and calcineurin phosphatase, which can increase the intracellular Ca2+ concentration and activate T nuclear factors, to play a role in cancer inhibition (23). In Xenopus laevis and zebrafish, Wnt5a activates the Wnt-Ca2+ signaling pathway to regulate contraction and extension (24,25). The Wnt/PCP signal transduction pathway is the Wnt/JNK (c-Jun N-terminal kinase) kinase pathway, which is activated by GTPase Rho A protein. The activated JNK phosphorylates by binding to the transcription factors c-jun and ATF2 amino-terminal region, thereby regulating gene expression and participating in some important processes, such as gastrula formation and localization cell repair (11,26). There is also a cross-interaction between the canonical Wnt signaling pathway and the non-canonical Wnt signaling pathway, such as Wnt-Ca2+ channel which can inhibit the β-catenin pathway, Wnt-Ca2+ signaling pathway activating Protein kinase C (PKC), blocking the Disheveled (Dsh) Protein phosphorylation of the canonical β-catenin upstream channel (27).