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).