2. Wnt5a and its receptors
As a member of the Wnt family protein and a representative of the non-canonical Wnt pathway, Wnt5a is expressed in monocytes and macrophages (28). It was discovered by Clark et al. of Thomas Jefferson University in the 1990s. It is composed of 1,172 adenines, 884 cytosines, 946 guanines, and 1,172 thymidines, and plays an important role in embryo formation, organ homeostasis and cell maturation (9,29,30). It has been reported in the literature that the Wnt5a gene encodes for two subtypes by selecting promoters 1A and 1B, and is closely related to several signaling pathways including Nuclear factor-kappa B (NF-κB), Transforming growth factor-beta (TGF-β), Notch and Hedgehog (31). Like other Wnt proteins, Wnt5a goes through two important modifications after translation to become a full-functional protein finally. In the process of binding to specific receptors and secretion, Wnt5a needs to be modified by lipids and glycation, and secretory Wnt5a can be modified by lipids to obtain hydrophobicity (9,32–34).
Wnt5a binds to the cellular transmembrane receptor, which can transmit signals into the cell to produce a series of reactions. In different cells, Wnt5a can bind to different types of receptors, forming complex regulatory networks through canonical and non-canonical Wnt pathways, and participate in the regulation of cell response. The most common receptor is the FZD receptor (a seven-fold transmembrane receptor protein). At present, FZD2, FZD3, FZD4, FZD5, FZD7, and FZD8 receptors are involved in the Wnt5a signaling pathway at least. Among them, FZD2 can mediate wnt5a-dependent cells to increase calcium ion concentration. FZD4 receptor can activate the β-catenin pathway (canonical pathway) through binding to Wnt5a. The combination of FZD5 receptor and Wnt5a can regulate the expression of IL-12 in antigen-presenting cells induced by micro-organisms, to regulate the inflammatory response of human monocytes stimulated by micro-organisms. Besides, FZD7 is involved in Wnt5a-induced AP-1 activation and Dv1 activation in mouse fibroblasts (35). Another receptor that binds to Wnt5a, Ror2, is a single transmembrane receptor protein containing tyrosine kinases with only one tyrosine kinase domain (36), which can be used as a receptor or coreceptor of Wnt5a to regulate non-canonical Wnt signaling pathways (37-42). Wnt5a mediates Wnt-Ca2+ and Wnt-PCP pathways by binding to Ror2 receptor while inhibiting the β-catenin pathway (canonical pathway). The Wnt-Ca2+ transduction signaling pathway regulates cell proliferation, migration, and adhesion by activating CaMKII (Calmodulin dependent protein kinase II) and PKC; while Wnt-PCP transduction signaling pathway plays a role in regulating cell localization through small G protein or JNK (43). In the osteoblastic lineage, the Wnt5a/Ror2 signaling pathway can promote the occurrence of osteoclasts during the transformation of cells into osteoclast precursors, providing a new therapeutic direction for related diseases. Moreover, two other receptors have been proved to bind to Wnt5a. Receptor-like tyrosine kinase (Ryk) is involved in the regulation of axial growth, and tyrosine kinase-like receptor (PTK) is closely related to cell polarity. Nishita et al. have also shown that Wnt5a can bind the Ror2 receptor and FZD7 receptor to form a complex, thus acting on the Wnt signaling pathway (39). The diversity of the receptors that bind to Wnt5a leads to complex signaling pathways and dual regulation. For example, not only can it activate the β-catenin pathway with FZD receptors, but it also can inhibit the β-catenin pathway through Ror2 receptors (43-45). In another experiment, Okamoto’s team had demonstrated that the Wnt5a signaling pathway regulates osteoblasts and bone formation, however, it was indicated that plays an important role in osteoclast formation as well (46).