The WNT gene encodes a large family of secreted protein growth factors. During development, Wnt plays various roles in controlling cell fate, proliferation, migration, polarity, and death. In adults, WNT plays an important role in maintaining homeostasis, and abnormal activation of the WNT pathway is associated with various cancers.
WNT ligands signal through the Frizzled family of 7-transmembrane receptors and recently discovered LRP5 (low-density lipoprotein receptor-related protein-5) and LRP6 (low-density lipoprotein receptor-related protein-6) co-receptors. Structurally, Frizzled receptors have an extracellular Wnt binding domain, seven transmembrane regions, and an intracellular C-terminal tail.
Wnt signaling is transmitted through at least three different intracellular pathways, including the canonical Wnt/β-catenin pathway, the "non-canonical" Wnt/Ca2+ pathway, and the Wnt/PCP (planar cell polarity) pathway. The Wnt/β-catenin pathway primarily regulates cell fate during development, while the Wnt/PCP pathway's main function is to control cell skeleton organization.
The WNT/β-catenin pathway is activated by WNT1, WNT3, WNT3a, WNT7a, and WNT8, participating in transformation. WNT signaling can prevent cell apoptosis by upregulating anti-apoptotic proteins like Survivin and stimulate angiogenesis by upregulating vascular endothelial growth factor (VEGF). The canonical WNT pathway also regulates NRSF/REST and ENC1 (ectoderm-neocortex expressed-1) genes to control progenitor cells. Wnt signaling is inhibited by the secreted protein Dkk1, which inhibits Wnt signaling by binding to LRP5/6 and antagonizing LRP5/6. Krm2 forms a ternary complex with Dkk1 and LRP6, inducing rapid internalization and removal of LRP6 from the plasma membrane.
The non-canonical Wnt signaling pathway, also known as the non-canonical Wnt-Frizzled signaling pathway, consists of the Wnt/Ca2+ and Wnt/PCP two intracellular signaling cascades. In the WNT/Ca2+ pathway, WNT proteins mainly composed of WNT1, WNT5A, and WNT11 bind to the Frizzled transmembrane receptor on the cell surface, participating in several cellular processes that can stimulate nuclear factor NFAT and other transcription factors such as CREB (cAMP Response Element-Binding Protein-1). Therefore, the Wnt/Ca2+ pathway is likely a G protein-dependent signaling pathway.
In the Wnt/PCP pathway, Wnt proteins bind to the Frizzled transmembrane receptor on the cell surface, then activate Rho/Rac small GTPases and JNK through Dsh, subsequently assisting in the regulation of cell skeleton organization and gene expression.
