Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

Abstract

Wnt signaling is an evolutionarily conserved pathway involved in embryonic development and cell differentiation (Nusse & Clevers, 2017).In addition, it regulates many other processes, including cell growth and mitosis, adult stem cell homeostasis, and regeneration (Acebron & Niehrs, 2016;Nusse & Clevers, 2017;Reddien, 2018). Aberrant activation of the Wnt pathway lies at the basis of different types of malignancies, including colorectal, breast, and hepatic cancers.Historically, the first Wnt gene was identified in Drosophila melanogaster, following a screen for recessive mutant genes that affect segment patterning of fruit fly embryos. Because the mutant flies did not develop wings, the gene was named wingless (wg) (Sharma, 1973;Sharma & Chopra, 1976). Years later, the proto-oncogene integration site-1 (int-1) was discovered while studying mouse models of mammary carcinomas induced by DNA integrations of the mouse mammary tumor virus (MMTV) (Nusse & Varmus, 1982). Since Int-1 was found to be the mammalian orthologue of Wg, it was then renamed Wnt1 (Wingless + Int1) (Nusse et al., 1991).Wnts are secreted glycoproteins (Brown et al., 1987;Papkoff et al., 1987) that can activate divergent pathways, classically categorized as: (a) the canonical or β-catenin dependent pathway; and (b) the noncanonical branch, comprising the planar cell polarity and Ca 2+ pathways. Although some Wnts preferentially activate one or the other pathway, their specificity is less strict than previously thought and likely depends on the cell-specific context and the repertoire of receptors and components expressed, rather than on intrinsic properties. Indeed, while the serpentine Frizzled (Fzd) receptors are a shared component of all Wnt pathways, coreceptors such as the low-density lipoprotein receptor-related protein 5 and 6 (Lrp5/6;

HER2–CDH1 Interaction via Wnt/B-Catenin Is Associated with Patients’ Survival in HER2-Positive Metastatic Gastric Adenocarcinoma

“…Indeed, mounting evidence has suggested that overexpression of Wnt/β-catenin signaling not only affects gastric cell proliferation, but also the GC relapse and metastasis by giving rise to a new cancer population of stemness-associated self-renewal cells [ 41 , 42 ]. Furthermore, the self-renewal cell activity was found to increase in HER2-positive cancer stem cells via Wnt/β-catenin signaling [ 43 ] that had also been implicated in important tumor growth processes such as cell nutrient acquisition, cell metabolism, and immune response against the tumor cells [ 44 , 45 , 46 ].…”

“…Indeed, the activation of EGFR produces the detachment by SRC-mediated phosphorylation of the p120/E-CAD complex from the low-density lipoprotein receptor-related protein 5/6 (LRP5/6), which together with the frizzled receptors (FZD), activates the Wnt signalosome favoring the tumor cell growth [ 21 ]. Thus, HER2/EGFR activation by modulating the phosphorylation of E-CAD/βcatenin complex interferes with the sequestration of the Wnt signalosome and, in the same way, produces a reduction of E-CAD on the cell membrane and the release of sE-CAD that further may increase the EGFR signaling [ 22 , 46 ]. Moreover, serum sE-CAD/KLRG1 axis may inhibit KLRG1+ cytotoxic T-cells and NK cells function in the peripheral blood, probably suppressing their cytokine secretion and proliferation both in the periphery and in the tumor microenvironment.…”

NK4 Regulates Laryngeal Squamous Cell Carcinoma Cell Properties and Inhibits Tumorigenicity by Modulating the DKK1/Wnt/β-Catenin Axis

“…By Western blot Method to detect the expression of DKK1 increased, Wnt1 and β-Catenin protein in tumor tissues are reduced, and previous studies have confirmed that the Wnt1/β-catenin signaling pathway is abnormally activated in a variety of human malignant tumors, and promotes tumor invasion and metastasis. The Wnt/β-catenin signaling pathway is involved in various key cell functions, such as stem cell regeneration and organogenesis ( 25 ). In various types of malignant tumors, including breast, lung, and hematopoietic system, Wnt activation has been found, and it has been proven to help tumor recurrence ( 26 ).…”

TMEM205 Reduces the Sensitivity of Gastric Cancer to Cisplatin Through TAM/M2 Polarization

“…Activation of Wnt/β-catenin signaling pathway played important roles in tumor cell proliferation, stemness, migration and chemotherapy resistance [18,33] . The protein of β-catenin nuclear translocation could induce the activation of C-myc and CyclinD1, thereby activating the Wnt/β-catenin signaling pathway [34] .…”