Viral insertion resulted in increased expression of this “integration site 1” gene (Int1). Studies of Int1 were hampered

PERK inhibitor by the challenges associated with purifying the protein in biologically active form, so a central focus of early research on this gene focused on evaluating the genetic pathways associated with the homolog of Int1 in Drosophila, a gene known as wingless [30]. To provide clarity, researchers in the field then reorganized the nomenclature to reflect the contributions of studies focused on both Int1 and wingless, renaming the emerging protein family as “Wnt” (wingless + Int1) [31]. The clinical significance of this pathway came into sharper focus as downstream signaling components were identified. For example, one component, the adenomatous polyposis coli (APC) gene, is deleted in a significant majority of colorectal tumors

[32]. This, combined with numerous other studies, identified regulation of the cytoplasmic and nuclear levels of β-catenin as Quizartinib mw a key point of activity for Wnts. At the cellular level, Wnts activate several signaling cascades, including the most commonly studied (“canonical”) pathway, which results in stabilization of the β-catenin protein [33]. This pathway is initiated when a Wnt protein binds to a receptor complex that includes a member of the Frizzled family of seven-transmembrane receptors plus either Lrp5 (low-density lipoprotein-related receptor 5) or Lrp6 [34]. Formation of this receptor complex results in the phosphorylation of the cytoplasmic tail of Lrp5 or Lrp6, leading to the formation of a binding site for axin [35]. Axin is normally found in a multiprotein complex that also includes APC and glycogen synthase kinase 3 (GSK3). In the absence of an upstream Wnt signal, GSK3 phosphorylates residues near the amino terminus of β-catenin, targeting β-catenin for ubiquitin-dependent proteolysis. The recruitment of axin to the phosphorylated tail of Lrp5/6 inhibits the activity old of GSK3 towards

β-catenin (or perhaps the subsequent ubiquitination), leading to increased β-catenin levels in the cytoplasm. The increased cytoplasmic levels ultimately lead to β-catenin’s nuclear translocation, its binding to members of the LEF/TCF family of DNA binding proteins, and the transactivation of target-gene promoters. Recently, it has emerged that the stability and nuclear levels of the transcriptional activator TAZ are also regulated by the same process that controls β-catenin levels, because TAZ enters the nucleus as part of a β-catenin complex [36]. Thus, sites driven by TAZ transactivation, independent of TCF/LEF sites, may also be directly regulated by Wnt signaling (Fig. 1). Studies of the molecular mechanisms of Wnt signaling as related to osteoblast function were stimulated by three seminal studies published in 2001 and 2002.