The way Wnt works: Components and mechanism

Abstract

The canonical Wnt/β-catenin pathway is an ancient and evolutionarily conserved signaling pathway that is required for the proper development of all metazoans, from the basal demosponge Amphimedon queenslandica to humans. Misregulation of Wnt signaling is implicated in many human diseases, making this pathway an intense area of research in industry as well as academia. In this review, we explore our current understanding of the molecular steps involved in the transduction of a Wnt signal. We will focus on how the critical Wnt pathway component, β-catenin, is in a “futile cycle” of constant synthesis and degradation and how this cycle is disrupted upon pathway activation. We describe the role of the Wnt pathway in major human cancers and in the control of stem cell self-renewal in the developing organism and in adults. Finally, we describe well-accepted criteria that have been proposed as evidence for the involvement of a molecule in regulating the canonical Wnt pathway.

Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

“…In addition, the present study conducted for the first time a comparison between the expression levels of nuclear β-catenin in normal pituitary tissues, non-aggressive NFPAs and aggressive NFPAs by western blotting. The results revealed an abnormal accumulation of free β-catenin in the nuclei of NFPAs, which is the core step for the activation of the Wnt canonical signaling pathway (13). The expression of β-catenin was further confirmed by IHC.…”

“…Aberrant regulation of the Wnt signaling pathway has been suggested to be involved in tumorigenesis (12). Three intracellular pathways are known to induce Wnt signaling: i) The Wnt-β-catenin signaling pathway, in which Wnt signaling alters transcription, and it is referred to as 'canonical' Wnt signaling (13); ii) the Wnt-Ca 2+ signaling pathway; and iii) the Wnt-c-Jun N-terminal kinase signaling pathway, which do not involve the nucleus or transcription, but rather drive cytoplasmic changes involving the actin cytoskeleton and intracellular calcium stores. Activation of the Wnt-β-catenin signaling pathway results in the accumulation of free β-catenin in the nucleus (14).…”

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

“…The Wnt pathway is markedly decisive in the active surroundings of hepatic development and involved in the regulation of developmental processes such as differentiation, cell migration proliferation and survival of hepatocytes [40]. According to studies, aberrant signaling of the pathway can lead to a variety of human diseases ranging from birth defects to cancer [41].…”

“…Canonical Wnt pathway is the term used to describe a cascade that involves translocation of β-catenin from the cell membrane into the nucleus, where it acts as a coactivator of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and in turn regulates specific target genes, including c-myc, cyclin D, and survivin [40]. In the absence of Wnt ligands, most cellular β-catenin associates with E-cadherin in adherence junctions at the plasma membrane.…”

Update of Wnt signaling in implantation and decidualization

“…To date, 19 secreted cysteinerich Wnt ligands, ten transmembrane, G-protein coupled frizzled receptors (FZD), two low-density lipoprotein receptor-related protein co-receptors (LRP5/6), two receptor tyrosine kinase-like orphan receptors (ROR1/2) and receptor-like tyrosine kinase (RYK) have been identified in the mammalian Wnt family [14,15]. Based on the involvement of certain intracellular players, the Wnt signaling system can be divided into either b-catenin-dependent or b-catenin-independent pathways [16,17]. It is also important to bear in mind that the two aforementioned signaling pathways are highly interconnected and they cross-regulate each other [18].…”