Abstract
Wnt signaling is one of the key signaling pathways that govern numerous physiological activities such as growth, differentiation and migration during development and homeostasis. As pathway misregulation has been extensively linked to pathological processes including malignant tumors, a thorough understanding of pathway regulation is essential for development of effective therapeutic approaches. A prominent feature of cancer cells is that they significantly differ from healthy cells with respect to their plasma membrane composition and lipid organization. Here, we review the key role of membrane composition and lipid order in activation of Wnt signaling pathway by tightly regulating formation and interactions of the Wnt-receptor complex. We also discuss in detail how plasma membrane components, in particular the ligands, (co)receptors and extracellular or membrane-bound modulators, of Wnt pathways are affected in lung, colorectal, liver and breast cancers that have been associated with abnormal activation of Wnt signaling. Wnt-receptor complex components and their modulators are frequently misexpressed in these cancers and this appears to correlate with metastasis and cancer progression. Thus, composition and organization of the plasma membrane can be exploited to develop new anticancer drugs that are targeted in a highly specific manner to the Wnt-receptor complex, rendering a more effective therapeutic outcome possible.
Highlights
The Wnt signaling pathway is an evolutionarily conserved signal transduction cascade that controls a wide range of biological events from embryonic development to tissue regeneration (Nusse, 2005; Aman et al, 2018; Steinhart and Angers, 2018)
The plasma membrane is likewise vital for initiation of Wnt signaling where Wnt ligands bind to their receptor complexes in specialized membrane domains that are considered as dynamic assemblies of various saturated lipids, sterols and lipid-anchored proteins (Sezgin et al, 2017a,b, 2015) (Figure 1)
This heterogeneity leads to formation of ordered membrane domains, known as lipid rafts or lipid nanodomains, which are assembled from saturated lipids, sphingolipids, sterols, glycolipids, glycoproteins and certain lipid-anchored proteins such as glycosylphosphatidylinositol (GPI)-anchored proteins and fatty acylated proteins, leaving the relatively disordered domains occupied by unsaturated lipids and a large fraction of membrane proteins (Sezgin et al, 2015, 2017b; Fakhree et al, 2019; Kusumi et al, 2020; Figure 1)
Summary
The Wnt signaling pathway is an evolutionarily conserved signal transduction cascade that controls a wide range of biological events from embryonic development to tissue regeneration (Nusse, 2005; Aman et al, 2018; Steinhart and Angers, 2018). The plasma membrane is likewise vital for initiation of Wnt signaling where Wnt ligands bind to their receptor complexes in specialized membrane domains that are considered as dynamic assemblies of various saturated lipids, sterols and lipid-anchored proteins (Sezgin et al, 2017a,b, 2015) (Figure 1) Owing to their central roles in initiation of signaling, Wnt pathway components acting at the plasma membrane have been frequently investigated as drug targets (Gurney et al, 2012; Krishnamurthy and Kurzrock, 2018; Zeng et al, 2018a). Active canonical Wnt ligand, binds to its cell surface receptor frizzled (Fz) and co-receptor low-density lipoprotein receptor-related protein 5/6 (Lrp5/6) and recruits Dvl and Axin to the plasma membrane, leading to disassembly of the destruction complex (Figure 2). Active canonical Wnt ligand, binds to its cell surface receptor frizzled (Fz) and co-receptor low-density lipoprotein receptor-related protein 5/6 (Lrp5/6) and recruits Dvl and Axin to the plasma membrane, leading to disassembly of the destruction complex (Figure 2). β-catenin accumulates in the cytoplasm, translocates into the nucleus and interacts with the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to regulate the expression of target genes (Logan and Nusse, 2004; Taketo, 2004; Nusse, 2005; Angers and Moon, 2009; Clevers and Nusse, 2012)
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