Wnt lipidation: Roles in trafficking, modulation, and function

Abstract

The Wnt signaling pathway consists of various downstream target proteins that have substantial roles in mammalian cell proliferation, differentiation, and development. Its aberrant activity can lead to uncontrolled proliferation and tumorigenesis. The posttranslational connection of fatty acyl chains to Wnt proteins provides the unique capacity for regulation of Wnt activity. In spite of the past belief that Wnt molecules are subject to dual acylation, it has been shown that these proteins have only one acylation site and undergo monounsaturated fatty acylation. The Wnt monounsaturated fatty acyl chain is more than just a hydrophobic coating and appears to be critical for Wnt signaling, transport, and receptor activation. Here, we provide an overview of recent findings in Wnt monounsaturated fatty acylation and the mechanism by which this lipid moiety regulates Wnt activity from the site of production to its receptor interactions.

PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway

“…Epigenetic dysregulation of Wnt/β-catenin pathway plays a significant role in the pathogenesis of several human cancers [63][64][65]. The targeting of Wnt protein to the plasma membrane and the binding to its receptor are the initiation process of activating Wnt/β-catenin pathway [66]. As an important member of WNT gene family, WNT3A enhances β-catenin-dependent transcription through GSK3β inhibition or direct β-catenin phosphorylation at Ser 552 [67].…”

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

“…Palmitoylation occurs at the hydroxyl group of a conserved serine residue (e.g., S209 in Wnt3a and S187 in Wnt8) (Janda et al, 2012;Takada et al, 2006). The role of these posttranslational modifications in Wnt signaling has been covered in depth by several reviews (Coudreuse & Korswagen, 2007;Hosseini et al, 2019;Janda & Garcia, 2015). The hydrophobicity conferred by the palmitate necessitated complicated structural and biochemical characterization of Wnt proteins, until methods for large-scale Wnt production and purification were developed.…”

Disorders of FZ-CRD; insights towards FZ-CRD folding and therapeutic landscape

“…Mutations in Wnt cysteine residues result in irreversible oxidation of the Wnt proteins which causes the protein complex to bury the lipid modified Ser-residue internally, reducing hydrophobicity of the protein (Hosseini et al 2019). Mutations in Wnt fatty acyl modification proteins are shown to cause certain embryonic developmental abnormalities (Hosseini et al 2019).…”

“…The CRD groove’s amino acid sequence is conserved across all 10 members of the FZDs receptors (Yang et al 2018b; Tao et al 2016). On dimerization and at the dimer interface, two lipid binding grooves close in on each other creating a lipid-binding cavity resembling a U-shaped cleft (Hosseini et al 2019). Lipidation can directly affect protein activity and free cis -unsaturated fatty acids act as ligands able to induce FZ-CRD dimerization and higher-order oligomerization (Hosseini et al 2019; Nile and Hannoush 2016).…”

“…On dimerization and at the dimer interface, two lipid binding grooves close in on each other creating a lipid-binding cavity resembling a U-shaped cleft (Hosseini et al 2019). Lipidation can directly affect protein activity and free cis -unsaturated fatty acids act as ligands able to induce FZ-CRD dimerization and higher-order oligomerization (Hosseini et al 2019; Nile and Hannoush 2016). FZ2-CRD binding site for the lipid co-receptor can accept exogenous and endogenous lipids and Wnt PAM in-vitro ( Tao et al 2016 ) .…”