Wnt Ligands Receptors Proteins


 Creative BioMart Wnt Ligands Receptors Proteins Product List
 Wnt Ligands Receptors Proteins Background

Wnt family members are defined by amino acid sequence rather than functional properties. In mammals there are 19 different secreted Wnt proteins. These proteins are typically 350-400 amino acids long and are characterized by a highly conserved cysteine rich region. Despite the presence of an N-terminal signal sequence which targets the protein for secretion, Wnt ligands are virtually insoluble. This unexpected observation is due to the fact that Wnts are palmitoylated at a conserved cysteine that is essential for protein function.

The Drosophila gene porcupine (por) is believed to be responsible for the palmitoylation of Wnt ligands due to it sequence homology with acyl-transferases. This is supported by the observation por is required in Wnt producing cells but not cells that receive Wnt signals. In 2006, genetic studies in Drosophila revealed that secretion of Wnt proteins depended on a gene named wntless (wls), also known as evenness interrupted (evi). The wntless encoded protein was found to be primarily localized in the Golgi, and loss of expression retains Wnt ligands inside the cell that produces them. Wnt ligand secretion also requires the retromer complex, a highly evolutionary conserved multi-protein complex involved in intracellular trafficking.

Tissue staining demonstrates that Wnts form long-range gradients and are believed to function as morphogens, meaning that their signaling is long range and concentration dependent. How these gradients are formed and regulated is not fully understood. Cytonemes (long and thin filopodial processes) have been speculated to carry Wnts away from signaling cells. One other possibility is that palmitoylation of Wnts limits diffusion from membranes and lipid particles, tethering Wnts to intercellular transport vesicles and lipoproteins. Additionally, evidence suggests that heparin sulfate proteoglycans (HSPG) may stabilize and transport of secreted Wnt proteins in Drosophila

 

Wnt receptors and inhibitors

In 1996 Frizzled (Fz) was identified as the receptor for Wnt ligands and in humans ten members of this family of proteins have been identified. Fz receptors possess seven transmembrane domains and long amino-terminal cysteine-rich domain (CRD). Interestingly, Fz receptors contain both internal and carboxy terminal PDZ ligands. Wnt ligands bind directly to the CRD domain of Fz with high affinity. Studies in Drosophila and cell culture suggest that Fz receptor activation during canonical signaling is ligand-dependent, and overexpression of receptor in the absence of ligand is insufficient for signaling activation. In addition to Fz, Wnt ligand induced activation also relies on arrow in Drosophila and low-density-lipoprotein-related protein 5 and 6 (LRP5/6) in vertebrates, both single pass transmembrane receptors required for canonical Wnt signaling. In vertebrates Wnt, Fz and LRP have been reported to form a ternary complex, suggesting that Wnt ligands may physically mediate the interaction between Fz and LRP5/6. In addition to Wnt, the protein Norrin, which shares no sequence homology with Wnt ligands, can bind to Fz4 and LRP5/6 to promote canonical Wnt signaling.

Wnt signaling is antagonized extracellularly through a diverse group of Wnt inhibitors: secreted Frizzled-Related Protein (sFRPs), Wnt-inhibitory factor-1 (WIF-1), and the Dickkopf (Dkk) family of inhibitors are just a few examples. The Dkk family of Wnt inhibitors binds to and antagonizes LRP5/6 receptors and are considered specific inhibitors of Wnt/β-catenin signaling. Although some evidence suggests Dkk1 can induce the internalization and degradation of LRP5/6 through its interaction with Kremen proteins, the currently more accepted model of Dkk1 action is that it disrupts the formation of the Wnt-induced Fz-LRP5/6 complex. SOST, another LRP5/6 antagonist, is also believed to function through this mechanism.

WIF and sFRPs bind to Wnt and, in the case of sFRPs, also to Fz, thereby antagonizing both canonical and non-canonical Wnt signaling. Genetic studies in mice indicate significant redundancy of sFRPs, and some sFRPs have been shown to possess Wnt-independent activity such as regulation of axon guidance and proteinase inhibition. Shisha proteins are a distinct family of Wnt antagonists that trap Fz protein in the endoplasmic reticulum and prevent localization of the receptor to the cell surface.