Modulating Wnt signaling at the root: Porcupine and Wnt acylation

Communication between cells occurs through secreted molecules, among which Wnt ligands play a critical role in balancing cell proliferation, differentiation and cellular homeostasis. The action of Wnt signaling can be modulated at several levels, including posttranslational modification of the Wnt ligands, whose acylation is critical for biological activity. At least three enzymes are necessary for Wnt acylation/deacylation: stearoyl CoA desaturase (SCD), porcupine (PORCN) and Notum. At the endoplasmic reticulum (ER), SCD provides the monounsaturated fatty acid to PORCN, which adds it to the Wnt ligand; at the extracellular matrix, the fatty acid is removed by Notum. Obviously, the interplay between these enzymes will define Wnt signaling ligand secretion and activity. Excessive activation of Wnt signaling has been observed in a variety of solid tumors, which has led the pharmaceutical industry to develop specific inhibitors for this pathway that mainly target PORCN, some of which are in early clinical trials. In the central nervous system (CNS), Wnt signaling activation has been shown to have a neuroprotective effect, and conversely, its inhibition induces neurodegeneration, which implies that the inhibition of PORCN in cancer therapies should be used with caution, and the cognitive performance of the patient should be monitored during treatment. This review collects information about the PORCN enzyme in relation to its role in the Wnt pathway through the acylation of Wnt ligands, its inhibition by drugs in the treatment of some cancers, and its putative modulation in the treatment of neurodegenerative diseases.