Wntless

Wntless, also known as WLS, is a conserved multi-pass transmembrane protein that functions as a cargo receptor required for the secretion of Wnt family signaling proteins. In humans the gene is WLS (also known as GPR177). Wntless is essential for the secretion of all Wnt ligands, enabling them to travel from the secretory pathway to the cell surface where they can act on neighboring cells.

Wnt proteins undergo lipid modification by Porcupine in the endoplasmic reticulum. Wntless associates with lipid-modified Wnts in the Golgi and escorts them to the plasma membrane. After secretion, Wntless is recycled from endosomes back to the Golgi/secretory compartments via the Retromer complex, ensuring a sustained supply of Wnt for secretion.

Wntless function is conserved across species, from Drosophila to vertebrates, and is required for both canonical Wnt/beta-catenin signaling and noncanonical Wnt pathways, depending on the cellular context. Loss or mutation of WLS leads to reduced extracellular Wnts and diminished Wnt signaling, producing developmental defects and impaired tissue homeostasis in model organisms.

In research and clinical contexts, Wntless is studied as a regulator of Wnt signaling, with interest in its potential as a therapeutic target to modulate Wnt activity in diseases such as cancer, fibrosis, and regenerative processes. Its activity also highlights the reliance of Wnt signaling on coordinated trafficking and secretion, not only on ligand production.