Wntless Wnt ligand secretion mediator (WLS) (WLS)

Wntless Wnt ligand secretion mediator (WLS), also known as GPR177, is a highly conserved multipass transmembrane protein that serves as a dedicated cargo receptor for the secretion of Wnt ligands [1, 2]. It functions by binding to Wnt proteins in the Golgi apparatus and transporting them to the cell surface for release, a process essential for both canonical and non-canonical Wnt signaling [1, 5]. Because Wnt signaling is a master regulator of cell fate, stem cell maintenance, and proliferation, the dysregulation of WLS is frequently linked to the development and progression of various cancers, including colorectal, breast, and glioblastoma [3, 4]. Targeting WLS mRNA using RNA interference (RNAi) or antisense oligonucleotides (ASOs) provides a unique therapeutic opportunity to inhibit the entire Wnt pathway at the secretion level, rather than targeting individual receptors or downstream components [3, 4]. This approach effectively reduces the availability of all 19 human Wnt ligands, potentially overcoming the redundancy often seen in Wnt-driven pathologies [4, 5]. Preclinical studies have demonstrated that silencing WLS mRNA can significantly reduce tumor growth and sensitize cancer cells to other treatments, although challenges remain regarding the systemic inhibition of homeostatic Wnt signaling in healthy tissues [3, 4].

Other names

GPR177EVIEvenness interruptedWntless homologMRPC1orf139

RNA interference or antisense-mediated degradation of WLS mRNA to prevent the translation of Wntless protein, thereby inhibiting the secretion of Wnt ligands and suppressing downstream Wnt signaling pathways.