{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWntless (WLS), also known as Wnt‐interacting protein (Wntless/Evi/GPR177), is an evolutionarily conserved multipass transmembrane protein that plays a pivotal role in mediating Wnt protein secretion. WLS binds the lipid‐modified Wnt ligands in the endoplasmic reticulum and escorts them through a specialized secretory pathway that involves transit through the Golgi apparatus, delivery to the plasma membrane, and subsequent endocytic recycling. Structural studies have revealed that WLS’s transmembrane domain adopts a GPCR‐like fold harboring a conserved hydrophobic cavity into which a Wnt hairpin and its palmitoleate moiety insert, thus facilitating ligand loading and release. Moreover, its dynamic engagement with factors of the COPI/COPII machinery and clathrin‐mediated endocytosis ensures the formation and proper export of early Wnt secretory vesicles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWLS‐mediated secretion of Wnt ligands is essential for proper embryonic development and tissue homeostasis. In the skin, for instance, conditional deletion of WLS in the epidermis disrupts normal differentiation and leads to inflammatory phenotypes reminiscent of human psoriasis. Likewise, genetic studies have implicated WLS in skeletogenesis, with variants affecting bone mineral density and ossification processes. In addition, its role extends to odontogenesis, where proper retrograde trafficking of Wnt is required for tooth development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant WLS expression and function are tightly linked to tumorigenesis and cancer progression. In malignant astrocytomas, WLS is overexpressed and its elevated activity sustains both canonical and non‐canonical Wnt signaling, thereby promoting tumor cell proliferation, migration, and in vivo tumor formation. Similarly, dysregulated WLS expression is observed in colorectal carcinomas, melanomas, gastric, ovarian, and hepatocellular cancers, as well as osteosarcoma, where its altered trafficking and signaling activity correlate with metastasis and poor clinical outcome. Moreover, studies in oral squamous cell carcinoma have implicated microRNA‐mediated regulation of WLS in controlling key downstream targets such as cyclin D1 and c‐MYC."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in development and oncogenesis, WLS influences a range of additional pathophysiological processes. In the hematopoietic compartment, overexpression of WLS in B‐cell precursor acute lymphoblastic leukemia (BCP ALL) associates with disease relapse and poor survival, underscoring its importance as a regulator of autocrine Wnt signaling in leukemogenesis. In the nervous system, WLS has been implicated in modulating opioid receptor function and, via a GPR177–Wnt5a–TRPV1 axis, in the development of diabetic neuropathic pain. Furthermore, biallelic pathogenic variants in WLS underlie congenital multisystem anomalies (Zaki syndrome), expanding the spectrum of diseases linked to defective Wnt secretion. Stress conditions in the tumor microenvironment also appear to modulate WLS expression and function, suggesting potential avenues for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jay Jin, Megan Morse, Colleen Frey, et al. 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