{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLURP1 is a small, secreted member of the Ly‐6/uPAR family that is predominantly expressed in epithelial tissues, especially in the skin. Mutations in the SLURP1‐encoding gene underlie Mal de Meleda, an autosomal recessive palmoplantar keratoderma characterized by hyperkeratosis and inflammation. The protein is secreted by keratinocytes and other epithelial cells in sites such as the exocervix, stomach, and esophagus, where it contributes to epidermal homeostasis and the maintenance of the structural integrity of the epithelial barrier. Its loss or mutation is directly associated with the clinical spectrum seen in Mal de Meleda, as evidenced by several mutational studies demonstrating allelic heterogeneity across diverse populations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSLURP1 functions as an autocrine/paracrine modulator of cholinergic signaling by binding to nicotinic acetylcholine receptors (nAChRs), particularly the α7 subtype, present on keratinocytes and other cell types. Through allosteric interactions with these receptors, SLURP1 modulates signal transduction pathways that regulate cell proliferation, differentiation, and apoptosis. In keratinocytes, it exerts antiproliferative effects, enhances caspase activity, and upregulates key markers of differentiation and cell-cycle arrest, thereby fine-tuning epidermal growth and turnover. Moreover, by modulating NF‐κB expression and other downstream signaling cascades in both Ca²⁺‐dependent and independent manners, SLURP1 contributes to the control of inflammatory responses. Detailed structure–function studies, including investigations with synthetic SLURP1, have further elucidated its allosteric binding mechanisms at various nAChR subtypes and its consequent impact on both receptor and “metabotropic” intracellular signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its well‐documented role in the skin, SLURP1 also influences functions in other epithelial systems. Its expression modulates inflammatory responses in the airway by affecting cytokine secretion and enhancing ciliary beat frequency, suggesting an important role in diseases such as asthma. In the gastrointestinal tract and colon, SLURP1 appears to be involved in regulating cell survival and immune function, with implications in tumor suppression and carcinogenesis. Furthermore, SLURP1 has been shown to interact with molecules such as secreted frizzled‐related protein 5 to regulate lipid metabolism and may contribute to the maintenance of periodontal ligament fibroblast survival. In addition, altered SLURP1 expression has been implicated in psoriasis pathogenesis, further underscoring its broad importance in epithelial biology and inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Katja Martina Eckl, Howard P Stevens, Gilles G Lestringant, et al. 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