{"gene":"SLURP1","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2001,"finding":"Mutations in the SLURP1 gene (encoding SLURP-1, a secreted Ly-6/uPAR-related protein) cause Mal de Meleda (MDM), an autosomal recessive palmoplantar keratoderma. Three different homozygous loss-of-function mutations (deletion, nonsense, splice site) were identified in 19 affected families, establishing SLURP1 as the causal gene.","method":"Genetic mapping, mutation identification (deletion, nonsense, splice site mutations) in affected individuals","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct mutation identification in 19 families with multiple mutation types, replicated across labs","pmids":["11285253"],"is_preprint":false},{"year":2005,"finding":"Recombinant SLURP-1 binds to the conventional ligand-binding site of keratinocyte nicotinic acetylcholine receptors (nAChR), showing higher affinity for the [3H]nicotine-sensitive nAChR compared to [3H]epibatidine-sensitive nAChR. SLURP-1 acts as an allosteric agonist at keratinocyte nAChR, increasing caspase-3 and caspase-8 activities, inducing apoptosis, and upregulating transglutaminase type I, cytokeratin 10, p21, and caspase-3 expression.","method":"Radioligand binding assay, caspase activity assays, TUNEL, real-time PCR, in-cell western with recombinant SLURP-1 and monoclonal antibody","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (radioligand binding, caspase assays, TUNEL, PCR) in a single rigorous study, with allosteric agonist mechanism confirmed by carbachol augmentation","pmids":["16354194"],"is_preprint":false},{"year":2006,"finding":"SLURP1 is expressed as a late epidermal differentiation marker predominantly in the granular layer of skin (notably acrosyringium) and is secreted into biological fluids (sweat, saliva, tears, urine). MDM mutations in SLURP1 (including W15R in the signal peptide and G86R) cause absence or barely detectable protein, indicating that most MDM mutations affect SLURP1 expression, integrity, or stability.","method":"Immunohistochemistry, immunoblot of biological fluids, transfection of HEK293T cells with mutant SLURP1 constructs","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by IHC with functional validation via mutant protein expression studies, replicated across MDM patient samples","pmids":["17008884"],"is_preprint":false},{"year":2003,"finding":"SLURP-1 (ARS Component B) is localized to human skin, exocervix, gums, stomach and esophagus by immunohistochemistry. Keratinocytes underlying the stratum corneum are highly positive, and cultured keratinocytes secrete the expected 9 kDa protein. SLURP1 mRNA expression is regulated by retinoic acid, epidermal growth factor and interferon-gamma.","method":"Immunohistochemistry, western blot of cultured keratinocyte conditioned medium, mRNA regulation studies","journal":"European journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by IHC and secretion confirmed by western blot, single lab with multiple methods","pmids":["14721776"],"is_preprint":false},{"year":2007,"finding":"SLURP-1 reportedly binds to α7 nAChRs and enhances the amplitude of macroscopic currents induced by ACh, leading to facilitation of apoptosis. SLURP-1 mRNA is expressed in immune cells including T cells, B cells, bone marrow-derived dendritic cells and macrophages. Recombinant human SLURP-1 stimulation of MOLT-3 human leukemic T cells evoked intracellular Ca2+ signaling.","method":"RT-PCR for tissue expression, intracellular Ca2+ signaling assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional Ca2+ signaling assay in T cells, expression profiling across immune tissues, single lab","pmids":["17286989"],"is_preprint":false},{"year":2007,"finding":"SLURP-1 and SLURP-2 function as autocrine and paracrine ligands of keratinocyte nAChRs; recombinant SLURP-1 preincubation considerably reduced colony formation in soft agar and tumor nodule formation in Nu/Nu mice from nitrosamine-transformed oral keratinocytes, preventing tobacco nitrosamine-induced malignant transformation.","method":"Soft agar colony formation assay, nude mouse xenograft assay, RT-PCR for SLURP expression, siRNA knockdown of nAChR subunits","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assays with mechanistic link to nAChR signaling via siRNA, single lab","pmids":["17280689"],"is_preprint":false},{"year":2010,"finding":"SLURP-1 upregulates NF-κB expression via α7-nAChR through two complementary signaling pathways: a Ca2+-entry-dependent CaMKII/PKC pathway and a Ca2+-independent Jak2 pathway, both converging on Raf-1/MEK1/ERK1/2 cascade activation.","method":"Ca2+-free medium, ion channel blockers (Cd2+, Zn2+), kinase inhibitors (MEK1, Jak2, CaMKII, PKC), mRNA and protein quantification of NF-κB","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of signaling pathway with multiple inhibitors and complementary approaches, single lab","pmids":["20660165"],"is_preprint":false},{"year":2010,"finding":"PBMCs from MDM patients with homozygous SLURP-1 G86R mutation showed impaired T-cell activation upon anti-CD3/anti-CD28 stimulation, which was restored by addition of 0.5 μg/mL recombinant human SLURP-1, establishing that functional SLURP-1 is required for normal T-cell activation.","method":"T-cell stimulation assay (anti-CD3/CD28), stimulation index measurement, rescue with recombinant SLURP-1","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function patient cells combined with rescue by recombinant protein, single lab, single method","pmids":["20854438"],"is_preprint":false},{"year":2012,"finding":"KLF4 transcription factor directly regulates SLURP1 expression in the cornea via binding to the SLURP1 promoter (demonstrated by ChIP and transient transfection). Klf4 conditional null (Klf4CN) corneas show significantly decreased Slurp1 with elevated cytokines and neutrophil influx. Slurp1 expression is abrogated within 24 hours of LPS injection or HSV-1/adenoviral infection, and exogenous Slurp1 expression via adenoviral vectors reduces corneal inflammation and neutrophilic infiltration.","method":"ChIP, transient transfection (promoter activity), qPCR, immunoblots, immunofluorescent staining, adenoviral Slurp1 overexpression, flow cytometry","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirms direct KLF4 binding to SLURP1 promoter, combined with KO mouse model, adenoviral rescue, and multiple orthogonal methods","pmids":["23139280"],"is_preprint":false},{"year":2014,"finding":"Slurp1-deficient mice (Slurp1-/- and Slurp1X-/-) develop severe palmoplantar keratoderma characterized by increased keratinocyte proliferation, accumulation of lipid droplets in stratum corneum, and a water barrier defect. They also exhibit metabolic abnormalities (reduced adiposity, protection from obesity, low plasma lipid levels) and a neuromuscular abnormality (hind-limb clasping), establishing Slurp1 as required for keratinocyte homeostasis, metabolic regulation, and neuromuscular function.","method":"Knockout mouse generation (exon 2 replacement and nonsense mutation), histology, lipid analysis, metabolic phenotyping","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KO mouse lines with identical phenotypes, multiple orthogonal phenotypic readouts, rigorous controls for neighboring gene effects","pmids":["24499735"],"is_preprint":false},{"year":2014,"finding":"SLURP1 modulates corneal homeostasis by acting as a soluble scavenger of urokinase-type plasminogen activator (uPA). SLURP1 directly interacts with uPA (demonstrated by ligand blots, ELISA, and pull-down assays), reduces cell surface-bound uPA at leading edges of migrating cells, and suppresses uPA-dependent corneal epithelial cell proliferation and migration. SLURP1-expressing cells fail to respond to exogenous uPA in gap-filling assays.","method":"Ligand blot, ELISA, pull-down assay, lentiviral stable expression, cell proliferation and migration assays, immunofluorescent staining","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding confirmed by three orthogonal methods (ligand blot, ELISA, pull-down), with functional consequence demonstrated via stable overexpression and gap-filling assays","pmids":["25168896"],"is_preprint":false},{"year":2015,"finding":"IL-22 upregulates SLURP1 mRNA expression in normal human epidermal keratinocytes via STAT3, as confirmed by STAT3 inhibitor and siRNA knockdown. SLURP1 significantly suppresses the growth of Staphylococcus aureus, demonstrating a direct antimicrobial activity.","method":"RT-PCR, STAT3 inhibitor treatment, siRNA knockdown of STAT3, bacterial growth assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STAT3 pathway confirmed by both pharmacological inhibition and siRNA, antimicrobial activity directly tested, single lab","pmids":["26474319"],"is_preprint":false},{"year":2017,"finding":"Synthetic human SLURP-1 (81 amino acids, 3D structure characterized by NMR) does not compete with [125I]-α-bungarotoxin binding to α7 or muscle-type nAChRs or AChBPs. SLURP-1 inhibits human α3β4, α4β4, α3β2, and α9α10 nAChRs, but only inhibits α7-mediated currents in the presence of the allosteric modulator PNU120596, indicating an allosteric binding mechanism. SLURP-1 inhibition of α9α10 nAChRs was accentuated at higher ACh concentrations.","method":"Chemical synthesis of SLURP-1, NMR structure determination, radioligand competition assay ([125I]-α-bungarotoxin), electrophysiology (current inhibition assays)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — chemically synthesized protein, NMR structure, radioligand binding, and electrophysiology establish allosteric mechanism at multiple nAChR subtypes","pmids":["29192197"],"is_preprint":false},{"year":2017,"finding":"SLURP1 suppresses HUVEC tube formation by blocking nuclear translocation of NFκB. Exogenous SLURP1 suppresses TNF-α-stimulated HUVEC tube length, area, and branch points, as well as IL-8 and TNF-α production, ECM adhesion, and cell migration, without affecting cell viability or proliferation. SLURP1 expression is decreased in corneas subjected to alkali burn-induced neovascularization.","method":"HUVEC tube formation assay, NFκB nuclear localization assay, cytokine ELISA, cell adhesion assay, migration assay, QPCR/immunoblot for corneal expression","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional tube formation assay with mechanistic NF-κB nuclear translocation data, multiple readouts, single lab","pmids":["28803936"],"is_preprint":false},{"year":2018,"finding":"In CHRNA7-high pancreatic cancer cell lines (COLO357, PANC-1), SLURP1 exerts anti-malignant effects through CHRNA7 (α7-nAChR) while nicotine exerts pro-malignant effects independently of CHRNA7; the two ligands act without reciprocally interfering with each other's receptor binding or downstream signaling, suggesting functional antagonism.","method":"Cell viability assays, receptor binding assays, downstream signaling analysis, CHRNA7-high cell line selection","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor binding and downstream signaling confirmed, functional antagonism demonstrated with orthogonal experiments, single lab","pmids":["29545933"],"is_preprint":false},{"year":2019,"finding":"SLURP1 overexpression in Human Corneal Limbal Epithelial (HCLE) cells upregulates expression of desmoplakin (DSP1), desmoglein (DSG1), tight junction protein (TJP1) and E-Cadherin (stabilizing epithelial cell junctions) and suppresses TNF-α-induced upregulation of IL-8, IL-1β, CXCL1 and CXCL2. The anti-inflammatory effect is mediated by suppression of NF-κB nuclear translocation via elevated cytosolic IκB.","method":"Stable SLURP1 overexpression via lentiviral vectors, RT-PCR, immunoblot, ELISA, NF-κB nuclear localization assay, IκB protein measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable overexpression with two independent clones, multiple orthogonal readouts for junction stabilization and anti-inflammatory mechanism, single lab","pmids":["31387745"],"is_preprint":false},{"year":2020,"finding":"Recombinant SLURP-1 (rSLURP-1) at concentrations >10 nM significantly decreases A549 lung adenocarcinoma cell growth (~70%) and fully abolishes nicotine-induced cell proliferation increase, PTEN downregulation, and α7-nAChR expression upregulation. The antiproliferative effect is mediated through α7-nAChR, EGF receptors, and β-adrenergic receptors, with downstream involvement of IP3 receptors and STAT3 transcription factor. SLURP-1 does not affect normal WI-38 fibroblast proliferation up to 1 μM.","method":"Cell proliferation assay, siRNA against α7-nAChR, pharmacological inhibitors of different receptors, IP3 receptor and STAT3 pathway analysis, co-treatment with clinical drugs","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus multiple pharmacological inhibitors dissect receptor specificity and downstream pathway, single lab","pmids":["32106059"],"is_preprint":false},{"year":2025,"finding":"Slurp1 mediates anti-tumor effects of lobeline in colorectal cancer by inhibiting alternative (M2-like) activation of tumor-associated macrophages. Mechanistically, lobeline binds MAPK14 and prevents its nuclear translocation, reducing phosphorylated p53 levels, thereby relieving p53-mediated transcriptional repression of SLURP1 and increasing SLURP1 secretion. The antitumor effect is abolished in Slurp1-deficient MC38 cells.","method":"scRNA-seq, subcutaneous tumor model with Slurp1-deficient cells, target-responsive accessibility profiling (MAPK14 as lobeline target), nuclear translocation assay, phospho-p53 analysis, SLURP1 transcription/secretion measurement","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Slurp1-deficient cell rescue experiment establishes causal role, MAPK14-p53-SLURP1 axis supported by multiple approaches, single lab","pmids":["39840525"],"is_preprint":false}],"current_model":"SLURP-1 is a secreted Ly-6/uPAR-related protein expressed in the granular layer of epidermis and mucosal epithelia that functions as an allosteric modulator of multiple nicotinic acetylcholine receptor (nAChR) subtypes—inhibiting α3β4, α4β4, α3β2, and α9α10 nAChRs and allosterically modulating α7-nAChR—to regulate keratinocyte apoptosis, differentiation, and proliferation via Ca2+-dependent (CaMKII/PKC) and Ca2+-independent (Jak2) signaling cascades converging on NF-κB and ERK1/2; it also acts as a soluble scavenger of urokinase-type plasminogen activator (uPA) to suppress uPAR-dependent cell migration, exerts direct antimicrobial activity against S. aureus, and suppresses angiogenesis and inflammatory cytokine production, with loss-of-function mutations causing the palmoplantar keratoderma Mal de Meleda."},"narrative":{"mechanistic_narrative":"SLURP-1 is a secreted Ly-6/uPAR-related protein expressed as a late differentiation marker in the granular layer of epidermis and mucosal epithelia (skin, gums, stomach, esophagus, cornea) and released into biological fluids, where it governs keratinocyte and epithelial homeostasis, differentiation, proliferation, and inflammation [PMID:17008884, PMID:14721776]. Loss-of-function mutations in SLURP1 cause the autosomal recessive palmoplantar keratoderma Mal de Meleda, with most disease alleles abolishing protein expression, integrity, or stability [PMID:11285253, PMID:17008884]; Slurp1-deficient mice recapitulate the keratoderma with increased keratinocyte proliferation and a water-barrier defect, together with metabolic and neuromuscular abnormalities [PMID:24499735]. Mechanistically, SLURP-1 is a ligand and allosteric modulator of multiple nicotinic acetylcholine receptor (nAChR) subtypes: it engages keratinocyte nAChR to promote caspase-dependent apoptosis and induce differentiation markers [PMID:16354194], and the chemically synthesized protein inhibits α3β4, α4β4, α3β2, and α9α10 nAChRs while modulating α7-nAChR only allosterically [PMID:29192197]. Signaling through α7-nAChR drives NF-κB activation via complementary Ca2+-dependent CaMKII/PKC and Ca2+-independent Jak2 pathways that converge on the Raf-1/MEK1/ERK1/2 cascade [PMID:20660165]. Independently of receptor signaling, SLURP-1 acts as a soluble scavenger of urokinase-type plasminogen activator (uPA), binding uPA directly to reduce cell-surface uPA and suppress epithelial proliferation and migration [PMID:25168896]. It also exerts anti-inflammatory and anti-angiogenic functions by blocking NF-κB nuclear translocation through elevated cytosolic IκB, stabilizing epithelial junctions, and suppressing cytokine output [PMID:28803936, PMID:31387745], displays direct antimicrobial activity against S. aureus [PMID:26474319], and exhibits anti-malignant activity across oral, pancreatic, lung, and colorectal cancer models [PMID:17280689, PMID:29545933, PMID:32106059, PMID:39840525]. SLURP1 transcription is controlled by KLF4 in cornea, by STAT3 downstream of IL-22, and by p53-mediated repression relieved through the MAPK14 axis [PMID:23139280, PMID:26474319, PMID:39840525].","teleology":[{"year":2001,"claim":"Establishing the disease gene was the first step: it was unknown what caused Mal de Meleda, and identifying loss-of-function SLURP1 mutations defined the gene as essential for palmoplantar epidermal integrity.","evidence":"Genetic mapping and identification of deletion, nonsense, and splice-site mutations in 19 affected families","pmids":["11285253"],"confidence":"High","gaps":["Did not establish the molecular function of SLURP-1 or its target receptors","No tissue distribution or secretion data"]},{"year":2003,"claim":"Defined where SLURP-1 acts and how its expression is controlled, localizing it to stratified epithelia and showing secretion of a 9 kDa protein under regulation by retinoic acid, EGF, and IFN-γ.","evidence":"Immunohistochemistry, western blot of keratinocyte conditioned medium, mRNA regulation studies","pmids":["14721776"],"confidence":"Medium","gaps":["No receptor or downstream signaling mechanism identified","Single-lab localization"]},{"year":2005,"claim":"Provided the first molecular mechanism by showing SLURP-1 binds keratinocyte nAChR at the ligand-binding site as an allosteric agonist driving apoptosis and differentiation, linking receptor engagement to the epidermal phenotype.","evidence":"Radioligand binding, caspase activity assays, TUNEL, RT-PCR with recombinant SLURP-1 and carbachol augmentation","pmids":["16354194"],"confidence":"High","gaps":["Did not resolve which specific nAChR subunits are engaged","Downstream signaling cascade not mapped"]},{"year":2006,"claim":"Connected genotype to protein loss, confirming SLURP-1 as a late granular-layer differentiation marker secreted into fluids and showing that MDM mutations abolish detectable protein.","evidence":"IHC, immunoblot of biological fluids, transfection of HEK293T with mutant SLURP1 constructs","pmids":["17008884"],"confidence":"High","gaps":["Mechanism by which protein loss causes hyperkeratosis not addressed"]},{"year":2007,"claim":"Extended SLURP-1's reach beyond skin, identifying immune-cell expression and α7-nAChR-coupled Ca2+ signaling and showing it prevents nitrosamine-induced malignant transformation of oral keratinocytes.","evidence":"RT-PCR tissue profiling, intracellular Ca2+ assays in T cells, soft-agar and nude-mouse xenograft assays with nAChR siRNA","pmids":["17286989","17280689"],"confidence":"Medium","gaps":["α7 binding mode (allosteric vs orthosteric) not resolved here","Single-lab functional assays"]},{"year":2010,"claim":"Dissected the α7-nAChR signaling logic, showing SLURP-1 activates NF-κB through parallel Ca2+-dependent CaMKII/PKC and Ca2+-independent Jak2 pathways converging on Raf-1/MEK1/ERK1/2; a parallel study showed functional SLURP-1 is required for T-cell activation.","evidence":"Pharmacological pathway dissection with channel blockers and kinase inhibitors; MDM patient PBMC T-cell stimulation with recombinant SLURP-1 rescue","pmids":["20660165","20854438"],"confidence":"Medium","gaps":["Pathway mapped pharmacologically without genetic confirmation of each node","T-cell rescue from a single patient genotype"]},{"year":2012,"claim":"Identified KLF4 as a direct transcriptional activator of SLURP1 in cornea and tied SLURP1 to control of corneal inflammation, with adenoviral SLURP1 reducing neutrophil influx.","evidence":"ChIP, promoter transfection, Klf4 conditional null corneas, adenoviral Slurp1 rescue, flow cytometry","pmids":["23139280"],"confidence":"High","gaps":["Receptor/effector mediating the anti-inflammatory effect not defined here"]},{"year":2014,"claim":"Two complementary 2014 studies established loss-of-function consequences in vivo and a receptor-independent mechanism: Slurp1-knockout mice develop keratoderma with metabolic and neuromuscular defects, and SLURP-1 was shown to directly scavenge uPA to suppress epithelial proliferation and migration.","evidence":"Two independent KO mouse lines with histology/lipid/metabolic phenotyping; ligand blot, ELISA, pull-down, stable expression, and gap-filling migration assays","pmids":["24499735","25168896"],"confidence":"High","gaps":["Relative contribution of nAChR vs uPA-scavenging pathways to keratoderma unresolved","Mechanism of metabolic and neuromuscular phenotypes unexplained"]},{"year":2017,"claim":"Defined the precise pharmacology against a panel of nAChRs and added anti-angiogenic function: synthetic NMR-characterized SLURP-1 inhibits α3β4, α4β4, α3β2, and α9α10 nAChRs and modulates α7 only allosterically, and SLURP1 suppresses HUVEC tube formation by blocking NF-κB nuclear translocation.","evidence":"Chemical synthesis, NMR structure, α-bungarotoxin competition, electrophysiology; HUVEC tube formation, NF-κB localization, cytokine ELISA","pmids":["29192197","28803936"],"confidence":"High","gaps":["Physiological concentrations at each receptor in vivo not defined","Link between angiogenesis suppression and receptor pharmacology not established"]},{"year":2019,"claim":"Refined the anti-inflammatory mechanism, showing SLURP1 overexpression stabilizes epithelial junctions and suppresses TNF-α-driven cytokines through IκB-mediated blockade of NF-κB nuclear translocation.","evidence":"Stable lentiviral SLURP1 overexpression in corneal epithelial cells, RT-PCR, immunoblot, ELISA, NF-κB localization and IκB measurement","pmids":["31387745"],"confidence":"Medium","gaps":["Receptor mediating junction stabilization not identified","Single cell-type, overexpression-based"]},{"year":2020,"claim":"Characterized SLURP-1 as a tumor-selective antiproliferative agent in lung adenocarcinoma acting through α7-nAChR, EGFR, and β-adrenergic receptors with IP3R/STAT3 downstream, sparing normal fibroblasts.","evidence":"Cell proliferation assays, α7-nAChR siRNA, receptor inhibitors, IP3R/STAT3 pathway analysis with recombinant SLURP-1","pmids":["32106059"],"confidence":"Medium","gaps":["Multi-receptor model not deconvolved into primary target","Single cell line, single lab"]},{"year":2025,"claim":"Placed SLURP1 in a transcriptional control circuit relevant to tumor immunity, showing a MAPK14–p53 axis represses SLURP1 and that SLURP1 mediates lobeline's inhibition of M2 macrophage polarization in colorectal cancer.","evidence":"scRNA-seq, Slurp1-deficient MC38 tumor model, MAPK14 target profiling, phospho-p53 and SLURP1 transcription/secretion measurement","pmids":["39840525"],"confidence":"Medium","gaps":["Receptor on macrophages mediating SLURP1 effect not identified","Single tumor model"]},{"year":null,"claim":"How the receptor-dependent (multi-nAChR allosteric) and receptor-independent (uPA-scavenging) activities of SLURP-1 are integrated to produce the in vivo keratoderma, metabolic, and neuromuscular phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SLURP-1 bound to any nAChR subtype","Mechanism of metabolic/neuromuscular phenotypes in knockout mice unexplained","Primary receptor versus uPA contribution to disease not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,5,12]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3,10]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,13,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,9]}],"complexes":[],"partners":["CHRNA7","PLAU"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55000","full_name":"Secreted Ly-6/uPAR-related protein 1","aliases":["ARS component B","ARS(component B)-81/S","Anti-neoplastic urinary protein","ANUP"],"length_aa":103,"mass_kda":11.2,"function":"Has an antitumor activity (PubMed:8742060). Was found to be a marker of late differentiation of the skin. Implicated in maintaining the physiological and structural integrity of the keratinocyte layers of the skin (PubMed:14721776, PubMed:17008884). In vitro down-regulates keratinocyte proliferation; the function may involve the proposed role as modulator of nicotinic acetylcholine receptors (nAChRs) activity. In vitro inhibits alpha-7-dependent nAChR currents in an allosteric manner (PubMed:14506129, PubMed:26905431). In T cells may be involved in regulation of intracellular Ca(2+) signaling (PubMed:17286989). Seems to have an immunomodulatory function in the cornea (By similarity). The function may implicate a possible role as a scavenger receptor for PLAU thereby blocking PLAU-dependent functions of PLAUR such as in cell migration and proliferation (PubMed:25168896)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P55000/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLURP1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLURP1","total_profiled":1310},"omim":[{"mim_id":"615598","title":"PALMOPLANTAR KERATODERMA, NAGASHIMA TYPE; PPKN","url":"https://www.omim.org/entry/615598"},{"mim_id":"614594","title":"OLMSTED SYNDROME 1; OLMS1","url":"https://www.omim.org/entry/614594"},{"mim_id":"613359","title":"LY6/PLAUR DOMAIN-CONTAINING PROTEIN 6; LYPD6","url":"https://www.omim.org/entry/613359"},{"mim_id":"612863","title":"CHROMOSOME 6q24-q25 DELETION SYNDROME","url":"https://www.omim.org/entry/612863"},{"mim_id":"606119","title":"SECRETED LY6/PLAUR DOMAIN-CONTAINING PROTEIN 1; SLURP1","url":"https://www.omim.org/entry/606119"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":1037.0},{"tissue":"skin 1","ntpm":854.7}],"url":"https://www.proteinatlas.org/search/SLURP1"},"hgnc":{"alias_symbol":["ARS","ANUP","MDM","ArsB","LY6LS","LY6-MT"],"prev_symbol":[]},"alphafold":{"accession":"P55000","domains":[{"cath_id":"2.10.60.10","chopping":"21-103","consensus_level":"medium","plddt":87.0239,"start":21,"end":103}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55000","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55000-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55000-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLURP1","jax_strain_url":"https://www.jax.org/strain/search?query=SLURP1"},"sequence":{"accession":"P55000","fasta_url":"https://rest.uniprot.org/uniprotkb/P55000.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55000/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55000"}},"corpus_meta":[{"pmid":"1535557","id":"PMC_1535557","title":"The 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European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/23476038","citation_count":22,"is_preprint":false},{"pmid":"31387745","id":"PMC_31387745","title":"The secreted Ly-6/uPAR related protein-1 (SLURP1) stabilizes epithelial cell junctions and suppresses TNF-α-induced cytokine production.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31387745","citation_count":21,"is_preprint":false},{"pmid":"28803936","id":"PMC_28803936","title":"Inhibition of HUVEC tube formation via suppression of NFκB suggests an anti-angiogenic role for SLURP1 in the transparent cornea.","date":"2017","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/28803936","citation_count":21,"is_preprint":false},{"pmid":"29733383","id":"PMC_29733383","title":"PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signalling in cardiac myocytes.","date":"2018","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/29733383","citation_count":21,"is_preprint":false},{"pmid":"27661115","id":"PMC_27661115","title":"Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27661115","citation_count":21,"is_preprint":false},{"pmid":"32106059","id":"PMC_32106059","title":"Human secreted protein SLURP-1 abolishes nicotine-induced proliferation, PTEN down-regulation and α7-nAChR expression up-regulation in lung cancer cells.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32106059","citation_count":21,"is_preprint":false},{"pmid":"10388814","id":"PMC_10388814","title":"DNA sequence and functional analysis of homologous ARS elements of Saccharomyces cerevisiae and S. carlsbergensis.","date":"1999","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10388814","citation_count":20,"is_preprint":false},{"pmid":"7982210","id":"PMC_7982210","title":"Elevated levels of MDM-2 and p53 expression are associated with high grade non-Hodgkin's lymphomas.","date":"1994","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/7982210","citation_count":20,"is_preprint":false},{"pmid":"29373606","id":"PMC_29373606","title":"Modulation of HIV replication in monocyte derived macrophages (MDM) by steroid hormones.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29373606","citation_count":20,"is_preprint":false},{"pmid":"28686579","id":"PMC_28686579","title":"Synergy between Prkdc and Trp53 regulates stem cell proliferation and GI-ARS after irradiation.","date":"2017","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/28686579","citation_count":19,"is_preprint":false},{"pmid":"29192197","id":"PMC_29192197","title":"Interaction of Synthetic Human SLURP-1 with the Nicotinic Acetylcholine Receptors.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29192197","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51342,"output_tokens":5183,"usd":0.115886,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13497,"output_tokens":4573,"usd":0.090905,"stage2_stop_reason":"end_turn"},"total_usd":0.206791,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Mutations in the SLURP1 gene (encoding SLURP-1, a secreted Ly-6/uPAR-related protein) cause Mal de Meleda (MDM), an autosomal recessive palmoplantar keratoderma. Three different homozygous loss-of-function mutations (deletion, nonsense, splice site) were identified in 19 affected families, establishing SLURP1 as the causal gene.\",\n      \"method\": \"Genetic mapping, mutation identification (deletion, nonsense, splice site mutations) in affected individuals\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct mutation identification in 19 families with multiple mutation types, replicated across labs\",\n      \"pmids\": [\"11285253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Recombinant SLURP-1 binds to the conventional ligand-binding site of keratinocyte nicotinic acetylcholine receptors (nAChR), showing higher affinity for the [3H]nicotine-sensitive nAChR compared to [3H]epibatidine-sensitive nAChR. SLURP-1 acts as an allosteric agonist at keratinocyte nAChR, increasing caspase-3 and caspase-8 activities, inducing apoptosis, and upregulating transglutaminase type I, cytokeratin 10, p21, and caspase-3 expression.\",\n      \"method\": \"Radioligand binding assay, caspase activity assays, TUNEL, real-time PCR, in-cell western with recombinant SLURP-1 and monoclonal antibody\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (radioligand binding, caspase assays, TUNEL, PCR) in a single rigorous study, with allosteric agonist mechanism confirmed by carbachol augmentation\",\n      \"pmids\": [\"16354194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SLURP1 is expressed as a late epidermal differentiation marker predominantly in the granular layer of skin (notably acrosyringium) and is secreted into biological fluids (sweat, saliva, tears, urine). MDM mutations in SLURP1 (including W15R in the signal peptide and G86R) cause absence or barely detectable protein, indicating that most MDM mutations affect SLURP1 expression, integrity, or stability.\",\n      \"method\": \"Immunohistochemistry, immunoblot of biological fluids, transfection of HEK293T cells with mutant SLURP1 constructs\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by IHC with functional validation via mutant protein expression studies, replicated across MDM patient samples\",\n      \"pmids\": [\"17008884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SLURP-1 (ARS Component B) is localized to human skin, exocervix, gums, stomach and esophagus by immunohistochemistry. Keratinocytes underlying the stratum corneum are highly positive, and cultured keratinocytes secrete the expected 9 kDa protein. SLURP1 mRNA expression is regulated by retinoic acid, epidermal growth factor and interferon-gamma.\",\n      \"method\": \"Immunohistochemistry, western blot of cultured keratinocyte conditioned medium, mRNA regulation studies\",\n      \"journal\": \"European journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by IHC and secretion confirmed by western blot, single lab with multiple methods\",\n      \"pmids\": [\"14721776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SLURP-1 reportedly binds to α7 nAChRs and enhances the amplitude of macroscopic currents induced by ACh, leading to facilitation of apoptosis. SLURP-1 mRNA is expressed in immune cells including T cells, B cells, bone marrow-derived dendritic cells and macrophages. Recombinant human SLURP-1 stimulation of MOLT-3 human leukemic T cells evoked intracellular Ca2+ signaling.\",\n      \"method\": \"RT-PCR for tissue expression, intracellular Ca2+ signaling assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional Ca2+ signaling assay in T cells, expression profiling across immune tissues, single lab\",\n      \"pmids\": [\"17286989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SLURP-1 and SLURP-2 function as autocrine and paracrine ligands of keratinocyte nAChRs; recombinant SLURP-1 preincubation considerably reduced colony formation in soft agar and tumor nodule formation in Nu/Nu mice from nitrosamine-transformed oral keratinocytes, preventing tobacco nitrosamine-induced malignant transformation.\",\n      \"method\": \"Soft agar colony formation assay, nude mouse xenograft assay, RT-PCR for SLURP expression, siRNA knockdown of nAChR subunits\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assays with mechanistic link to nAChR signaling via siRNA, single lab\",\n      \"pmids\": [\"17280689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SLURP-1 upregulates NF-κB expression via α7-nAChR through two complementary signaling pathways: a Ca2+-entry-dependent CaMKII/PKC pathway and a Ca2+-independent Jak2 pathway, both converging on Raf-1/MEK1/ERK1/2 cascade activation.\",\n      \"method\": \"Ca2+-free medium, ion channel blockers (Cd2+, Zn2+), kinase inhibitors (MEK1, Jak2, CaMKII, PKC), mRNA and protein quantification of NF-κB\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of signaling pathway with multiple inhibitors and complementary approaches, single lab\",\n      \"pmids\": [\"20660165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PBMCs from MDM patients with homozygous SLURP-1 G86R mutation showed impaired T-cell activation upon anti-CD3/anti-CD28 stimulation, which was restored by addition of 0.5 μg/mL recombinant human SLURP-1, establishing that functional SLURP-1 is required for normal T-cell activation.\",\n      \"method\": \"T-cell stimulation assay (anti-CD3/CD28), stimulation index measurement, rescue with recombinant SLURP-1\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function patient cells combined with rescue by recombinant protein, single lab, single method\",\n      \"pmids\": [\"20854438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KLF4 transcription factor directly regulates SLURP1 expression in the cornea via binding to the SLURP1 promoter (demonstrated by ChIP and transient transfection). Klf4 conditional null (Klf4CN) corneas show significantly decreased Slurp1 with elevated cytokines and neutrophil influx. Slurp1 expression is abrogated within 24 hours of LPS injection or HSV-1/adenoviral infection, and exogenous Slurp1 expression via adenoviral vectors reduces corneal inflammation and neutrophilic infiltration.\",\n      \"method\": \"ChIP, transient transfection (promoter activity), qPCR, immunoblots, immunofluorescent staining, adenoviral Slurp1 overexpression, flow cytometry\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirms direct KLF4 binding to SLURP1 promoter, combined with KO mouse model, adenoviral rescue, and multiple orthogonal methods\",\n      \"pmids\": [\"23139280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Slurp1-deficient mice (Slurp1-/- and Slurp1X-/-) develop severe palmoplantar keratoderma characterized by increased keratinocyte proliferation, accumulation of lipid droplets in stratum corneum, and a water barrier defect. They also exhibit metabolic abnormalities (reduced adiposity, protection from obesity, low plasma lipid levels) and a neuromuscular abnormality (hind-limb clasping), establishing Slurp1 as required for keratinocyte homeostasis, metabolic regulation, and neuromuscular function.\",\n      \"method\": \"Knockout mouse generation (exon 2 replacement and nonsense mutation), histology, lipid analysis, metabolic phenotyping\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KO mouse lines with identical phenotypes, multiple orthogonal phenotypic readouts, rigorous controls for neighboring gene effects\",\n      \"pmids\": [\"24499735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLURP1 modulates corneal homeostasis by acting as a soluble scavenger of urokinase-type plasminogen activator (uPA). SLURP1 directly interacts with uPA (demonstrated by ligand blots, ELISA, and pull-down assays), reduces cell surface-bound uPA at leading edges of migrating cells, and suppresses uPA-dependent corneal epithelial cell proliferation and migration. SLURP1-expressing cells fail to respond to exogenous uPA in gap-filling assays.\",\n      \"method\": \"Ligand blot, ELISA, pull-down assay, lentiviral stable expression, cell proliferation and migration assays, immunofluorescent staining\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding confirmed by three orthogonal methods (ligand blot, ELISA, pull-down), with functional consequence demonstrated via stable overexpression and gap-filling assays\",\n      \"pmids\": [\"25168896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 upregulates SLURP1 mRNA expression in normal human epidermal keratinocytes via STAT3, as confirmed by STAT3 inhibitor and siRNA knockdown. SLURP1 significantly suppresses the growth of Staphylococcus aureus, demonstrating a direct antimicrobial activity.\",\n      \"method\": \"RT-PCR, STAT3 inhibitor treatment, siRNA knockdown of STAT3, bacterial growth assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STAT3 pathway confirmed by both pharmacological inhibition and siRNA, antimicrobial activity directly tested, single lab\",\n      \"pmids\": [\"26474319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Synthetic human SLURP-1 (81 amino acids, 3D structure characterized by NMR) does not compete with [125I]-α-bungarotoxin binding to α7 or muscle-type nAChRs or AChBPs. SLURP-1 inhibits human α3β4, α4β4, α3β2, and α9α10 nAChRs, but only inhibits α7-mediated currents in the presence of the allosteric modulator PNU120596, indicating an allosteric binding mechanism. SLURP-1 inhibition of α9α10 nAChRs was accentuated at higher ACh concentrations.\",\n      \"method\": \"Chemical synthesis of SLURP-1, NMR structure determination, radioligand competition assay ([125I]-α-bungarotoxin), electrophysiology (current inhibition assays)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chemically synthesized protein, NMR structure, radioligand binding, and electrophysiology establish allosteric mechanism at multiple nAChR subtypes\",\n      \"pmids\": [\"29192197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLURP1 suppresses HUVEC tube formation by blocking nuclear translocation of NFκB. Exogenous SLURP1 suppresses TNF-α-stimulated HUVEC tube length, area, and branch points, as well as IL-8 and TNF-α production, ECM adhesion, and cell migration, without affecting cell viability or proliferation. SLURP1 expression is decreased in corneas subjected to alkali burn-induced neovascularization.\",\n      \"method\": \"HUVEC tube formation assay, NFκB nuclear localization assay, cytokine ELISA, cell adhesion assay, migration assay, QPCR/immunoblot for corneal expression\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional tube formation assay with mechanistic NF-κB nuclear translocation data, multiple readouts, single lab\",\n      \"pmids\": [\"28803936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In CHRNA7-high pancreatic cancer cell lines (COLO357, PANC-1), SLURP1 exerts anti-malignant effects through CHRNA7 (α7-nAChR) while nicotine exerts pro-malignant effects independently of CHRNA7; the two ligands act without reciprocally interfering with each other's receptor binding or downstream signaling, suggesting functional antagonism.\",\n      \"method\": \"Cell viability assays, receptor binding assays, downstream signaling analysis, CHRNA7-high cell line selection\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor binding and downstream signaling confirmed, functional antagonism demonstrated with orthogonal experiments, single lab\",\n      \"pmids\": [\"29545933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLURP1 overexpression in Human Corneal Limbal Epithelial (HCLE) cells upregulates expression of desmoplakin (DSP1), desmoglein (DSG1), tight junction protein (TJP1) and E-Cadherin (stabilizing epithelial cell junctions) and suppresses TNF-α-induced upregulation of IL-8, IL-1β, CXCL1 and CXCL2. The anti-inflammatory effect is mediated by suppression of NF-κB nuclear translocation via elevated cytosolic IκB.\",\n      \"method\": \"Stable SLURP1 overexpression via lentiviral vectors, RT-PCR, immunoblot, ELISA, NF-κB nuclear localization assay, IκB protein measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable overexpression with two independent clones, multiple orthogonal readouts for junction stabilization and anti-inflammatory mechanism, single lab\",\n      \"pmids\": [\"31387745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Recombinant SLURP-1 (rSLURP-1) at concentrations >10 nM significantly decreases A549 lung adenocarcinoma cell growth (~70%) and fully abolishes nicotine-induced cell proliferation increase, PTEN downregulation, and α7-nAChR expression upregulation. The antiproliferative effect is mediated through α7-nAChR, EGF receptors, and β-adrenergic receptors, with downstream involvement of IP3 receptors and STAT3 transcription factor. SLURP-1 does not affect normal WI-38 fibroblast proliferation up to 1 μM.\",\n      \"method\": \"Cell proliferation assay, siRNA against α7-nAChR, pharmacological inhibitors of different receptors, IP3 receptor and STAT3 pathway analysis, co-treatment with clinical drugs\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus multiple pharmacological inhibitors dissect receptor specificity and downstream pathway, single lab\",\n      \"pmids\": [\"32106059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Slurp1 mediates anti-tumor effects of lobeline in colorectal cancer by inhibiting alternative (M2-like) activation of tumor-associated macrophages. Mechanistically, lobeline binds MAPK14 and prevents its nuclear translocation, reducing phosphorylated p53 levels, thereby relieving p53-mediated transcriptional repression of SLURP1 and increasing SLURP1 secretion. The antitumor effect is abolished in Slurp1-deficient MC38 cells.\",\n      \"method\": \"scRNA-seq, subcutaneous tumor model with Slurp1-deficient cells, target-responsive accessibility profiling (MAPK14 as lobeline target), nuclear translocation assay, phospho-p53 analysis, SLURP1 transcription/secretion measurement\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Slurp1-deficient cell rescue experiment establishes causal role, MAPK14-p53-SLURP1 axis supported by multiple approaches, single lab\",\n      \"pmids\": [\"39840525\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLURP-1 is a secreted Ly-6/uPAR-related protein expressed in the granular layer of epidermis and mucosal epithelia that functions as an allosteric modulator of multiple nicotinic acetylcholine receptor (nAChR) subtypes—inhibiting α3β4, α4β4, α3β2, and α9α10 nAChRs and allosterically modulating α7-nAChR—to regulate keratinocyte apoptosis, differentiation, and proliferation via Ca2+-dependent (CaMKII/PKC) and Ca2+-independent (Jak2) signaling cascades converging on NF-κB and ERK1/2; it also acts as a soluble scavenger of urokinase-type plasminogen activator (uPA) to suppress uPAR-dependent cell migration, exerts direct antimicrobial activity against S. aureus, and suppresses angiogenesis and inflammatory cytokine production, with loss-of-function mutations causing the palmoplantar keratoderma Mal de Meleda.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLURP-1 is a secreted Ly-6/uPAR-related protein expressed as a late differentiation marker in the granular layer of epidermis and mucosal epithelia (skin, gums, stomach, esophagus, cornea) and released into biological fluids, where it governs keratinocyte and epithelial homeostasis, differentiation, proliferation, and inflammation [#2, #3]. Loss-of-function mutations in SLURP1 cause the autosomal recessive palmoplantar keratoderma Mal de Meleda, with most disease alleles abolishing protein expression, integrity, or stability [#0, #2]; Slurp1-deficient mice recapitulate the keratoderma with increased keratinocyte proliferation and a water-barrier defect, together with metabolic and neuromuscular abnormalities [#9]. Mechanistically, SLURP-1 is a ligand and allosteric modulator of multiple nicotinic acetylcholine receptor (nAChR) subtypes: it engages keratinocyte nAChR to promote caspase-dependent apoptosis and induce differentiation markers [#1], and the chemically synthesized protein inhibits \\u03b13\\u03b24, \\u03b14\\u03b24, \\u03b13\\u03b22, and \\u03b19\\u03b110 nAChRs while modulating \\u03b17-nAChR only allosterically [#12]. Signaling through \\u03b17-nAChR drives NF-\\u03baB activation via complementary Ca2+-dependent CaMKII/PKC and Ca2+-independent Jak2 pathways that converge on the Raf-1/MEK1/ERK1/2 cascade [#6]. Independently of receptor signaling, SLURP-1 acts as a soluble scavenger of urokinase-type plasminogen activator (uPA), binding uPA directly to reduce cell-surface uPA and suppress epithelial proliferation and migration [#10]. It also exerts anti-inflammatory and anti-angiogenic functions by blocking NF-\\u03baB nuclear translocation through elevated cytosolic I\\u03baB, stabilizing epithelial junctions, and suppressing cytokine output [#13, #15], displays direct antimicrobial activity against S. aureus [#11], and exhibits anti-malignant activity across oral, pancreatic, lung, and colorectal cancer models [#5, #14, #16, #17]. SLURP1 transcription is controlled by KLF4 in cornea, by STAT3 downstream of IL-22, and by p53-mediated repression relieved through the MAPK14 axis [#8, #11, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the disease gene was the first step: it was unknown what caused Mal de Meleda, and identifying loss-of-function SLURP1 mutations defined the gene as essential for palmoplantar epidermal integrity.\",\n      \"evidence\": \"Genetic mapping and identification of deletion, nonsense, and splice-site mutations in 19 affected families\",\n      \"pmids\": [\"11285253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the molecular function of SLURP-1 or its target receptors\", \"No tissue distribution or secretion data\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined where SLURP-1 acts and how its expression is controlled, localizing it to stratified epithelia and showing secretion of a 9 kDa protein under regulation by retinoic acid, EGF, and IFN-\\u03b3.\",\n      \"evidence\": \"Immunohistochemistry, western blot of keratinocyte conditioned medium, mRNA regulation studies\",\n      \"pmids\": [\"14721776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or downstream signaling mechanism identified\", \"Single-lab localization\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided the first molecular mechanism by showing SLURP-1 binds keratinocyte nAChR at the ligand-binding site as an allosteric agonist driving apoptosis and differentiation, linking receptor engagement to the epidermal phenotype.\",\n      \"evidence\": \"Radioligand binding, caspase activity assays, TUNEL, RT-PCR with recombinant SLURP-1 and carbachol augmentation\",\n      \"pmids\": [\"16354194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which specific nAChR subunits are engaged\", \"Downstream signaling cascade not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected genotype to protein loss, confirming SLURP-1 as a late granular-layer differentiation marker secreted into fluids and showing that MDM mutations abolish detectable protein.\",\n      \"evidence\": \"IHC, immunoblot of biological fluids, transfection of HEK293T with mutant SLURP1 constructs\",\n      \"pmids\": [\"17008884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which protein loss causes hyperkeratosis not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended SLURP-1's reach beyond skin, identifying immune-cell expression and \\u03b17-nAChR-coupled Ca2+ signaling and showing it prevents nitrosamine-induced malignant transformation of oral keratinocytes.\",\n      \"evidence\": \"RT-PCR tissue profiling, intracellular Ca2+ assays in T cells, soft-agar and nude-mouse xenograft assays with nAChR siRNA\",\n      \"pmids\": [\"17286989\", \"17280689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"\\u03b17 binding mode (allosteric vs orthosteric) not resolved here\", \"Single-lab functional assays\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissected the \\u03b17-nAChR signaling logic, showing SLURP-1 activates NF-\\u03baB through parallel Ca2+-dependent CaMKII/PKC and Ca2+-independent Jak2 pathways converging on Raf-1/MEK1/ERK1/2; a parallel study showed functional SLURP-1 is required for T-cell activation.\",\n      \"evidence\": \"Pharmacological pathway dissection with channel blockers and kinase inhibitors; MDM patient PBMC T-cell stimulation with recombinant SLURP-1 rescue\",\n      \"pmids\": [\"20660165\", \"20854438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway mapped pharmacologically without genetic confirmation of each node\", \"T-cell rescue from a single patient genotype\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified KLF4 as a direct transcriptional activator of SLURP1 in cornea and tied SLURP1 to control of corneal inflammation, with adenoviral SLURP1 reducing neutrophil influx.\",\n      \"evidence\": \"ChIP, promoter transfection, Klf4 conditional null corneas, adenoviral Slurp1 rescue, flow cytometry\",\n      \"pmids\": [\"23139280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/effector mediating the anti-inflammatory effect not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two complementary 2014 studies established loss-of-function consequences in vivo and a receptor-independent mechanism: Slurp1-knockout mice develop keratoderma with metabolic and neuromuscular defects, and SLURP-1 was shown to directly scavenge uPA to suppress epithelial proliferation and migration.\",\n      \"evidence\": \"Two independent KO mouse lines with histology/lipid/metabolic phenotyping; ligand blot, ELISA, pull-down, stable expression, and gap-filling migration assays\",\n      \"pmids\": [\"24499735\", \"25168896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of nAChR vs uPA-scavenging pathways to keratoderma unresolved\", \"Mechanism of metabolic and neuromuscular phenotypes unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the precise pharmacology against a panel of nAChRs and added anti-angiogenic function: synthetic NMR-characterized SLURP-1 inhibits \\u03b13\\u03b24, \\u03b14\\u03b24, \\u03b13\\u03b22, and \\u03b19\\u03b110 nAChRs and modulates \\u03b17 only allosterically, and SLURP1 suppresses HUVEC tube formation by blocking NF-\\u03baB nuclear translocation.\",\n      \"evidence\": \"Chemical synthesis, NMR structure, \\u03b1-bungarotoxin competition, electrophysiology; HUVEC tube formation, NF-\\u03baB localization, cytokine ELISA\",\n      \"pmids\": [\"29192197\", \"28803936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological concentrations at each receptor in vivo not defined\", \"Link between angiogenesis suppression and receptor pharmacology not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the anti-inflammatory mechanism, showing SLURP1 overexpression stabilizes epithelial junctions and suppresses TNF-\\u03b1-driven cytokines through I\\u03baB-mediated blockade of NF-\\u03baB nuclear translocation.\",\n      \"evidence\": \"Stable lentiviral SLURP1 overexpression in corneal epithelial cells, RT-PCR, immunoblot, ELISA, NF-\\u03baB localization and I\\u03baB measurement\",\n      \"pmids\": [\"31387745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating junction stabilization not identified\", \"Single cell-type, overexpression-based\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Characterized SLURP-1 as a tumor-selective antiproliferative agent in lung adenocarcinoma acting through \\u03b17-nAChR, EGFR, and \\u03b2-adrenergic receptors with IP3R/STAT3 downstream, sparing normal fibroblasts.\",\n      \"evidence\": \"Cell proliferation assays, \\u03b17-nAChR siRNA, receptor inhibitors, IP3R/STAT3 pathway analysis with recombinant SLURP-1\",\n      \"pmids\": [\"32106059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Multi-receptor model not deconvolved into primary target\", \"Single cell line, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SLURP1 in a transcriptional control circuit relevant to tumor immunity, showing a MAPK14\\u2013p53 axis represses SLURP1 and that SLURP1 mediates lobeline's inhibition of M2 macrophage polarization in colorectal cancer.\",\n      \"evidence\": \"scRNA-seq, Slurp1-deficient MC38 tumor model, MAPK14 target profiling, phospho-p53 and SLURP1 transcription/secretion measurement\",\n      \"pmids\": [\"39840525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on macrophages mediating SLURP1 effect not identified\", \"Single tumor model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the receptor-dependent (multi-nAChR allosteric) and receptor-independent (uPA-scavenging) activities of SLURP-1 are integrated to produce the in vivo keratoderma, metabolic, and neuromuscular phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SLURP-1 bound to any nAChR subtype\", \"Mechanism of metabolic/neuromuscular phenotypes in knockout mice unexplained\", \"Primary receptor versus uPA contribution to disease not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 5, 12]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 13, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CHRNA7\", \"PLAU\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}