{"gene":"KREMEN1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2002,"finding":"KREMEN1 and KREMEN2 are high-affinity DKK1 receptors that functionally cooperate with DKK1 to block Wnt/β-catenin signaling. KREMEN2 forms a ternary complex with DKK1 and LRP6, inducing rapid endocytosis and removal of the Wnt co-receptor LRP6 from the plasma membrane.","method":"Co-immunoprecipitation, endocytosis assays, Xenopus embryo overexpression/rescue experiments, binding assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional endocytosis assay, in vivo Xenopus rescue, replicated across multiple labs","pmids":["12050670"],"is_preprint":false},{"year":2002,"finding":"Kremen1 and Kremen2 functionally interact with Dkk1 to regulate anteroposterior CNS patterning in Xenopus. Morpholino knockdown of Krm1/2 leads to anterior neural defects, and Krm2 synergizes with Dkk1 in inhibiting Wnt/LRP6 signaling in axis duplication assays.","method":"Antisense morpholino knockdown, axis duplication assays, antibody rescue experiments, Xenopus embryology","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (MO knockdown, epistasis assays, antibody experiments), replicates functional findings of PMID 12050670","pmids":["12421700"],"is_preprint":false},{"year":2007,"finding":"Kremen2 functions independently of Dkks during neural crest induction in Xenopus: Krm2 binds LRP6, promotes its cell-surface localization, and stimulates LRP6-mediated Wnt/β-catenin signaling. Morpholino-mediated Krm2 knockdown reduces LRP6 protein levels in neural crest explants and inhibits neural crest induction.","method":"Morpholino knockdown, overexpression, cell-surface localization assays, LRP6 protein quantification in explants","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, cell-surface localization experiment with functional consequence, multiple orthogonal methods in single study","pmids":["17978005"],"is_preprint":false},{"year":2008,"finding":"DKK1 residues Arg197, Ser198, and Lys232 are specifically required for DKK1 binding to Kremen (but not LRP6), localized on the opposite surface from the LRP6-binding site. DKK1 mutants at these Kremen-binding residues retain Wnt antagonism unless both LRP6 and Kremen are co-expressed, suggesting Kremen is not essential for DKK1-mediated Wnt antagonism except when LRP5/6 is highly expressed.","method":"Site-directed mutagenesis, binding assays, Wnt signaling reporter assays, 3D structural modeling based on DKK2 structure","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis with functional readout and structural modeling, multiple binding and activity assays in single study","pmids":["18502762"],"is_preprint":false},{"year":2006,"finding":"Kremen1 knockout in mice causes severe defects in thymic cortical architecture including large epithelial-free regions and failure of epithelial maturation, with a 2-fold increase in canonical Wnt signaling in TEC lines derived from krm1−/− mice compared to wild-type.","method":"Knockout mouse analysis, TOPFlash Wnt reporter assay, FACS, immunostaining","journal":"Clinical & developmental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular/architectural phenotype and Wnt reporter quantification, single lab","pmids":["17162372"],"is_preprint":false},{"year":2015,"finding":"Kremen1 acts as a dependence receptor, triggering cell death (apoptosis) in the absence of its ligand DKK1 through a Wnt-independent mechanism. A specific motif in the cytoplasmic tail of Kremen1, conserved only in placental mammals, is strictly required for apoptosis induction. Pro-apoptotic and anti-Wnt functions are separable by mutagenesis.","method":"Whole embryo culture, Wnt-activity reporter assays, mutagenesis of cytoplasmic tail, phylogenetic analysis, loss-of-function experiments","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis separating apoptotic from Wnt functions, multiple orthogonal assays (reporter, whole embryo culture, phylogenetic validation), single lab","pmids":["26206087"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of the human KREMEN1 ectodomain (KRM1ECD) at 1.9–3.2 Å reveal a rigid molecule with a triangular arrangement of Kringle, WSC, and CUB domains. A low-resolution ternary complex crystal structure with LRP6 PE3PE4 and DKK1 CRD2 shows DKK1 CRD2 sandwiched between LRP6 PE3 and KRM1 Kringle-WSC, with surface plasmon resonance suggesting a direct interaction between KRM1 CUB and LRP6 PE2.","method":"X-ray crystallography (multiple structures), surface plasmon resonance, structural modeling","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at atomic resolution with orthogonal SPR binding validation, single lab but rigorous structural methods","pmids":["27524201"],"is_preprint":false},{"year":2018,"finding":"KREMEN1 is an entry receptor for Coxsackievirus A10 (CV-A10) and a related phylogenetic group of EV-A enteroviruses. Loss of KREMEN1 renders cells resistant to CV-A10 infection; KREMEN1 overexpression enhances CV-A10 binding and susceptibility; the KREMEN1 extracellular domain neutralizes infection. Kremen-deficient mice are resistant to CV-A10-induced lethal paralysis.","method":"Haploid genetic screen, CRISPR/loss-of-function, overexpression, soluble ectodomain neutralization assay, Kremen-knockout mouse infection model","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic screen, KO cells, OE, in vivo mouse model), replicated across cell types and in vivo","pmids":["29681460"],"is_preprint":false},{"year":2020,"finding":"Crystal structures of CV-A10 alone, in complex with KRM1, and of the CV-A10 A-particle reveal that KRM1 spans the viral canyon with a large footprint, and that KRM1 binding induces release of a pocket factor and produces expanded (uncoating-primed) viral particles, identifying KRM1 as a two-in-one attachment and uncoating receptor.","method":"Cryo-EM and X-ray crystallography, in vitro uncoating assay at acidic pH","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution structures of virus-receptor complex plus orthogonal in vitro functional uncoating assay, replicated by independent structural study (PMID 32690697)","pmids":["31911601","32690697"],"is_preprint":false},{"year":2012,"finding":"KREMEN1 is internalized from the cell surface by clathrin-mediated endocytosis via an atypical dileucine motif (DXXXLV) in its cytoplasmic tail. Mutation of LV to AA in this motif blocks internalization. AP-2 knockdown or clathrin inhibition with pitstop 2 also blocks KREMEN1 internalization.","method":"Site-directed mutagenesis of endocytic motif, siRNA knockdown of AP-2, pharmacological clathrin inhibition, cell-surface internalization assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional endocytosis readout plus pharmacological and genetic inhibition, single lab","pmids":["23251700"],"is_preprint":false},{"year":2019,"finding":"Kremen1 apoptotic signaling requires homodimerization; forced dimerization increases apoptotic signaling while DKK1 binding inhibits Kremen1 multimerization and alleviates cell death. Kremen2 (which has no intrinsic apoptotic activity) binds Kremen1 and acts as a potent inhibitor of Kremen1-induced cell death through heterodimerization.","method":"Dimerization assays, forced dimerization constructs, co-immunoprecipitation of Kremen1/Kremen2 heterodimers, cell death assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for heterodimerization, forced dimerization with functional readout, single lab with multiple orthogonal approaches","pmids":["31069116"],"is_preprint":false},{"year":2016,"finding":"Kremen1 is expressed in prosensory cells during cochlear development and in supporting cells of the adult mouse cochlea. Gain- and loss-of-function experiments show Kremen1 is sufficient to bias cells towards supporting cell fate and suppresses hair cell formation. Loss of Kremen1 in zebrafish results in more hair cells per neuromast.","method":"Gain-of-function overexpression, loss-of-function (genetic/MO), immunolocalization, hair cell counting in mouse cochlea and zebrafish lateral line","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementary gain- and loss-of-function in two model organisms with quantitative cellular phenotype readout, single lab","pmids":["27550540"],"is_preprint":false},{"year":2014,"finding":"In the zebrafish posterior lateral line primordium, Kremen1 loss causes decreased (rather than increased) Wnt signaling phenotypes in a non-cell-autonomous manner. Ectopic Dkk1b-mTangerine shows larger spread in krm1 mutant primordia, indicating that Kremen1 restricts the diffusion range of secreted Dkk proteins, modulating Wnt activity by limiting Dkk spread rather than solely facilitating LRP6 endocytosis.","method":"Zebrafish kremen1 mutant analysis, transplantation rescue assay (non-cell-autonomy test), fluorescent Dkk1b fusion protein imaging","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant with non-cell-autonomy demonstrated by transplantation, fluorescent protein imaging to track Dkk spread, single lab","pmids":["25038040"],"is_preprint":false},{"year":2021,"finding":"KREMEN1 is sufficient to mediate SARS-CoV-2 (but not SARS-CoV) entry into cells independently of ACE2. KREMEN1 binds the SARS-CoV-2 spike protein and supports viral entry in vitro and in vivo. SARS-CoV-2 uses distinct ACE2/ASGR1/KREMEN1 receptor combinations depending on cell type.","method":"Genome-wide receptor screen (5054 membrane proteins), viral entry assays (in vitro and in vivo), neutralizing antibody blockade, human lung organoid infection","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genomic screen plus orthogonal in vitro and in vivo entry assays and antibody neutralization in organoids, single lab but multiple methods","pmids":["34837059"],"is_preprint":false},{"year":2020,"finding":"DKK3 co-localizes with Kremen-1 in microglia following intracerebral hemorrhage. In vivo Kremen-1 siRNA knockdown attenuates the protective effects of exogenous DKK3 on brain edema and neuroinflammation, placing Kremen-1 downstream of DKK3 in a pathway suppressing JNK/AP-1-mediated neuroinflammation.","method":"siRNA knockdown in vivo, Western blot, immunofluorescence co-localization, behavioral neuroscience readouts","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo siRNA knockdown with defined neuroinflammation phenotype and co-localization, single lab, single method for pathway placement","pmids":["32331523"],"is_preprint":false},{"year":2018,"finding":"DKK4 CRD2 mediates high-affinity binding to both LRP6 E1E2 and the Kremen1 extracellular domain. DKK4 and Kremen1 function synergistically to inhibit Wnt signaling. The N-terminal region (CRD1) does not interact with Kremen proteins.","method":"Surface plasmon resonance, NMR structural analysis, Wnt reporter assay (synergy), domain-deletion binding experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — SPR binding with NMR structural analysis and functional reporter assays, single lab, multiple orthogonal methods","pmids":["29925589"],"is_preprint":false},{"year":2016,"finding":"Homozygous KREMEN1 p.F209S variant (in the extracellular WSC domain) causes autosomal recessive ectodermal dysplasia with oligodontia in Palestinian families, demonstrating that Kremen1 WSC domain function is required for normal ectodermal/dental development in humans.","method":"Exome sequencing, Sanger genotyping in 56 relatives, variant localization to WSC domain","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — human genetics identifying disease-causing variant with domain localization, no direct functional assay of the variant in this paper","pmids":["27049303"],"is_preprint":false},{"year":2025,"finding":"Disease-associated KREMEN1 variants (Cys111Ser, Gly166Asp, Phe209Ser, Phe258_Pro259del) show reduced N- and O-glycosylation compared to wild type. These variants have reduced ability to form ternary complexes with DKK1 and LRP6 (though KREMEN1-LRP6 binary interaction is not impaired by missense variants). Patient fibroblasts show higher basal WNT activity and attenuated response to WNT3A stimulation.","method":"Ectopic expression in HEK293T cells, glycosylation analysis, co-immunoprecipitation of ternary and binary complexes, WNT pathway reporter assays in patient fibroblasts","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple disease variants tested with Co-IP and reporter assays, patient fibroblast validation, single lab","pmids":["40553753"],"is_preprint":false},{"year":2026,"finding":"Kremen1 induces cell death with autophagic (rather than apoptotic) features when unbound by DKK1. Proximity labeling identified SEC24C (COP-II complex component) as a critical effector. Kremen1 is in proximity with SEC24C and ATG9A after vesicular trafficking; this fosters proximity of SEC24C with ATG8, ERGIC, and ATG9A, increasing autophagosomes and leading to cell death.","method":"Pharmacological inhibition of autophagy, genetic silencing of autophagy effectors, biotin proximity labeling (BioID/TurboID) for protein-protein interactions, functional cell death assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling with genetic validation of key effectors and pharmacological orthogonal approach, single lab","pmids":["41807954"],"is_preprint":false},{"year":2025,"finding":"VP2 residue K140 (K2140) is completely conserved in all KRM1-dependent enteroviruses and is essential for KRM1 receptor recognition and infection by CVA2-CVA6, CVA10, CVA12, and CVA8. KRM1 residue D90 engages directly with K2140 to mediate receptor binding.","method":"Mutational analysis, viral binding and infection assays, in vivo mouse pathogenicity, receptor-identification assay for CVA8","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis across multiple viruses with in vitro and in vivo validation, single lab","pmids":["39817751"],"is_preprint":false},{"year":2008,"finding":"DKK1 and Kremen1 are co-expressed and dynamically regulated in embryos and uterine stroma during the window of implantation. Antisense oligonucleotide knockdown of Kremen1 inhibits blastocyst adhesion and outgrowth on fibronectin in vitro, and DKK1 antisense injection into mouse uterine horns inhibits embryo implantation in vivo.","method":"Immunofluorescence/immunohistochemistry for co-expression, antisense ODN knockdown in vitro and in vivo, blastocyst adhesion assay","journal":"Fertility and sterility","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined implantation phenotype in vitro and in vivo, single lab, limited mechanistic depth","pmids":["18068158"],"is_preprint":false},{"year":2018,"finding":"Silencing Kremen1 with miR-431 prevents amyloid-β-mediated synapse loss (reduction in pre- and post-synaptic puncta) and neurite degeneration in cortico-hippocampal cultures from 3xTg-AD mice, demonstrating a required role for Kremen1 in DKK1/Aβ-induced synaptic degeneration.","method":"miRNA transfection (miR-431) targeting Kremen1, synaptic puncta quantification, neurite degeneration assay in primary neuronal cultures","journal":"Frontiers in cellular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single miRNA knockdown approach in cell culture, indirect targeting of Kremen1 via miRNA, single lab","pmids":["29643768"],"is_preprint":false},{"year":2001,"finding":"KREMEN (KREMEN1) is a type-I transmembrane protein with a kringle domain, a WSC domain, and CUB domains in the extracellular region and no conserved signaling motif in its intracellular region. Its mRNA increases during embryonic development and during differentiation of C2C12 and NIE-115 cells into muscle and neural cells respectively.","method":"Kringle-SAGE cloning strategy, sequence/domain analysis, Northern blot expression analysis, in situ hybridization in mouse embryos","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — original molecular cloning with domain characterization and expression analysis, foundational structural annotation, single lab","pmids":["11267660"],"is_preprint":false}],"current_model":"KREMEN1 is a type-I transmembrane protein with extracellular Kringle, WSC, and CUB domains that functions as a high-affinity receptor for DKK family proteins; in the presence of DKK1, it forms a ternary complex with DKK1 and LRP5/6 that is internalized via clathrin-mediated endocytosis (using an atypical dileucine cytoplasmic motif), thereby removing LRP5/6 from the cell surface and inhibiting canonical Wnt/β-catenin signaling; in the absence of DKK1, KREMEN1 can instead promote LRP6 surface localization and activate Wnt signaling, and additionally acts as a dependence receptor that triggers autophagic cell death (requiring homodimerization, SEC24C, and ATG9A) unless bound by DKK1—a Wnt-independent apoptotic/autophagic function encoded in a placental mammal-specific cytoplasmic motif; KREMEN1 also serves as the cellular entry receptor for multiple hand-foot-and-mouth disease enteroviruses (CV-A2–A6, A8, A10, A12) and as an alternative SARS-CoV-2 receptor, with the viral canyon-rim residue K140 and KREMEN1 residue D90 being key interaction determinants."},"narrative":{"mechanistic_narrative":"KREMEN1 is a type-I transmembrane protein with extracellular Kringle, WSC, and CUB domains that acts as a high-affinity receptor for DKK family ligands and a context-dependent modulator of Wnt/β-catenin signaling [PMID:11267660, PMID:12050670, PMID:27524201]. In the presence of DKK1, KREMEN1 cooperates with DKK1 to assemble a ternary complex with the Wnt co-receptor LRP5/6, driving its rapid endocytosis and removal from the cell surface to antagonize Wnt signaling; structurally, DKK1 CRD2 is sandwiched between LRP6 and the KREMEN1 Kringle-WSC module, with the CUB domain contacting LRP6 [PMID:12050670, PMID:27524201, PMID:29925589]. This internalization proceeds by clathrin-mediated endocytosis through an atypical dileucine (DXXXLV) motif in the cytoplasmic tail that engages AP-2 [PMID:23251700]. KREMEN1's effect on Wnt is context-dependent: independent of DKKs it can bind LRP6, stabilize its surface localization, and promote Wnt signaling during neural crest induction, and it can also restrict the diffusion range of secreted Dkk proteins to shape Wnt activity non-cell-autonomously [PMID:17978005, PMID:25038040]. Beyond Wnt, KREMEN1 functions as a dependence receptor: in the absence of DKK1 it triggers ligand-withdrawal cell death through a placental-mammal-specific cytoplasmic motif that is genetically separable from its anti-Wnt function, requires homodimerization (inhibited by DKK1 binding and by KREMEN2 heterodimerization), and engages an autophagic effector route via SEC24C and ATG9A [PMID:26206087, PMID:31069116, PMID:41807954]. These activities place KREMEN1 in developmental programs including thymic epithelial architecture, cochlear supporting-cell versus hair-cell fate, and embryo implantation [PMID:17162372, PMID:27550540, PMID:18068158]. Homozygous KREMEN1 variants in the extracellular domain cause autosomal recessive ectodermal dysplasia with oligodontia, and disease variants show reduced glycosylation, impaired ternary-complex formation, and elevated basal Wnt activity [PMID:27049303, PMID:40553753]. Independently of its Wnt and death functions, KREMEN1 serves as a cell-entry receptor: it is a two-in-one attachment and uncoating receptor for a group of hand-foot-and-mouth disease enteroviruses (CV-A10 and related EV-A viruses, via viral residue K140 and KREMEN1 residue D90) and an ACE2-independent alternative receptor for SARS-CoV-2 [PMID:29681460, PMID:31911601, PMID:32690697, PMID:39817751, PMID:34837059].","teleology":[{"year":2001,"claim":"Defining KREMEN1 as a type-I transmembrane protein with a distinctive Kringle/WSC/CUB ectodomain and no recognized intracellular signaling motif established the structural framework for all later receptor functions.","evidence":"Kringle-SAGE cloning, domain/sequence analysis, and developmental expression profiling in mouse","pmids":["11267660"],"confidence":"Medium","gaps":["No ligand or functional partner identified at cloning","Intracellular function undefined given absence of a canonical signaling motif"]},{"year":2002,"claim":"Identification of KREMEN1/2 as high-affinity DKK1 receptors that form a ternary complex with DKK1 and LRP6 and drive its endocytosis answered how DKK1 removes the Wnt co-receptor to antagonize Wnt signaling.","evidence":"Reciprocal Co-IP, endocytosis assays, and Xenopus overexpression/rescue; complemented by morpholino knockdown showing roles in anteroposterior CNS patterning","pmids":["12050670","12421700"],"confidence":"High","gaps":["Endocytic machinery used by KREMEN not yet defined","Quantitative requirement for KREMEN versus DKK1/LRP6 ratios unresolved"]},{"year":2007,"claim":"Demonstration that Kremen2 can bind LRP6, promote its surface localization, and stimulate Wnt signaling independently of Dkks established that KREMEN's Wnt output is context-dependent rather than purely inhibitory.","evidence":"Morpholino knockdown, overexpression, and LRP6 surface localization/protein quantification in Xenopus neural crest explants","pmids":["17978005"],"confidence":"High","gaps":["Molecular switch between Wnt-promoting and Wnt-inhibiting modes not defined","Whether KREMEN1 behaves identically to KREMEN2 in this mode untested"]},{"year":2008,"claim":"Mapping DKK1 residues (Arg197/Ser198/Lys232) required for Kremen binding to a surface distinct from the LRP6 site clarified that Kremen engagement is genetically separable from LRP6 binding and dispensable for Wnt antagonism except when LRP5/6 is highly expressed.","evidence":"Site-directed mutagenesis, binding and Wnt reporter assays, structural modeling on the DKK2 scaffold","pmids":["18502762"],"confidence":"High","gaps":["Defines DKK1 determinants but not reciprocal KREMEN1 binding residues","Physiological conditions where Kremen becomes essential not enumerated"]},{"year":2006,"claim":"Knockout phenotyping linked KREMEN1 loss to disrupted thymic epithelial architecture with elevated Wnt signaling, providing the first in vivo developmental requirement tied to its Wnt-modulating role.","evidence":"Knockout mouse analysis with TOPFlash reporter, FACS, and immunostaining of thymic epithelial cells","pmids":["17162372"],"confidence":"Medium","gaps":["Causal chain from Wnt elevation to epithelial defect not dissected","Single-lab phenotype"]},{"year":2008,"claim":"Co-expression and loss-of-function data placed KREMEN1 in embryo implantation, showing its requirement for blastocyst adhesion and outgrowth.","evidence":"Immunostaining co-expression, antisense ODN knockdown in vitro and in vivo, blastocyst adhesion assay","pmids":["18068158"],"confidence":"Medium","gaps":["Mechanism (Wnt vs adhesion) underlying implantation defect unresolved","Limited mechanistic depth"]},{"year":2012,"claim":"Identification of an atypical dileucine (DXXXLV) motif mediating AP-2/clathrin-dependent internalization defined the endocytic mechanism by which KREMEN1 traffics from the cell surface.","evidence":"Mutagenesis of the endocytic motif, AP-2 siRNA, pitstop 2 inhibition, and surface internalization assays","pmids":["23251700"],"confidence":"Medium","gaps":["Whether the same motif governs DKK1/LRP6 ternary internalization untested","Post-endocytic fate of KREMEN1 not tracked"]},{"year":2014,"claim":"The finding that Kremen1 loss decreases Wnt signaling non-cell-autonomously by restricting Dkk diffusion revealed a function beyond LRP6 endocytosis: spatial control of secreted Dkk range.","evidence":"Zebrafish kremen1 mutant analysis, transplantation non-cell-autonomy test, and fluorescent Dkk1b fusion imaging in the lateral line primordium","pmids":["25038040"],"confidence":"Medium","gaps":["Molecular basis of Dkk sequestration/diffusion limitation undefined","Generality beyond the primordium unknown"]},{"year":2015,"claim":"Discovery that KREMEN1 acts as a dependence receptor triggering ligand-withdrawal cell death via a placental-mammal-specific cytoplasmic motif established a Wnt-independent pro-death function separable from its anti-Wnt activity.","evidence":"Whole-embryo culture, Wnt reporter assays, cytoplasmic-tail mutagenesis, and phylogenetic analysis","pmids":["26206087"],"confidence":"High","gaps":["Downstream death effectors not identified in this study","Physiological contexts of dependence-receptor signaling unclear"]},{"year":2016,"claim":"Crystal structures of the rigid Kringle/WSC/CUB ectodomain and a ternary complex with LRP6 and DKK1 provided the atomic architecture of the inhibitory complex, including the DKK1 CRD2 sandwich and a CUB–LRP6 contact.","evidence":"X-ray crystallography of multiple constructs with SPR validation","pmids":["27524201"],"confidence":"High","gaps":["Ternary complex resolved only at low resolution","Conformational basis of Wnt-promoting versus inhibiting modes not captured"]},{"year":2016,"claim":"Loss- and gain-of-function across mouse and zebrafish showed KREMEN1 biases inner-ear cells toward supporting-cell fate and suppresses hair-cell formation, extending its developmental remit to sensory cell-fate decisions.","evidence":"Overexpression, genetic/MO loss-of-function, immunolocalization, and hair-cell counting in cochlea and lateral line","pmids":["27550540"],"confidence":"Medium","gaps":["Whether fate bias is Wnt-dependent not resolved","Single-lab finding"]},{"year":2016,"claim":"A homozygous WSC-domain variant (p.F209S) causing recessive ectodermal dysplasia with oligodontia established a human disease requirement for KREMEN1 ectodomain function in ectodermal/dental development.","evidence":"Exome sequencing and Sanger genotyping across 56 relatives in Palestinian families with domain localization","pmids":["27049303"],"confidence":"Medium","gaps":["No functional assay of the variant in this study","Molecular pathway connecting variant to dental phenotype not shown"]},{"year":2018,"claim":"Identification of KREMEN1 as the entry receptor for CV-A10 and related EV-A enteroviruses revealed a function entirely distinct from Wnt biology, with in vivo protection in Kremen-deficient mice.","evidence":"Haploid genetic screen, CRISPR knockout, overexpression, soluble ectodomain neutralization, and KO mouse infection","pmids":["29681460"],"confidence":"High","gaps":["Structural basis of virus engagement not yet resolved at this stage","Whether viral entry uses the same endocytic machinery as DKK1 unknown"]},{"year":2018,"claim":"Extension of DKK–KREMEN1 binding to DKK4 (and biophysical mapping to CRD2) generalized the high-affinity ligand interaction across the DKK family and confirmed synergistic Wnt inhibition.","evidence":"SPR, NMR structural analysis, domain-deletion binding, and Wnt synergy reporter assays","pmids":["29925589"],"confidence":"Medium","gaps":["Functional roles of DKK4–KREMEN1 in vivo not addressed","Single-lab biochemistry"]},{"year":2019,"claim":"Demonstration that KREMEN1 death signaling requires homodimerization—blocked by DKK1 and by KREMEN2 heterodimerization—defined the molecular switch controlling its dependence-receptor activity.","evidence":"Forced-dimerization constructs, KREMEN1/2 heterodimer Co-IP, and cell death assays","pmids":["31069116"],"confidence":"Medium","gaps":["Structural basis of the homodimer interface unresolved","How dimerization couples to downstream death machinery not shown"]},{"year":2020,"claim":"Structures of CV-A10–KRM1 complexes and the A-particle showed KREMEN1 spans the viral canyon, expels the pocket factor, and primes uncoating, defining KREMEN1 as a two-in-one attachment and uncoating receptor.","evidence":"Cryo-EM and X-ray crystallography of virus–receptor complexes plus an in vitro acidic-pH uncoating assay; independently replicated","pmids":["31911601","32690697"],"confidence":"High","gaps":["Membrane events downstream of uncoating not resolved","Receptor residues governing specificity not fully mapped at this stage"]},{"year":2020,"claim":"Placing Kremen-1 downstream of DKK3 in microglia identified a role in suppressing JNK/AP-1 neuroinflammation after intracerebral hemorrhage.","evidence":"In vivo Kremen-1 siRNA knockdown, Western blot, co-localization, and behavioral readouts","pmids":["32331523"],"confidence":"Medium","gaps":["Direct DKK3–KREMEN1 binding not demonstrated","Pathway placement rests on a single in vivo knockdown"]},{"year":2021,"claim":"A genome-wide receptor screen established KREMEN1 as an ACE2-independent SARS-CoV-2 entry receptor that binds spike, broadening its viral-receptor repertoire to a coronavirus in a cell-type-dependent manner.","evidence":"Screen of 5054 membrane proteins, in vitro/in vivo entry assays, neutralizing antibody blockade, and lung organoid infection","pmids":["34837059"],"confidence":"High","gaps":["Spike–KREMEN1 interaction interface not structurally defined","Relative in vivo contribution versus ACE2 unclear"]},{"year":2025,"claim":"Functional dissection of disease variants tied reduced glycosylation and impaired ternary-complex formation (with intact binary KREMEN1–LRP6 binding) to elevated basal Wnt activity, linking ectodermal dysplasia variants to a defined molecular defect.","evidence":"Ectopic expression, glycosylation analysis, ternary/binary Co-IP, and Wnt reporter assays in patient fibroblasts","pmids":["40553753"],"confidence":"Medium","gaps":["Whether the dependence-receptor function is also affected by these variants untested","In vivo confirmation in patient tissue limited"]},{"year":2025,"claim":"Mapping the conserved enterovirus VP2 K140 residue and its direct partner KREMEN1 D90 defined the molecular determinant of KRM1-dependent enterovirus recognition across CVA2–A6, A8, A10, and A12.","evidence":"Systematic mutagenesis, viral binding/infection assays, and in vivo mouse pathogenicity","pmids":["39817751"],"confidence":"Medium","gaps":["Whether the same residues govern SARS-CoV-2 binding not addressed","Single-lab determination"]},{"year":2026,"claim":"Proximity labeling reframed KREMEN1 ligand-withdrawal death as autophagic, identifying SEC24C and ATG9A as effectors that drive autophagosome accumulation, providing the downstream machinery for its dependence-receptor function.","evidence":"BioID/TurboID proximity labeling, genetic silencing of autophagy effectors, pharmacological autophagy inhibition, and cell death assays","pmids":["41807954"],"confidence":"Medium","gaps":["How cytoplasmic-tail dimerization recruits SEC24C mechanistically unresolved","Reconciliation of apoptotic versus autophagic death readouts pending"]},{"year":null,"claim":"How KREMEN1 integrates its mutually distinct roles—Wnt modulation, dependence-receptor death, and viral entry—through a single ectodomain and a short cytoplasmic tail, and what governs the switch between Wnt-promoting and Wnt-inhibiting modes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking the ligand-bound, homodimeric, and virus-bound states","Switch determinants between Wnt activation and inhibition undefined","Endogenous regulators of dependence-receptor death poorly characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[7,8,13,19]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,15]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,22]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,11,16,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,10,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,13,16,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18]}],"complexes":["KREMEN1-DKK1-LRP6 ternary complex"],"partners":["DKK1","LRP6","KREMEN2","DKK4","SEC24C","ATG9A","AP-2","DKK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96MU8","full_name":"Kremen protein 1","aliases":["Dickkopf receptor","Kringle domain-containing transmembrane protein 1","Kringle-containing protein marking the eye and the nose"],"length_aa":473,"mass_kda":51.7,"function":"Receptor for Dickkopf proteins. Cooperates with DKK1/2 to inhibit Wnt/beta-catenin signaling by promoting the endocytosis of Wnt receptors LRP5 and LRP6. In the absence of DKK1, potentiates Wnt-beta-catenin signaling by maintaining LRP5 or LRP6 at the cell membrane. Can trigger apoptosis in a Wnt-independent manner and this apoptotic activity is inhibited upon binding of the ligand DKK1. Plays a role in limb development; attenuates Wnt signaling in the developing limb to allow normal limb patterning and can also negatively regulate bone formation. Modulates cell fate decisions in the developing cochlea with an inhibitory role in hair cell fate specification","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96MU8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KREMEN1","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/KREMEN1","total_profiled":1310},"omim":[{"mim_id":"618428","title":"POPOV-CHANG SYNDROME; POPCHAS","url":"https://www.omim.org/entry/618428"},{"mim_id":"617392","title":"ECTODERMAL DYSPLASIA 13, HAIR/TOOTH TYPE; ECTD13","url":"https://www.omim.org/entry/617392"},{"mim_id":"609898","title":"KRINGLE DOMAIN-CONTAINING TRANSMEMBRANE PROTEIN 1; KREMEN1","url":"https://www.omim.org/entry/609898"},{"mim_id":"601288","title":"TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN, ZETA ISOFORM; YWHAZ","url":"https://www.omim.org/entry/601288"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KREMEN1"},"hgnc":{"alias_symbol":["KRM1"],"prev_symbol":["KREMEN"]},"alphafold":{"accession":"Q96MU8","domains":[{"cath_id":"2.40.20.10","chopping":"29-116","consensus_level":"medium","plddt":96.1325,"start":29,"end":116},{"cath_id":"2.60.120.290","chopping":"215-321","consensus_level":"high","plddt":97.0598,"start":215,"end":321},{"cath_id":"3.50.4","chopping":"118-207","consensus_level":"high","plddt":98.0414,"start":118,"end":207}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MU8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MU8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MU8-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KREMEN1","jax_strain_url":"https://www.jax.org/strain/search?query=KREMEN1"},"sequence":{"accession":"Q96MU8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96MU8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96MU8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MU8"}},"corpus_meta":[{"pmid":"12050670","id":"PMC_12050670","title":"Kremen 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KREMEN2 forms a ternary complex with DKK1 and LRP6, inducing rapid endocytosis and removal of the Wnt co-receptor LRP6 from the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, endocytosis assays, Xenopus embryo overexpression/rescue experiments, binding assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional endocytosis assay, in vivo Xenopus rescue, replicated across multiple labs\",\n      \"pmids\": [\"12050670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Kremen1 and Kremen2 functionally interact with Dkk1 to regulate anteroposterior CNS patterning in Xenopus. Morpholino knockdown of Krm1/2 leads to anterior neural defects, and Krm2 synergizes with Dkk1 in inhibiting Wnt/LRP6 signaling in axis duplication assays.\",\n      \"method\": \"Antisense morpholino knockdown, axis duplication assays, antibody rescue experiments, Xenopus embryology\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (MO knockdown, epistasis assays, antibody experiments), replicates functional findings of PMID 12050670\",\n      \"pmids\": [\"12421700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kremen2 functions independently of Dkks during neural crest induction in Xenopus: Krm2 binds LRP6, promotes its cell-surface localization, and stimulates LRP6-mediated Wnt/β-catenin signaling. Morpholino-mediated Krm2 knockdown reduces LRP6 protein levels in neural crest explants and inhibits neural crest induction.\",\n      \"method\": \"Morpholino knockdown, overexpression, cell-surface localization assays, LRP6 protein quantification in explants\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, cell-surface localization experiment with functional consequence, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17978005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DKK1 residues Arg197, Ser198, and Lys232 are specifically required for DKK1 binding to Kremen (but not LRP6), localized on the opposite surface from the LRP6-binding site. DKK1 mutants at these Kremen-binding residues retain Wnt antagonism unless both LRP6 and Kremen are co-expressed, suggesting Kremen is not essential for DKK1-mediated Wnt antagonism except when LRP5/6 is highly expressed.\",\n      \"method\": \"Site-directed mutagenesis, binding assays, Wnt signaling reporter assays, 3D structural modeling based on DKK2 structure\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis with functional readout and structural modeling, multiple binding and activity assays in single study\",\n      \"pmids\": [\"18502762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Kremen1 knockout in mice causes severe defects in thymic cortical architecture including large epithelial-free regions and failure of epithelial maturation, with a 2-fold increase in canonical Wnt signaling in TEC lines derived from krm1−/− mice compared to wild-type.\",\n      \"method\": \"Knockout mouse analysis, TOPFlash Wnt reporter assay, FACS, immunostaining\",\n      \"journal\": \"Clinical & developmental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular/architectural phenotype and Wnt reporter quantification, single lab\",\n      \"pmids\": [\"17162372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kremen1 acts as a dependence receptor, triggering cell death (apoptosis) in the absence of its ligand DKK1 through a Wnt-independent mechanism. A specific motif in the cytoplasmic tail of Kremen1, conserved only in placental mammals, is strictly required for apoptosis induction. Pro-apoptotic and anti-Wnt functions are separable by mutagenesis.\",\n      \"method\": \"Whole embryo culture, Wnt-activity reporter assays, mutagenesis of cytoplasmic tail, phylogenetic analysis, loss-of-function experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis separating apoptotic from Wnt functions, multiple orthogonal assays (reporter, whole embryo culture, phylogenetic validation), single lab\",\n      \"pmids\": [\"26206087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of the human KREMEN1 ectodomain (KRM1ECD) at 1.9–3.2 Å reveal a rigid molecule with a triangular arrangement of Kringle, WSC, and CUB domains. A low-resolution ternary complex crystal structure with LRP6 PE3PE4 and DKK1 CRD2 shows DKK1 CRD2 sandwiched between LRP6 PE3 and KRM1 Kringle-WSC, with surface plasmon resonance suggesting a direct interaction between KRM1 CUB and LRP6 PE2.\",\n      \"method\": \"X-ray crystallography (multiple structures), surface plasmon resonance, structural modeling\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at atomic resolution with orthogonal SPR binding validation, single lab but rigorous structural methods\",\n      \"pmids\": [\"27524201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KREMEN1 is an entry receptor for Coxsackievirus A10 (CV-A10) and a related phylogenetic group of EV-A enteroviruses. Loss of KREMEN1 renders cells resistant to CV-A10 infection; KREMEN1 overexpression enhances CV-A10 binding and susceptibility; the KREMEN1 extracellular domain neutralizes infection. Kremen-deficient mice are resistant to CV-A10-induced lethal paralysis.\",\n      \"method\": \"Haploid genetic screen, CRISPR/loss-of-function, overexpression, soluble ectodomain neutralization assay, Kremen-knockout mouse infection model\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic screen, KO cells, OE, in vivo mouse model), replicated across cell types and in vivo\",\n      \"pmids\": [\"29681460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structures of CV-A10 alone, in complex with KRM1, and of the CV-A10 A-particle reveal that KRM1 spans the viral canyon with a large footprint, and that KRM1 binding induces release of a pocket factor and produces expanded (uncoating-primed) viral particles, identifying KRM1 as a two-in-one attachment and uncoating receptor.\",\n      \"method\": \"Cryo-EM and X-ray crystallography, in vitro uncoating assay at acidic pH\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution structures of virus-receptor complex plus orthogonal in vitro functional uncoating assay, replicated by independent structural study (PMID 32690697)\",\n      \"pmids\": [\"31911601\", \"32690697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KREMEN1 is internalized from the cell surface by clathrin-mediated endocytosis via an atypical dileucine motif (DXXXLV) in its cytoplasmic tail. Mutation of LV to AA in this motif blocks internalization. AP-2 knockdown or clathrin inhibition with pitstop 2 also blocks KREMEN1 internalization.\",\n      \"method\": \"Site-directed mutagenesis of endocytic motif, siRNA knockdown of AP-2, pharmacological clathrin inhibition, cell-surface internalization assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional endocytosis readout plus pharmacological and genetic inhibition, single lab\",\n      \"pmids\": [\"23251700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kremen1 apoptotic signaling requires homodimerization; forced dimerization increases apoptotic signaling while DKK1 binding inhibits Kremen1 multimerization and alleviates cell death. Kremen2 (which has no intrinsic apoptotic activity) binds Kremen1 and acts as a potent inhibitor of Kremen1-induced cell death through heterodimerization.\",\n      \"method\": \"Dimerization assays, forced dimerization constructs, co-immunoprecipitation of Kremen1/Kremen2 heterodimers, cell death assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for heterodimerization, forced dimerization with functional readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"31069116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Kremen1 is expressed in prosensory cells during cochlear development and in supporting cells of the adult mouse cochlea. Gain- and loss-of-function experiments show Kremen1 is sufficient to bias cells towards supporting cell fate and suppresses hair cell formation. Loss of Kremen1 in zebrafish results in more hair cells per neuromast.\",\n      \"method\": \"Gain-of-function overexpression, loss-of-function (genetic/MO), immunolocalization, hair cell counting in mouse cochlea and zebrafish lateral line\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementary gain- and loss-of-function in two model organisms with quantitative cellular phenotype readout, single lab\",\n      \"pmids\": [\"27550540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the zebrafish posterior lateral line primordium, Kremen1 loss causes decreased (rather than increased) Wnt signaling phenotypes in a non-cell-autonomous manner. Ectopic Dkk1b-mTangerine shows larger spread in krm1 mutant primordia, indicating that Kremen1 restricts the diffusion range of secreted Dkk proteins, modulating Wnt activity by limiting Dkk spread rather than solely facilitating LRP6 endocytosis.\",\n      \"method\": \"Zebrafish kremen1 mutant analysis, transplantation rescue assay (non-cell-autonomy test), fluorescent Dkk1b fusion protein imaging\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant with non-cell-autonomy demonstrated by transplantation, fluorescent protein imaging to track Dkk spread, single lab\",\n      \"pmids\": [\"25038040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KREMEN1 is sufficient to mediate SARS-CoV-2 (but not SARS-CoV) entry into cells independently of ACE2. KREMEN1 binds the SARS-CoV-2 spike protein and supports viral entry in vitro and in vivo. SARS-CoV-2 uses distinct ACE2/ASGR1/KREMEN1 receptor combinations depending on cell type.\",\n      \"method\": \"Genome-wide receptor screen (5054 membrane proteins), viral entry assays (in vitro and in vivo), neutralizing antibody blockade, human lung organoid infection\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genomic screen plus orthogonal in vitro and in vivo entry assays and antibody neutralization in organoids, single lab but multiple methods\",\n      \"pmids\": [\"34837059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DKK3 co-localizes with Kremen-1 in microglia following intracerebral hemorrhage. In vivo Kremen-1 siRNA knockdown attenuates the protective effects of exogenous DKK3 on brain edema and neuroinflammation, placing Kremen-1 downstream of DKK3 in a pathway suppressing JNK/AP-1-mediated neuroinflammation.\",\n      \"method\": \"siRNA knockdown in vivo, Western blot, immunofluorescence co-localization, behavioral neuroscience readouts\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo siRNA knockdown with defined neuroinflammation phenotype and co-localization, single lab, single method for pathway placement\",\n      \"pmids\": [\"32331523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DKK4 CRD2 mediates high-affinity binding to both LRP6 E1E2 and the Kremen1 extracellular domain. DKK4 and Kremen1 function synergistically to inhibit Wnt signaling. The N-terminal region (CRD1) does not interact with Kremen proteins.\",\n      \"method\": \"Surface plasmon resonance, NMR structural analysis, Wnt reporter assay (synergy), domain-deletion binding experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR binding with NMR structural analysis and functional reporter assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29925589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Homozygous KREMEN1 p.F209S variant (in the extracellular WSC domain) causes autosomal recessive ectodermal dysplasia with oligodontia in Palestinian families, demonstrating that Kremen1 WSC domain function is required for normal ectodermal/dental development in humans.\",\n      \"method\": \"Exome sequencing, Sanger genotyping in 56 relatives, variant localization to WSC domain\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — human genetics identifying disease-causing variant with domain localization, no direct functional assay of the variant in this paper\",\n      \"pmids\": [\"27049303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Disease-associated KREMEN1 variants (Cys111Ser, Gly166Asp, Phe209Ser, Phe258_Pro259del) show reduced N- and O-glycosylation compared to wild type. These variants have reduced ability to form ternary complexes with DKK1 and LRP6 (though KREMEN1-LRP6 binary interaction is not impaired by missense variants). Patient fibroblasts show higher basal WNT activity and attenuated response to WNT3A stimulation.\",\n      \"method\": \"Ectopic expression in HEK293T cells, glycosylation analysis, co-immunoprecipitation of ternary and binary complexes, WNT pathway reporter assays in patient fibroblasts\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple disease variants tested with Co-IP and reporter assays, patient fibroblast validation, single lab\",\n      \"pmids\": [\"40553753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Kremen1 induces cell death with autophagic (rather than apoptotic) features when unbound by DKK1. Proximity labeling identified SEC24C (COP-II complex component) as a critical effector. Kremen1 is in proximity with SEC24C and ATG9A after vesicular trafficking; this fosters proximity of SEC24C with ATG8, ERGIC, and ATG9A, increasing autophagosomes and leading to cell death.\",\n      \"method\": \"Pharmacological inhibition of autophagy, genetic silencing of autophagy effectors, biotin proximity labeling (BioID/TurboID) for protein-protein interactions, functional cell death assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling with genetic validation of key effectors and pharmacological orthogonal approach, single lab\",\n      \"pmids\": [\"41807954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VP2 residue K140 (K2140) is completely conserved in all KRM1-dependent enteroviruses and is essential for KRM1 receptor recognition and infection by CVA2-CVA6, CVA10, CVA12, and CVA8. KRM1 residue D90 engages directly with K2140 to mediate receptor binding.\",\n      \"method\": \"Mutational analysis, viral binding and infection assays, in vivo mouse pathogenicity, receptor-identification assay for CVA8\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis across multiple viruses with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"39817751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DKK1 and Kremen1 are co-expressed and dynamically regulated in embryos and uterine stroma during the window of implantation. Antisense oligonucleotide knockdown of Kremen1 inhibits blastocyst adhesion and outgrowth on fibronectin in vitro, and DKK1 antisense injection into mouse uterine horns inhibits embryo implantation in vivo.\",\n      \"method\": \"Immunofluorescence/immunohistochemistry for co-expression, antisense ODN knockdown in vitro and in vivo, blastocyst adhesion assay\",\n      \"journal\": \"Fertility and sterility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined implantation phenotype in vitro and in vivo, single lab, limited mechanistic depth\",\n      \"pmids\": [\"18068158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Silencing Kremen1 with miR-431 prevents amyloid-β-mediated synapse loss (reduction in pre- and post-synaptic puncta) and neurite degeneration in cortico-hippocampal cultures from 3xTg-AD mice, demonstrating a required role for Kremen1 in DKK1/Aβ-induced synaptic degeneration.\",\n      \"method\": \"miRNA transfection (miR-431) targeting Kremen1, synaptic puncta quantification, neurite degeneration assay in primary neuronal cultures\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single miRNA knockdown approach in cell culture, indirect targeting of Kremen1 via miRNA, single lab\",\n      \"pmids\": [\"29643768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"KREMEN (KREMEN1) is a type-I transmembrane protein with a kringle domain, a WSC domain, and CUB domains in the extracellular region and no conserved signaling motif in its intracellular region. Its mRNA increases during embryonic development and during differentiation of C2C12 and NIE-115 cells into muscle and neural cells respectively.\",\n      \"method\": \"Kringle-SAGE cloning strategy, sequence/domain analysis, Northern blot expression analysis, in situ hybridization in mouse embryos\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — original molecular cloning with domain characterization and expression analysis, foundational structural annotation, single lab\",\n      \"pmids\": [\"11267660\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KREMEN1 is a type-I transmembrane protein with extracellular Kringle, WSC, and CUB domains that functions as a high-affinity receptor for DKK family proteins; in the presence of DKK1, it forms a ternary complex with DKK1 and LRP5/6 that is internalized via clathrin-mediated endocytosis (using an atypical dileucine cytoplasmic motif), thereby removing LRP5/6 from the cell surface and inhibiting canonical Wnt/β-catenin signaling; in the absence of DKK1, KREMEN1 can instead promote LRP6 surface localization and activate Wnt signaling, and additionally acts as a dependence receptor that triggers autophagic cell death (requiring homodimerization, SEC24C, and ATG9A) unless bound by DKK1—a Wnt-independent apoptotic/autophagic function encoded in a placental mammal-specific cytoplasmic motif; KREMEN1 also serves as the cellular entry receptor for multiple hand-foot-and-mouth disease enteroviruses (CV-A2–A6, A8, A10, A12) and as an alternative SARS-CoV-2 receptor, with the viral canyon-rim residue K140 and KREMEN1 residue D90 being key interaction determinants.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KREMEN1 is a type-I transmembrane protein with extracellular Kringle, WSC, and CUB domains that acts as a high-affinity receptor for DKK family ligands and a context-dependent modulator of Wnt/β-catenin signaling [#22, #0, #6]. In the presence of DKK1, KREMEN1 cooperates with DKK1 to assemble a ternary complex with the Wnt co-receptor LRP5/6, driving its rapid endocytosis and removal from the cell surface to antagonize Wnt signaling; structurally, DKK1 CRD2 is sandwiched between LRP6 and the KREMEN1 Kringle-WSC module, with the CUB domain contacting LRP6 [#0, #6, #15]. This internalization proceeds by clathrin-mediated endocytosis through an atypical dileucine (DXXXLV) motif in the cytoplasmic tail that engages AP-2 [#9]. KREMEN1's effect on Wnt is context-dependent: independent of DKKs it can bind LRP6, stabilize its surface localization, and promote Wnt signaling during neural crest induction, and it can also restrict the diffusion range of secreted Dkk proteins to shape Wnt activity non-cell-autonomously [#2, #12]. Beyond Wnt, KREMEN1 functions as a dependence receptor: in the absence of DKK1 it triggers ligand-withdrawal cell death through a placental-mammal-specific cytoplasmic motif that is genetically separable from its anti-Wnt function, requires homodimerization (inhibited by DKK1 binding and by KREMEN2 heterodimerization), and engages an autophagic effector route via SEC24C and ATG9A [#5, #10, #18]. These activities place KREMEN1 in developmental programs including thymic epithelial architecture, cochlear supporting-cell versus hair-cell fate, and embryo implantation [#4, #11, #20]. Homozygous KREMEN1 variants in the extracellular domain cause autosomal recessive ectodermal dysplasia with oligodontia, and disease variants show reduced glycosylation, impaired ternary-complex formation, and elevated basal Wnt activity [#16, #17]. Independently of its Wnt and death functions, KREMEN1 serves as a cell-entry receptor: it is a two-in-one attachment and uncoating receptor for a group of hand-foot-and-mouth disease enteroviruses (CV-A10 and related EV-A viruses, via viral residue K140 and KREMEN1 residue D90) and an ACE2-independent alternative receptor for SARS-CoV-2 [#7, #8, #19, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining KREMEN1 as a type-I transmembrane protein with a distinctive Kringle/WSC/CUB ectodomain and no recognized intracellular signaling motif established the structural framework for all later receptor functions.\",\n      \"evidence\": \"Kringle-SAGE cloning, domain/sequence analysis, and developmental expression profiling in mouse\",\n      \"pmids\": [\"11267660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand or functional partner identified at cloning\", \"Intracellular function undefined given absence of a canonical signaling motif\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of KREMEN1/2 as high-affinity DKK1 receptors that form a ternary complex with DKK1 and LRP6 and drive its endocytosis answered how DKK1 removes the Wnt co-receptor to antagonize Wnt signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, endocytosis assays, and Xenopus overexpression/rescue; complemented by morpholino knockdown showing roles in anteroposterior CNS patterning\",\n      \"pmids\": [\"12050670\", \"12421700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytic machinery used by KREMEN not yet defined\", \"Quantitative requirement for KREMEN versus DKK1/LRP6 ratios unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstration that Kremen2 can bind LRP6, promote its surface localization, and stimulate Wnt signaling independently of Dkks established that KREMEN's Wnt output is context-dependent rather than purely inhibitory.\",\n      \"evidence\": \"Morpholino knockdown, overexpression, and LRP6 surface localization/protein quantification in Xenopus neural crest explants\",\n      \"pmids\": [\"17978005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular switch between Wnt-promoting and Wnt-inhibiting modes not defined\", \"Whether KREMEN1 behaves identically to KREMEN2 in this mode untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping DKK1 residues (Arg197/Ser198/Lys232) required for Kremen binding to a surface distinct from the LRP6 site clarified that Kremen engagement is genetically separable from LRP6 binding and dispensable for Wnt antagonism except when LRP5/6 is highly expressed.\",\n      \"evidence\": \"Site-directed mutagenesis, binding and Wnt reporter assays, structural modeling on the DKK2 scaffold\",\n      \"pmids\": [\"18502762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Defines DKK1 determinants but not reciprocal KREMEN1 binding residues\", \"Physiological conditions where Kremen becomes essential not enumerated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Knockout phenotyping linked KREMEN1 loss to disrupted thymic epithelial architecture with elevated Wnt signaling, providing the first in vivo developmental requirement tied to its Wnt-modulating role.\",\n      \"evidence\": \"Knockout mouse analysis with TOPFlash reporter, FACS, and immunostaining of thymic epithelial cells\",\n      \"pmids\": [\"17162372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from Wnt elevation to epithelial defect not dissected\", \"Single-lab phenotype\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Co-expression and loss-of-function data placed KREMEN1 in embryo implantation, showing its requirement for blastocyst adhesion and outgrowth.\",\n      \"evidence\": \"Immunostaining co-expression, antisense ODN knockdown in vitro and in vivo, blastocyst adhesion assay\",\n      \"pmids\": [\"18068158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism (Wnt vs adhesion) underlying implantation defect unresolved\", \"Limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of an atypical dileucine (DXXXLV) motif mediating AP-2/clathrin-dependent internalization defined the endocytic mechanism by which KREMEN1 traffics from the cell surface.\",\n      \"evidence\": \"Mutagenesis of the endocytic motif, AP-2 siRNA, pitstop 2 inhibition, and surface internalization assays\",\n      \"pmids\": [\"23251700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the same motif governs DKK1/LRP6 ternary internalization untested\", \"Post-endocytic fate of KREMEN1 not tracked\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The finding that Kremen1 loss decreases Wnt signaling non-cell-autonomously by restricting Dkk diffusion revealed a function beyond LRP6 endocytosis: spatial control of secreted Dkk range.\",\n      \"evidence\": \"Zebrafish kremen1 mutant analysis, transplantation non-cell-autonomy test, and fluorescent Dkk1b fusion imaging in the lateral line primordium\",\n      \"pmids\": [\"25038040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of Dkk sequestration/diffusion limitation undefined\", \"Generality beyond the primordium unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that KREMEN1 acts as a dependence receptor triggering ligand-withdrawal cell death via a placental-mammal-specific cytoplasmic motif established a Wnt-independent pro-death function separable from its anti-Wnt activity.\",\n      \"evidence\": \"Whole-embryo culture, Wnt reporter assays, cytoplasmic-tail mutagenesis, and phylogenetic analysis\",\n      \"pmids\": [\"26206087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream death effectors not identified in this study\", \"Physiological contexts of dependence-receptor signaling unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystal structures of the rigid Kringle/WSC/CUB ectodomain and a ternary complex with LRP6 and DKK1 provided the atomic architecture of the inhibitory complex, including the DKK1 CRD2 sandwich and a CUB–LRP6 contact.\",\n      \"evidence\": \"X-ray crystallography of multiple constructs with SPR validation\",\n      \"pmids\": [\"27524201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ternary complex resolved only at low resolution\", \"Conformational basis of Wnt-promoting versus inhibiting modes not captured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Loss- and gain-of-function across mouse and zebrafish showed KREMEN1 biases inner-ear cells toward supporting-cell fate and suppresses hair-cell formation, extending its developmental remit to sensory cell-fate decisions.\",\n      \"evidence\": \"Overexpression, genetic/MO loss-of-function, immunolocalization, and hair-cell counting in cochlea and lateral line\",\n      \"pmids\": [\"27550540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether fate bias is Wnt-dependent not resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A homozygous WSC-domain variant (p.F209S) causing recessive ectodermal dysplasia with oligodontia established a human disease requirement for KREMEN1 ectodomain function in ectodermal/dental development.\",\n      \"evidence\": \"Exome sequencing and Sanger genotyping across 56 relatives in Palestinian families with domain localization\",\n      \"pmids\": [\"27049303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay of the variant in this study\", \"Molecular pathway connecting variant to dental phenotype not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of KREMEN1 as the entry receptor for CV-A10 and related EV-A enteroviruses revealed a function entirely distinct from Wnt biology, with in vivo protection in Kremen-deficient mice.\",\n      \"evidence\": \"Haploid genetic screen, CRISPR knockout, overexpression, soluble ectodomain neutralization, and KO mouse infection\",\n      \"pmids\": [\"29681460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of virus engagement not yet resolved at this stage\", \"Whether viral entry uses the same endocytic machinery as DKK1 unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extension of DKK–KREMEN1 binding to DKK4 (and biophysical mapping to CRD2) generalized the high-affinity ligand interaction across the DKK family and confirmed synergistic Wnt inhibition.\",\n      \"evidence\": \"SPR, NMR structural analysis, domain-deletion binding, and Wnt synergy reporter assays\",\n      \"pmids\": [\"29925589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of DKK4–KREMEN1 in vivo not addressed\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that KREMEN1 death signaling requires homodimerization—blocked by DKK1 and by KREMEN2 heterodimerization—defined the molecular switch controlling its dependence-receptor activity.\",\n      \"evidence\": \"Forced-dimerization constructs, KREMEN1/2 heterodimer Co-IP, and cell death assays\",\n      \"pmids\": [\"31069116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the homodimer interface unresolved\", \"How dimerization couples to downstream death machinery not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Structures of CV-A10–KRM1 complexes and the A-particle showed KREMEN1 spans the viral canyon, expels the pocket factor, and primes uncoating, defining KREMEN1 as a two-in-one attachment and uncoating receptor.\",\n      \"evidence\": \"Cryo-EM and X-ray crystallography of virus–receptor complexes plus an in vitro acidic-pH uncoating assay; independently replicated\",\n      \"pmids\": [\"31911601\", \"32690697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane events downstream of uncoating not resolved\", \"Receptor residues governing specificity not fully mapped at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placing Kremen-1 downstream of DKK3 in microglia identified a role in suppressing JNK/AP-1 neuroinflammation after intracerebral hemorrhage.\",\n      \"evidence\": \"In vivo Kremen-1 siRNA knockdown, Western blot, co-localization, and behavioral readouts\",\n      \"pmids\": [\"32331523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DKK3–KREMEN1 binding not demonstrated\", \"Pathway placement rests on a single in vivo knockdown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A genome-wide receptor screen established KREMEN1 as an ACE2-independent SARS-CoV-2 entry receptor that binds spike, broadening its viral-receptor repertoire to a coronavirus in a cell-type-dependent manner.\",\n      \"evidence\": \"Screen of 5054 membrane proteins, in vitro/in vivo entry assays, neutralizing antibody blockade, and lung organoid infection\",\n      \"pmids\": [\"34837059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spike–KREMEN1 interaction interface not structurally defined\", \"Relative in vivo contribution versus ACE2 unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Functional dissection of disease variants tied reduced glycosylation and impaired ternary-complex formation (with intact binary KREMEN1–LRP6 binding) to elevated basal Wnt activity, linking ectodermal dysplasia variants to a defined molecular defect.\",\n      \"evidence\": \"Ectopic expression, glycosylation analysis, ternary/binary Co-IP, and Wnt reporter assays in patient fibroblasts\",\n      \"pmids\": [\"40553753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the dependence-receptor function is also affected by these variants untested\", \"In vivo confirmation in patient tissue limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapping the conserved enterovirus VP2 K140 residue and its direct partner KREMEN1 D90 defined the molecular determinant of KRM1-dependent enterovirus recognition across CVA2–A6, A8, A10, and A12.\",\n      \"evidence\": \"Systematic mutagenesis, viral binding/infection assays, and in vivo mouse pathogenicity\",\n      \"pmids\": [\"39817751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the same residues govern SARS-CoV-2 binding not addressed\", \"Single-lab determination\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Proximity labeling reframed KREMEN1 ligand-withdrawal death as autophagic, identifying SEC24C and ATG9A as effectors that drive autophagosome accumulation, providing the downstream machinery for its dependence-receptor function.\",\n      \"evidence\": \"BioID/TurboID proximity labeling, genetic silencing of autophagy effectors, pharmacological autophagy inhibition, and cell death assays\",\n      \"pmids\": [\"41807954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How cytoplasmic-tail dimerization recruits SEC24C mechanistically unresolved\", \"Reconciliation of apoptotic versus autophagic death readouts pending\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KREMEN1 integrates its mutually distinct roles—Wnt modulation, dependence-receptor death, and viral entry—through a single ectodomain and a short cytoplasmic tail, and what governs the switch between Wnt-promoting and Wnt-inhibiting modes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking the ligand-bound, homodimeric, and virus-bound states\", \"Switch determinants between Wnt activation and inhibition undefined\", \"Endogenous regulators of dependence-receptor death poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [7, 8, 13, 19]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 15]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 22]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 11, 16, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 10, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 13, 16, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\"KREMEN1-DKK1-LRP6 ternary complex\"],\n    \"partners\": [\"DKK1\", \"LRP6\", \"KREMEN2\", \"DKK4\", \"SEC24C\", \"ATG9A\", \"AP-2\", \"DKK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}