Affinage

KREMEN1

Kremen protein 1 · UniProt Q96MU8

Length
473 aa
Mass
51.7 kDa
Annotated
2026-06-10
38 papers in source corpus 24 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 Medium

    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

    PMID:11267660

    Open questions at the time
    • No ligand or functional partner identified at cloning
    • Intracellular function undefined given absence of a canonical signaling motif
  2. 2002 High

    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

    PMID:12050670 PMID:12421700

    Open questions at the time
    • Endocytic machinery used by KREMEN not yet defined
    • Quantitative requirement for KREMEN versus DKK1/LRP6 ratios unresolved
  3. 2007 High

    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

    PMID:17978005

    Open questions at the time
    • Molecular switch between Wnt-promoting and Wnt-inhibiting modes not defined
    • Whether KREMEN1 behaves identically to KREMEN2 in this mode untested
  4. 2008 High

    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

    PMID:18502762

    Open questions at the time
    • Defines DKK1 determinants but not reciprocal KREMEN1 binding residues
    • Physiological conditions where Kremen becomes essential not enumerated
  5. 2006 Medium

    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

    PMID:17162372

    Open questions at the time
    • Causal chain from Wnt elevation to epithelial defect not dissected
    • Single-lab phenotype
  6. 2008 Medium

    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

    PMID:18068158

    Open questions at the time
    • Mechanism (Wnt vs adhesion) underlying implantation defect unresolved
    • Limited mechanistic depth
  7. 2012 Medium

    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

    PMID:23251700

    Open questions at the time
    • Whether the same motif governs DKK1/LRP6 ternary internalization untested
    • Post-endocytic fate of KREMEN1 not tracked
  8. 2014 Medium

    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

    PMID:25038040

    Open questions at the time
    • Molecular basis of Dkk sequestration/diffusion limitation undefined
    • Generality beyond the primordium unknown
  9. 2015 High

    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

    PMID:26206087

    Open questions at the time
    • Downstream death effectors not identified in this study
    • Physiological contexts of dependence-receptor signaling unclear
  10. 2016 High

    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

    PMID:27524201

    Open questions at the time
    • Ternary complex resolved only at low resolution
    • Conformational basis of Wnt-promoting versus inhibiting modes not captured
  11. 2016 Medium

    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

    PMID:27550540

    Open questions at the time
    • Whether fate bias is Wnt-dependent not resolved
    • Single-lab finding
  12. 2016 Medium

    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

    PMID:27049303

    Open questions at the time
    • No functional assay of the variant in this study
    • Molecular pathway connecting variant to dental phenotype not shown
  13. 2018 High

    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

    PMID:29681460

    Open questions at the time
    • Structural basis of virus engagement not yet resolved at this stage
    • Whether viral entry uses the same endocytic machinery as DKK1 unknown
  14. 2018 Medium

    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

    PMID:29925589

    Open questions at the time
    • Functional roles of DKK4–KREMEN1 in vivo not addressed
    • Single-lab biochemistry
  15. 2019 Medium

    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

    PMID:31069116

    Open questions at the time
    • Structural basis of the homodimer interface unresolved
    • How dimerization couples to downstream death machinery not shown
  16. 2020 High

    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

    PMID:31911601 PMID:32690697

    Open questions at the time
    • Membrane events downstream of uncoating not resolved
    • Receptor residues governing specificity not fully mapped at this stage
  17. 2020 Medium

    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

    PMID:32331523

    Open questions at the time
    • Direct DKK3–KREMEN1 binding not demonstrated
    • Pathway placement rests on a single in vivo knockdown
  18. 2021 High

    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

    PMID:34837059

    Open questions at the time
    • Spike–KREMEN1 interaction interface not structurally defined
    • Relative in vivo contribution versus ACE2 unclear
  19. 2025 Medium

    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

    PMID:40553753

    Open questions at the time
    • Whether the dependence-receptor function is also affected by these variants untested
    • In vivo confirmation in patient tissue limited
  20. 2025 Medium

    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

    PMID:39817751

    Open questions at the time
    • Whether the same residues govern SARS-CoV-2 binding not addressed
    • Single-lab determination
  21. 2026 Medium

    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

    PMID:41807954

    Open questions at the time
    • How cytoplasmic-tail dimerization recruits SEC24C mechanistically unresolved
    • Reconciliation of apoptotic versus autophagic death readouts pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0038024 cargo receptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 1
Partners
AP-2ATG9ADKK1DKK3DKK4KREMEN2LRP6SEC24C
Complex memberships
KREMEN1-DKK1-LRP6 ternary complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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. Co-immunoprecipitation, endocytosis assays, Xenopus embryo overexpression/rescue experiments, binding assays Nature High 12050670
2002 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. Antisense morpholino knockdown, axis duplication assays, antibody rescue experiments, Xenopus embryology Development (Cambridge, England) High 12421700
2007 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. Morpholino knockdown, overexpression, cell-surface localization assays, LRP6 protein quantification in explants Development (Cambridge, England) High 17978005
2008 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. Site-directed mutagenesis, binding assays, Wnt signaling reporter assays, 3D structural modeling based on DKK2 structure The Journal of biological chemistry High 18502762
2006 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. Knockout mouse analysis, TOPFlash Wnt reporter assay, FACS, immunostaining Clinical & developmental immunology Medium 17162372
2015 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. Whole embryo culture, Wnt-activity reporter assays, mutagenesis of cytoplasmic tail, phylogenetic analysis, loss-of-function experiments Cell death and differentiation High 26206087
2016 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. X-ray crystallography (multiple structures), surface plasmon resonance, structural modeling Structure (London, England : 1993) High 27524201
2018 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. Haploid genetic screen, CRISPR/loss-of-function, overexpression, soluble ectodomain neutralization assay, Kremen-knockout mouse infection model Cell host & microbe High 29681460
2020 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. Cryo-EM and X-ray crystallography, in vitro uncoating assay at acidic pH Nature communications High 31911601 32690697
2012 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. Site-directed mutagenesis of endocytic motif, siRNA knockdown of AP-2, pharmacological clathrin inhibition, cell-surface internalization assays PloS one Medium 23251700
2019 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. Dimerization assays, forced dimerization constructs, co-immunoprecipitation of Kremen1/Kremen2 heterodimers, cell death assays Cell death discovery Medium 31069116
2016 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. Gain-of-function overexpression, loss-of-function (genetic/MO), immunolocalization, hair cell counting in mouse cochlea and zebrafish lateral line Scientific reports Medium 27550540
2014 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. Zebrafish kremen1 mutant analysis, transplantation rescue assay (non-cell-autonomy test), fluorescent Dkk1b fusion protein imaging Development (Cambridge, England) Medium 25038040
2021 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. Genome-wide receptor screen (5054 membrane proteins), viral entry assays (in vitro and in vivo), neutralizing antibody blockade, human lung organoid infection Cell research High 34837059
2020 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. siRNA knockdown in vivo, Western blot, immunofluorescence co-localization, behavioral neuroscience readouts Journal of neuroinflammation Medium 32331523
2018 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. Surface plasmon resonance, NMR structural analysis, Wnt reporter assay (synergy), domain-deletion binding experiments The Journal of biological chemistry Medium 29925589
2016 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. Exome sequencing, Sanger genotyping in 56 relatives, variant localization to WSC domain European journal of human genetics : EJHG Medium 27049303
2025 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. Ectopic expression in HEK293T cells, glycosylation analysis, co-immunoprecipitation of ternary and binary complexes, WNT pathway reporter assays in patient fibroblasts The Journal of investigative dermatology Medium 40553753
2026 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. Pharmacological inhibition of autophagy, genetic silencing of autophagy effectors, biotin proximity labeling (BioID/TurboID) for protein-protein interactions, functional cell death assays Cell communication and signaling : CCS Medium 41807954
2025 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. Mutational analysis, viral binding and infection assays, in vivo mouse pathogenicity, receptor-identification assay for CVA8 mBio Medium 39817751
2008 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. Immunofluorescence/immunohistochemistry for co-expression, antisense ODN knockdown in vitro and in vivo, blastocyst adhesion assay Fertility and sterility Medium 18068158
2018 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. miRNA transfection (miR-431) targeting Kremen1, synaptic puncta quantification, neurite degeneration assay in primary neuronal cultures Frontiers in cellular neuroscience Low 29643768
2001 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. Kringle-SAGE cloning strategy, sequence/domain analysis, Northern blot expression analysis, in situ hybridization in mouse embryos Biochimica et biophysica acta Medium 11267660

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 885 12050670
2021 Receptome profiling identifies KREMEN1 and ASGR1 as alternative functional receptors of SARS-CoV-2. Cell research 150 34837059
2002 Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning. Development (Cambridge, England) 105 12421700
2008 Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism. The Journal of biological chemistry 75 18502762
2018 KREMEN1 Is a Host Entry Receptor for a Major Group of Enteroviruses. Cell host & microbe 74 29681460
2007 Kremen is required for neural crest induction in Xenopus and promotes LRP6-mediated Wnt signaling. Development (Cambridge, England) 74 17978005
2019 Knockdown of lncRNA SNHG1 attenuated Aβ25-35-inudced neuronal injury via regulating KREMEN1 by acting as a ceRNA of miR-137 in neuronal cells. Biochemical and biophysical research communications 64 31447119
2006 The Wnt signaling antagonist Kremen1 is required for development of thymic architecture. Clinical & developmental immunology 61 17162372
2010 Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2. PloS one 52 20436912
2007 The functions and possible significance of Kremen as the gatekeeper of Wnt signalling in development and pathology. Journal of cellular and molecular medicine 51 18088386
2018 miRNA-431 Prevents Amyloid-β-Induced Synapse Loss in Neuronal Cell Culture Model of Alzheimer's Disease by Silencing Kremen1. Frontiers in cellular neuroscience 45 29643768
2001 Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein. Biochimica et biophysica acta 45 11267660
2008 Context-dependent activation or inhibition of Wnt-beta-catenin signaling by Kremen. Science signaling 43 18314504
2015 Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner. Cell death and differentiation 42 26206087
2020 Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10. Nature communications 35 31911601
2016 Structure of the Dual-Mode Wnt Regulator Kremen1 and Insight into Ternary Complex Formation with LRP6 and Dickkopf. Structure (London, England : 1993) 32 27524201
2020 Molecular basis of Coxsackievirus A10 entry using the two-in-one attachment and uncoating receptor KRM1. Proceedings of the National Academy of Sciences of the United States of America 29 32690697
2018 DKK1 and Kremen Expression Predicts the Osteoblastic Response to Bone Metastasis. Translational oncology 29 29772510
2020 DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage. Journal of neuroinflammation 26 32331523
2018 Structural and functional analysis of Dickkopf 4 (Dkk4): New insights into Dkk evolution and regulation of Wnt signaling by Dkk and Kremen proteins. The Journal of biological chemistry 26 29925589
2016 Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families. European journal of human genetics : EJHG 26 27049303
2019 Kremen1-induced cell death is regulated by homo- and heterodimerization. Cell death discovery 21 31069116
2016 Kremen1 regulates mechanosensory hair cell development in the mammalian cochlea and the zebrafish lateral line. Scientific reports 21 27550540
2010 Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population. Schizophrenia research 18 20153141
2012 High-affinity Dkk1 receptor Kremen1 is internalized by clathrin-mediated endocytosis. PloS one 17 23251700
2008 Roles of Dickkopf-1 and its receptor Kremen1 during embryonic implantation in mice. Fertility and sterility 15 18068158
2024 Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions. Experimental & molecular medicine 12 38945954
2014 Kremen1 restricts Dkk activity during posterior lateral line development in zebrafish. Development (Cambridge, England) 11 25038040
2010 Embryonic expression and evolutionary analysis of the amphioxus Dickkopf and Kremen family genes. Journal of genetics and genomics = Yi chuan xue bao 8 20933216
2023 VP2 residue N142 of coxsackievirus A10 is critical for the interaction with KREMEN1 receptor and neutralizing antibodies and the pathogenicity in mice. PLoS pathogens 7 37788227
2025 Completely conserved VP2 residue K140 of KREMEN1-dependent enteroviruses is critical for virus-receptor interactions and viral infection. mBio 6 39817751
2023 Kremen1 regulates the regenerative capacity of support cells and mechanosensory hair cells in the zebrafish lateral line. iScience 4 38205258
2025 Construction of a Vero cell line expression human KREMEN1 for the development of CVA6 vaccines. Virology journal 3 39825444
2025 KREMEN1 Variants Associated with Ectodermal Dysplasia Impair Complex Formation of KREMEN1 with DKK1 and LRP6 and Attenuate WNT3A Response. The Journal of investigative dermatology 1 40553753
2023 Kremen1 regulates the regenerative capacity of support cells and mechanosensory hair cells in the zebrafish lateral line. bioRxiv : the preprint server for biology 1 37546780
2023 Presence of KREMEN receptors for DKK1 in the preimplantation bovine embryo. Reproduction & fertility 1 37582174
2026 Kremen1 dependence receptor induces SEC24C and ATG9A-dependent cell death. Cell communication and signaling : CCS 0 41807954
2026 Quantitative Analysis of Protein-Receptor Binding Using Solid-State Nanopores: Accurate Measurement of Dissociation Constants for KREMEN1 and ASGR1 with SARS-CoV-2 Spike RBD Protein. The journal of physical chemistry. B 0 42144848

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