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FLASH GENE
Symbol DKK1 contributors: mct/npt/pgu - updated : 07-08-2016
HGNC name dickkopf homolog 1 (Xenopus laevis)
HGNC id 2891
DNA
TYPE functioning gene
STRUCTURE 3.38 kb     4 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
cytosine-phosphate-guanine/HTF
Binding site
motif repetitive sequence   ALU   long interspersed repetitive elements
text structure
  • multiple beta-catenin/TCF4 sites in the promoter contributing to this activation
  • two GC-rich binding sites within this minimal region of DKK1 promoter were required for the DKK1 promoter activation by SP7
  • MAPPING cloned Y linked N status provisional
    Map cen- - D10S576 - D10S1416 - DKK1 - D10S107 - D10S1784 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 - 1815 - 266 - 2008 19040566
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   lowly
    Digestiveintestinelarge intestinecolon lowly
     intestinesmall intestine  highly
     liver    
    Endocrinethyroid   highly
    Nervousbrain    
    Reproductivefemale systemplacenta  highly
     male systemprostate   
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral   
    cell lineage
    cell lines
    fluid/secretion secreted
    at STAGE
    physiological period embryo, pregnancy
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • 31 AA N terminal peptide
  • two conserved cysteine rich domains, CYS1 and CYS2 (C-terminal CYS2 domain is able to bind to LRP6 and LRP5), and the second Cys-rich domains of DKK1 and DKK2 played a more important role in the inhibition of canonical Wnt signaling
  • two clusters of ten cysteine residues separated by a linker region
  • a potential C terminal N glycosylation site
  • conjugated GlycoP
    HOMOLOGY
    interspecies ortholog to head inducer in Xenopus laevis,secreted inducer of the Speeman's organizer
    Homologene
    FAMILY
  • dickkopf family
  • CATEGORY regulatory , RNA associated
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
    text mesenchymal tissue
    basic FUNCTION
  • potent inhibitor of Wnt signaling pathway and involved in embryonic development through its inhibition of the WNT signaling pathway
  • regulating the spatial patterning/morphogenesis of the mammalian central nervous system
  • mediating interactions between epithelial and mesenchymal cells
  • may be able to antagonize Wnt signaling and exert its tumor suppressive effects through beta-catenin-independent non-canonical pathways (i.e., the Wnt/JNK pathway)
  • required for the development of ischemic neuronal death
  • plays a key role in the remodeling of joints by two mechanisms: impairing local bone formation, which is particularly deleterious in rheumatoid arthritis, and low levels of DKK1 appear to be crucial for the emergence of osteophytes
  • antagonizes WNT signaling and plays essential roles in vertebrate embryogenesis including head induction, skeletal development, and limb patterning
  • playing a role in modulating movements of internalization and rostral progression of the mesendoderm
  • regulates gastrulation movement through interaction with LRP5/6 and coordinated modulations of Wnt/beta catenin and Wnt/planar cell polarity pathways
  • with WNT3A, shunt LRP6 to distinct internalization pathways in order to activate and inhibit the beta-catenin signaling, respectively
  • reduced the distribution of LRP6 in the lipid raft fraction where caveolin is associated
  • contributes to the pathophysiology of ischemic neuronal damage
  • induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling)
  • potentially controls kidney papilla development coordinated by WNT7B signalling
  • during eye development itself, retinal DKK1 activation is depending on cilia mediated GLI3 regulation
  • distinct functions of DKK1 and DKK2 in controlling angiogenesis
  • important roles for PROK1 and DKK1 during endometrial receptivity and early pregnancy, which include regulation of endometrial cell proliferation and decidualization
  • potent inhibitor of Wnt/BETA-catenin signaling, and controls post-natal mandibular molar dentin formation either directly or indirectly via the inhibition of Wnt signaling
  • functions as an inhibitor of Wnt signaling, which affects expression of numerous target genes that modulate ECM degradation, proliferation, apoptosis, transcription, and cell signaling
  • plays an important role on skeletal development and bone remodeling
  • blocks pericyte activation and transition to myofibroblasts and reverses myofibroblast activation, inhibiting fibrogenesis, capillary rarefaction, and inflammation
  • DKK1 and DKK2 have differential roles in normalization and functionality of tumor blood vessels, in addition to angiogenesis
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling signal transduction
    Wnt-beta catenin signaling pathway
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding KREMEN1, KREMEN2 (may not be essential for DKK1-mediated Wnt antagonism and may only play a role when cells express a high level of LRP5/6)
  • WNT proteins
  • binding by its C terminus and inducing removal of LRP6 from the plasma membrane, interaction inhibited by the N terminus of DKK1
  • binds to LRP5/6 and induces its endocytosis, leading to inhibition of the canonical WNT pathway
  • direct transcriptional target of RUNX2 in tooth development (stimulation by BMP4 before the formation of the ossification center, and necessary for bone formation)
  • high affinity antagonistic ligand for LRP6 (inhibition of LRP6 is independent of LRP6 internalization and degradation)
  • interacting with SFRP4 (DKK1 and SFRP4 perform an important function in adipogenesis in adipose tissue-derived mesenchymal stem cells)
  • interact with LRP5 and LRP6 to modulate canonical Wnt signaling during development, and are known to be expressed in the developing heart
  • interacting with ACVR1 (ACVR1 negatively regulates bone mass by suppressing Wnt signaling through SOST and DKK1)
  • regulatory mechanism of DNAJB6-mediated DKK1 transcriptional up-regulation that can influence EMT (epithelial-mesenchymal transition)
  • KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation, respectively
  • is antifibrotic and anti-inflammatory by inhibiting multiple signaling pathways in pericytes and myofibroblasts through binding to the cell-surface receptors LRP-5/-6, which in turn act as coreceptors for multiple signaling pathways
  • BMP2 decreases periosteal cell proliferation and induces apoptosis via the activation of Wnt inhibitors DKK1 and SOST
  • DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment
  • inhibition of MMP13 expression through GDF5 stimulation is mediated by DKK1
  • WNT10B/DKK1 can modulate hair follicle size during hair regeneration
  • OTX2 can interact with the H1 regulatory region of DKK1 to activate its expression
  • KAT2A regulated DKK1 expression by acetylation of Histone H3 lysine 9 (H3K9) and Histone H3 lysine 14 (H3K14) at its promoter region
  • AFF1 regulates the expression of DKK1 via binding to its promoter region
  • cell & other
    REGULATION
    activated by transiently in the early stages of adipogenesis
    induced by rapidly induced in neurons after induction of focal brain ischemia
    Other target of TP53
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in prostate carcinoma
    tumoral     --over  
    in bone marrow plasma and peripheral blood is associated with the presence of osteolytic bone lesions in multiple myeloma
    tumoral     --low  
    in colon cancer
    constitutional     --over  
    in arthritis is mediated by TNF-induced activation of MAPK14 signaling
    tumoral        
    in placental choriocarcinoma
    tumoral       loss of function
    contribute to epithelial ovarian cancer progression, metastasis, and chemoresistance
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductiveplacenta
    target in treatment of placental choriocarcinomas
    cardiovascular  
    DKK1 antagonists or drugs that rescue the Wnt pathway might be neuroprotective in stroke
    cancerhemopathy 
    potentially important antigen for immunotherapy in multiple myeloma
    osteoarticularboneostéoporosis
    sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair
    ANIMAL & CELL MODELS
    Dkk1-null mutant embryos display severe defects in head induction