DKK1

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DKK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDKK1, DKK-1, SK, dickkopf WNT signaling pathway inhibitor 1
External IDsMGI: 1329040 HomoloGene: 7689 GeneCards: DKK1
Gene location (Human)
Chromosome 10 (human)
Chr.Chromosome 10 (human)[1]
Chromosome 10 (human)
Genomic location for DKK1
Genomic location for DKK1
Band10q21.1Start52,314,296 bp[1]
End52,318,042 bp[1]
RNA expression pattern
PBB GE DKK1 204602 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_012242

NM_010051

RefSeq (protein)

NP_036374

NP_034181

Location (UCSC)Chr 10: 52.31 – 52.32 MbChr 19: 30.55 – 30.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.[5]

Function[edit]

This gene encodes a protein that is a member of the dickkopf family. It is a secreted protein with two cysteine rich regions and is involved in embryonic development through its inhibition of the Wnt signaling pathway. Dickkopf WNT signaling pathway inhibitor 1 (Dkk1) is a protein-coding gene that acts from the anterior visceral endoderm.[6][7] The dickkopf protein encoded by DKK1 is an antagonistic inhibitor of the WNT signaling pathway that acts by isolating the LRP6 co-receptor so that it cannot aid in activating the WNT signaling pathway.[8] DKK1 was also demonstrated to antagonize the Wnt/β-catenin pathway via a reduction in β-catenin and an increase in OCT4 expression.[9] This inhibition plays a key role in heart, head and forelimb development during anterior morphogenesis of the embryo.[5][10]

Interactions[edit]

DKK1 has been shown to interact with LRP6[11] and is a high affinity ligand of Kremen proteins.[12]

Clinical significance[edit]

Elevated levels of DKK1 in bone marrow, plasma and peripheral blood is associated with the presence of osteolytic bone lesions in patients with multiple myeloma.[5]

Animal studies[edit]

Scientists have created a DKK1 knockout model in mice that revealed the effects of this gene. All mice that were homozygous for the DKK1 knockout were dead at birth due to defects in the cranium and structures formed by the neural crest, such as failed development of eyes, olfactory placodes, frontonasal mass and mandibular processes, as well as incomplete development of the forebrain and midbrain and fusion of the digits of the forelimb.[7] This evidence supports the idea that inhibition of the Wnt signaling pathway by DKK1 is crucial to proper cranial development.

DKK1 is one of the most upregulated genes in androgen-potentiated balding, with DKK-1 messenger RNA upregulated a few hours after DHT treatment of hair follicles at the dermal papilla in vitro. Neutralizing antibody against DKK-1 reversed DHT effects on outer root sheath keratinocytes.[13] DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate.[14]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000107984 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024868 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ a b c "Entrez Gene: DKK1 dickkopf homolog 1 (Xenopus laevis)". 
  6. ^ Schneider VA, Mercola M (1999). "Spatially distinct head and heart inducers within the Xenopus organizer region". Curr Biol. 9: 800–809. doi:10.1016/s0960-9822(99)80363-7. 
  7. ^ a b Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, Dorward DW, Glinka A, Grinberg A, Huang SP, Niehrs C, Izpisúa Belmonte JC, Westphal H (Sep 2001). "Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse". Developmental Cell. 1 (3): 423–34. doi:10.1016/s1534-5807(01)00041-7. PMID 11702953. 
  8. ^ Lewis SL, Khoo PL, De Young RA, Steiner K, Wilcock C, Mukhopadhyay M, Westphal H, Jamieson RV, Robb L, Tam PP (May 2008). "Dkk1 and Wnt3 interact to control head morphogenesis in the mouse". Development. 135 (10): 1791–801. doi:10.1242/dev.018853. PMID 18403408. 
  9. ^ Ou L, Fang L, Tang H, Qiao H, Zhang X, Wang Z (Jan 2016). "Dickkopf Wnt signaling pathway inhibitor 1 regulates the differentiation of mouse embryonic stem cells in vitro and in vivo". Molecular Medicine Reports. 13 (1): 720–30. doi:10.3892/mmr.2015.4586. PMC 4686056Freely accessible. PMID 26648540. 
  10. ^ Schneider VA, Mercola M (2001). "Wnt antagonism initiates cardiogenesis in Xenopus laevis". Genes Dev. 15: 304–315. doi:10.1101/gad.855601. PMC 312618Freely accessible. PMID 11159911. 
  11. ^ Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (Jun 2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Current Biology. 11 (12): 951–61. doi:10.1016/S0960-9822(01)00290-1. PMID 11448771. 
  12. ^ Nakamura T, Nakamura T, Matsumoto K (2008). "The functions and possible significance of Kremen as the gatekeeper of Wnt signalling in development and pathology". Journal of Cellular and Molecular Medicine. 12 (2): 391–408. doi:10.1111/j.1582-4934.2007.00201.x. PMC 3822531Freely accessible. PMID 18088386. 
  13. ^ Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, Kim JC (Feb 2008). "Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes". The Journal of Investigative Dermatology. 128 (2): 262–9. doi:10.1038/sj.jid.5700999. PMID 17657240. 
  14. ^ Kwack MH, Ahn JS, Kim MK, Kim JC, Sung YK (Oct 2010). "Preventable effect of L-threonate, an ascorbate metabolite, on androgen-driven balding via repression of dihydrotestosterone-induced dickkopf-1 expression in human hair dermal papilla cells". BMB Reports. 43 (10): 688–92. doi:10.5483/BMBRep.2010.43.10.688. PMID 21034532. 

Further reading[edit]