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DKK1

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DKK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDKK1, DKK-1, SK, dickkopf WNT signaling pathway inhibitor 1
External IDsOMIM: 605189; MGI: 1329040; HomoloGene: 7689; GeneCards: DKK1; OMA:DKK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

22943

13380

Ensembl

ENSG00000107984

ENSMUSG00000024868

UniProt

O94907

O54908

RefSeq (mRNA)

NM_012242

NM_010051

RefSeq (protein)

NP_036374

NP_034181

Location (UCSC)Chr 10: 52.31 – 52.32 MbChr 19: 30.52 – 30.53 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

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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 antagonist of the Wnt/β-catenin signalling pathway that acts by isolating the LRP6 co-receptor so that it cannot aid in activating the WNT signaling pathway.[8] This inhibition plays a key role in heart, head and forelimb development during anterior morphogenesis of the embryo.[5][9]

Interactions

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DKK1 has been shown to interact with LRP6[10] and is a high affinity ligand of Kremen proteins.[11]

Clinical significance

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Elevated levels of DKK1 in bone marrow, plasma and peripheral blood are associated with the presence of osteolytic bone lesions in patients with multiple myeloma.[5] Due to the role of DKK1 in inflammation induced bone loss DKK1 is under investigation as target for therapeutic strategies in medicine and dentistry.[12][13][14]

Animal studies

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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.

In vitro studies

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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.[15] DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate.[16]

DKK1 and Alzheimer's

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Alzheimer's disease occurs due to the overproduction of amyloid beta that will cluster together to form amyloid plaques between neurons in the brain and disrupt cell function. In addition, there is an accumulation of neurofibrillary tangles of hyperphosphorylated tau inside the neuron.[17] The Wnt signaling pathway is crucial for brain development processes, which include neuron proliferation and differentiation as well as neuroblast migration and axon guidance.[18] Downregulation of this signaling has been shown in those with Alzheimer's as a result of high levels of DKK1.[18] Because of the hyperphosphorylation induced by DKK1, tau cannot interact with neuronal microtubules consequently compromising axonal transport resulting in synaptic loss and neuronal apoptosis.[17] Because of its antagonistic effects on the Wnt signaling pathway, it is believed that DKK1 is a common marker for neuronal death in neurodegenerative diseases like Alzheimer's.[18]

References

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  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:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  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". Current Biology. 9 (15): 800–9. Bibcode:1999CBio....9..800S. doi:10.1016/s0960-9822(99)80363-7. PMID 10469564. S2CID 16744197.
  7. ^ a b Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, et al. (September 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, et al. (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. ^ Schneider VA, Mercola M (February 2001). "Wnt antagonism initiates cardiogenesis in Xenopus laevis". Genes & Development. 15 (3): 304–15. doi:10.1101/gad.855601. PMC 312618. PMID 11159911.
  10. ^ Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (June 2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Current Biology. 11 (12): 951–61. Bibcode:2001CBio...11..951S. doi:10.1016/S0960-9822(01)00290-1. PMID 11448771. S2CID 15702819.
  11. ^ Nakamura T, Nakamura T, Matsumoto K (April 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 3822531. PMID 18088386.
  12. ^ Samiei M, Janjić K, Cvikl B, Moritz A, Agis H (2019-01-30). "The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines". F1000Research. 8: 128. doi:10.12688/f1000research.17801.1. PMC 6468704. PMID 31031968.
  13. ^ Ke HZ, Richards WG, Li X, Ominsky MS (October 2012). "Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases". Endocrine Reviews. 33 (5): 747–83. doi:10.1210/er.2011-1060. PMID 22723863.
  14. ^ McCarthy HS, Marshall MJ (February 2010). "Dickkopf-1 as a potential therapeutic target in Paget's disease of bone". Expert Opinion on Therapeutic Targets. 14 (2): 221–30. doi:10.1517/14728220903525720. PMID 20055719. S2CID 23456886.
  15. ^ Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, et al. (February 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.
  16. ^ Kwack MH, Ahn JS, Kim MK, Kim JC, Sung YK (October 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.
  17. ^ a b Boonen RA, van Tijn P, Zivkovic D (April 2009). "Wnt signaling in Alzheimer's disease: up or down, that is the question". Ageing Research Reviews. 8 (2): 71–82. doi:10.1016/j.arr.2008.11.003. PMID 19101658. S2CID 24424543.
  18. ^ a b c Huang Y, Liu L, Liu A (September 2018). "Dickkopf-1: Current knowledge and related diseases". Life Sciences. 209: 249–254. doi:10.1016/j.lfs.2018.08.019. PMID 30102902. S2CID 51974340.

Further reading

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