DKK1

Dickkopf WNT signaling pathway inhibitor 1
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3S2K​, 3S8V​, 3SOQ​
Identifiers
Symbols	DKK1 ; DKK-1; SK
External IDs	OMIM: 605189 MGI: 1329040 HomoloGene: 7689 ChEMBL: 6024 GeneCards: DKK1 Gene
Gene ontology Molecular function • signal transducer activity • protein binding • growth factor activity • receptor antagonist activity • low-density lipoprotein particle receptor binding Cellular component • extracellular region • extracellular space • plasma membrane • early endosome membrane Biological process • negative regulation of transcription from RNA polymerase II promoter • cell morphogenesis involved in differentiation • endoderm formation • mesoderm formation • hair follicle development • regulation of receptor internalization • negative regulation of Wnt signaling pathway • embryonic limb morphogenesis • negative regulation of BMP signaling pathway • forebrain development • negative regulation of protein complex assembly • response to retinoic acid • negative regulation of peptidyl-serine phosphorylation • negative regulation of mesodermal cell fate specification • regulation of endodermal cell fate specification • negative regulation of skeletal muscle tissue development • face morphogenesis • negative regulation of pathway-restricted SMAD protein phosphorylation • positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway • negative regulation of canonical Wnt signaling pathway • Wnt signaling pathway involved in somitogenesis • extracellular negative regulation of signal transduction • negative regulation of canonical Wnt signaling pathway involved in cardiac muscle cell fate commitment • negative regulation of cardiac muscle cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
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 Mb	Chr 19: 30.55 – 30.55 Mb
PubMed search

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

Function

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.^[2][3] 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.^[4] DKK1 was also demonstrated to antagonize the Wnt/β-catenin pathway via a reduction in β-catenin and an increase in OCT4 expression.^[5] This inhibition plays a key role in heart, head and forelimb development during anterior morphogenesis of the embryo.^[1][6]

Interactions

DKK1 has been shown to interact with LRP6.^[7]

Clinical significance

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.^[1]

Animal studies

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.^[3] 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 body against DKK-1 reversed DHT effects on outer root sheath keratinocytes.^[8] DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate.^[9]

References

1. "Entrez Gene: DKK1 dickkopf homolog 1 (Xenopus laevis)".
2. 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.
3. 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.
4. 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.
5. 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 4686056. PMID 26648540.
6. Schneider VA, Mercola M (2001). "Wnt antagonism initiates cardiogenesis in Xenopus laevis". Genes Dev 15: 304–315. doi:10.1101/gad.855601.
7. 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.
8. 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.
9. 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

• Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP, Kraus MH, Aaronson SA (Jul 1999). "Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling". The Journal of Biological Chemistry 274 (27): 19465–72. doi:10.1074/jbc.274.27.19465. PMID 10383463.
• Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L, Brown DE, Guyot D, Mays G, Leiby K, Chang B, Duong T, Goodearl AD, Gearing DP, Sokol SY, McCarthy SA (Oct 1999). "Functional and structural diversity of the human Dickkopf gene family". Gene 238 (2): 301–13. doi:10.1016/S0378-1119(99)00365-0. PMID 10570958.
• Roessler E, Du Y, Glinka A, Dutra A, Niehrs C, Muenke M (2000). "The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly". Cytogenetics and Cell Genetics 89 (3-4): 220–4. doi:10.1159/000015618. PMID 10965128.
• Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C (May 2001). "LDL-receptor-related protein 6 is a receptor for Dickkopf proteins". Nature 411 (6835): 321–5. doi:10.1038/35077108. PMID 11357136.
• 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.
• Zorn AM (Aug 2001). "Wnt signalling: antagonistic Dickkopfs". Current Biology 11 (15): R592–5. doi:10.1016/S0960-9822(01)00360-8. PMID 11516963.
• Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS (Jan 2002). "Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA". Oncogene 21 (6): 878–89. doi:10.1038/sj.onc.1205138. PMID 11840333.
• Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, Glinka A, Niehrs C (Jun 2002). "Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling". Nature 417 (6889): 664–7. doi:10.1038/nature756. PMID 12050670.
• Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, García JM, Muñoz A, Esteller M, González-Sancho JM (Jul 2006). "Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer". Oncogene 25 (29): 4116–21. doi:10.1038/sj.onc.1209439. PMID 16491118.
• Brott BK, Sokol SY (Sep 2002). "Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins". Molecular and Cellular Biology 22 (17): 6100–10. doi:10.1128/MCB.22.17.6100-6110.2002. PMC 133995. PMID 12167704.
• Gregory CA, Singh H, Perry AS, Prockop DJ (Jul 2003). "The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow". The Journal of Biological Chemistry 278 (30): 28067–78. doi:10.1074/jbc.M300373200. PMID 12740383.
• Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD (Dec 2003). "The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma". The New England Journal of Medicine 349 (26): 2483–94. doi:10.1056/NEJMoa030847. PMID 14695408.
• Yamaguchi Y, Itami S, Watabe H, Yasumoto K, Abdel-Malek ZA, Kubo T, Rouzaud F, Tanemura A, Yoshikawa K, Hearing VJ (Apr 2004). "Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation". The Journal of Cell Biology 165 (2): 275–85. doi:10.1083/jcb.200311122. PMC 2172049. PMID 15117970.
• Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F (Jun 2004). "Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain". The Journal of Neuroscience 24 (26): 6021–7. doi:10.1523/JNEUROSCI.1381-04.2004. PMID 15229249.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM (Jul 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Zhang Z, Henzel WJ (Oct 2004). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Science 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
• Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, Sugano S, Akiyama T (Nov 2004). "DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway". Oncogene 23 (52): 8520–6. doi:10.1038/sj.onc.1207892. PMID 15378020.
• Lee AY, He B, You L, Xu Z, Mazieres J, Reguart N, Mikami I, Batra S, Jablons DM (Oct 2004). "Dickkopf-1 antagonizes Wnt signaling independent of beta-catenin in human mesothelioma". Biochemical and Biophysical Research Communications 323 (4): 1246–50. doi:10.1016/j.bbrc.2004.09.001. PMID 15451431.