Dickkopf
{{short description|Family of proteins}}
{{Infobox protein
| name = Dickkopf-related protein 1
| AltNames =
| image =
| width =
| caption =
| Symbol = DKK1
| AltSymbols =
| DrugBank =
| EntrezGene = 22943
| HGNCid = 2891
| OMIM = 605189
| PDB =
| RefSeq = NP_036374
| UniProt = O94907
| Chromosome = 10
| Arm = q
| Band = 21.1
| LocusSupplementaryData =
}}
{{Infobox protein
| name = Dickkopf-related protein 2
| AltNames =
| image =
| width =
| caption =
| Symbol = DKK2
| AltSymbols =
| DrugBank =
| EntrezGene = 27123
| HGNCid = 2892
| OMIM = 605415
| PDB =
| RefSeq = NP_055236
| UniProt = Q9UBU2
| Chromosome = 4
| Arm = q
| Band = 25
| LocusSupplementaryData =
}}
{{Infobox protein
| name = Dickkopf-related protein 3
| AltNames =
| image =
| width =
| caption =
| Symbol = DKK3
| AltSymbols =
| DrugBank =
| EntrezGene = 27122
| HGNCid = 2893
| OMIM = 605416
| PDB =
| RefSeq = NP_037385
| UniProt = Q9QUN9
| Chromosome = 11
| Arm = p
| Band = 15.3
| LocusSupplementaryData =
}}
{{Infobox protein
| name = Dickkopf-related protein 4
| AltNames =
| image =
| width =
| caption =
| Symbol = DKK4
| AltSymbols =
| EntrezGene = 27121
| HGNCid = 2894
| OMIM = 605417
| RefSeq = NP_055235
| UniProt = Q9UBT3
| Chromosome = 8
| Arm = p
| Band = 11.21
| LocusSupplementaryData =
}}
Dickkopf (DKK) is a family of proteins consisting of five members as of 2020. That is, vertebrates usually contain five genes that are members of the family. The most well-studied is Dickkopf-related protein 1 (DKK1).{{Cite journal| vauthors = Jackstadt R, Hodder MC, Sansom OJ |date=2020-03-09|title=WNT and β-Catenin in Cancer: Genes and Therapy|journal=Annual Review of Cancer Biology|language=en|volume=4|issue=1|pages=177–196|doi=10.1146/annurev-cancerbio-030419-033628|issn=2472-3428|doi-access=free}} DKK proteins inhibit the Wnt signaling pathway coreceptors LRP5 and LRP6. They bind with high affinity as ligands to KREMEN1 and KREMEN2, which are transmembrane proteins.{{cite journal | vauthors = Niehrs C | title = Function and biological roles of the Dickkopf family of Wnt modulators | journal = Oncogene | volume = 25 | issue = 57 | pages = 7469–81 | date = December 2006 | pmid = 17143291 | doi = 10.1038/sj.onc.1210054 | s2cid = 27082767 | doi-access = }} DKK proteins have important roles in the development of vertebrates.
Etymology
{{langx|de|Dickkopf|label=none}} is a German word meaning "stubborn person", or literally, "thick head". It was coined as the name for these proteins in a 1998 Nature paper by Glinka et al.{{cite journal|vauthors=Glinka A, etal|title=Dickkopf-1 is a Member of a New Family of Secreted Proteins and Functions in Head Induction|journal=Nature|date=22 January 1998|volume=391|issue=6665|pages=357–362 |doi=10.1038/34848|pmid=9450748 |bibcode=1998Natur.391..357G |s2cid=29306691 |issn=0028-0836|oclc=918993798}} in reference to the discovery that DKK1 induces head formation in the embryogenesis of Xenopus.{{cite journal|vauthors=Kagey MH, He X|title=Rationale for Targeting the Wnt Signalling Modulator Dickkopf-1 for Oncology|journal=British Journal of Pharmacology|date=December 2017|volume=174|issue=24|pages=4637–4650 |doi=10.1111/bph.13894|pmid=28574171 |issn=0007-1188|oclc=1167996437|pmc=5727329}}
Structure
DKK proteins are glycoproteins consisting of 255–350 amino acids. DKK1, DKK2, and DKK4 have similar molecular weights, at 24–29 kDa (kilodaltons). DKK3 is heaviest, at 38 kDa. In addition to having similar weights, DKK1, -2, and -4 have high structural similarity, with two shared cysteine-rich domains. DKK3 differs from -1, -2, and -4 by the presence of a Soggy domain at its N-terminus.{{cite journal | vauthors = Baetta R, Banfi C | title = Dkk (Dickkopf) Proteins | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 39 | issue = 7 | pages = 1330–1342 | date = July 2019 | pmid = 31092014 | doi = 10.1161/ATVBAHA.119.312612 | doi-access = free }}
Proteins
Four DKK proteins and one DKK-like protein occur in humans and other vertebrates,{{cite journal | vauthors = Patel S, Barkell AM, Gupta D, Strong SL, Bruton S, Muskett FW, Addis PW, Renshaw PS, Slocombe PM, Doyle C, Clargo A, Taylor RJ, Prosser CE, Henry AJ, Robinson MK, Waters LC, Holdsworth G, Carr MD | display-authors = 6 | title = Structural and functional analysis of Dickkopf 4 (Dkk4): New insights into Dkk evolution and regulation of Wnt signaling by Dkk and Kremen proteins | journal = The Journal of Biological Chemistry | volume = 293 | issue = 31 | pages = 12149–12166 | date = August 2018 | pmid = 29925589 | pmc = 6078440 | doi = 10.1074/jbc.RA118.002918 | doi-access = free }} with five proteins in the family in total:{{cite journal | vauthors = Shao YC, Wei Y, Liu JF, Xu XY | title = The role of Dickkopf family in cancers: from Bench to Bedside | journal = American Journal of Cancer Research | volume = 7 | issue = 9 | pages = 1754–1768 | date = 2017 | pmid = 28979801 | pmc = 5622213 }}
Human disease
DKK proteins are believed to be involved with several human diseases, including bone cancer and neurodegenerative disease. Evidence also indicates DKK1 and DKK3 are involved in the pathophysiology of the artery, where they could contribute to atherosclerosis.