Dickkopf

Dickkopf (DKK) is a family of proteins consisting of five members as of 2020. The most well-studied is Dickkopf-related protein 1 (DKK1).[1] 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.[2] DKK proteins have important roles in the development of vertebrates.[2]

Dickkopf-related protein 1
Identifiers
SymbolDKK1
NCBI gene22943
HGNC2891
OMIM605189
RefSeqNP_036374
UniProtO94907
Other data
LocusChr. 10 q21.1
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Dickkopf-related protein 2
Identifiers
SymbolDKK2
NCBI gene27123
HGNC2892
OMIM605415
RefSeqNP_055236
UniProtQ9UBU2
Other data
LocusChr. 4 q25
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DomainsInterPro
Dickkopf-related protein 3
Identifiers
SymbolDKK3
NCBI gene27122
HGNC2893
OMIM605416
RefSeqNP_037385
UniProtQ9QUN9
Other data
LocusChr. 11 p15.3
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Dickkopf-related protein 4
Identifiers
SymbolDKK4
NCBI gene27121
HGNC2894
OMIM605417
RefSeqNP_055235
UniProtQ9UBT3
Other data
LocusChr. 8 p11.21
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Etymology

Dickkopf 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.[3] in reference to the discovery that DKK1 induces head formation in the embryogenesis of Xenopus.[4]

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.[2] 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.[5]

Proteins

Four DKK proteins and one DKK-like protein occur in humans and other vertebrates,[6] with five proteins in the family in total:[7]

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.[5]

References
  1. Jackstadt R, Hodder MC, Sansom OJ (2020-03-09). "WNT and β-Catenin in Cancer: Genes and Therapy". Annual Review of Cancer Biology. 4 (1): 177–196. doi:10.1146/annurev-cancerbio-030419-033628. ISSN 2472-3428.
  2. Niehrs C (December 2006). "Function and biological roles of the Dickkopf family of Wnt modulators". Oncogene. 25 (57): 7469–81. doi:10.1038/sj.onc.1210054. PMID 17143291.
  3. Glinka A, et al. (22 January 1998). "Dickkopf-1 is a Member of a New Family of Secreted Proteins and Functions in Head Induction". Nature. 391 (6665). doi:10.1038/34848. ISSN 0028-0836. OCLC 918993798.
  4. Kagey MH, He X (December 2017). "Rationale for Targeting the Wnt Signalling Modulator Dickkopf-1 for Oncology". British Journal of Pharmacology. 174 (24). doi:10.1111/bph.13894. ISSN 0007-1188. OCLC 1167996437. PMC 5727329.
  5. Baetta R, Banfi C (July 2019). "Dkk (Dickkopf) Proteins". Arteriosclerosis, Thrombosis, and Vascular Biology. 39 (7): 1330–1342. doi:10.1161/ATVBAHA.119.312612. PMID 31092014.
  6. Patel S, Barkell AM, Gupta D, Strong SL, Bruton S, Muskett FW, et al. (August 2018). "Structural and functional analysis of Dickkopf 4 (Dkk4): New insights into Dkk evolution and regulation of Wnt signaling by Dkk and Kremen proteins". The Journal of Biological Chemistry. 293 (31): 12149–12166. doi:10.1074/jbc.RA118.002918. PMC 6078440. PMID 29925589.
  7. Shao YC, Wei Y, Liu JF, Xu XY (2017). "The role of Dickkopf family in cancers: from Bench to Bedside". American Journal of Cancer Research. 7 (9): 1754–1768. PMC 5622213. PMID 28979801.
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