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FLASH GENE

Symbol

DKK1

contributors: mct/npt/pgu - updated : 07-08-2018

HGNC name	dickkopf homolog 1 (Xenopus laevis)
HGNC id	2891

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed variant 1 4 - 1815 - 266 - 2008 19040566

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic spleen       lowly Digestive intestine large intestine colon   lowly   intestine small intestine     highly   liver         Endocrine thyroid       highly Nervous brain         Reproductive female system placenta     highly   male system prostate       Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central

cell lineage
cell lines
fluid/secretion	secreted

at STAGE

physiological period

embryo, pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	31 AA N terminal peptide
	two conserved cysteine rich domains, CYS1 and CYS2 (C-terminal CYS2 domain is able to bind to LRP6 and LRP5), and the second Cys-rich domains of DKK1 and DKK2 played a more important role in the inhibition of canonical Wnt signaling
	two clusters of ten cysteine residues separated by a linker region
	a potential C terminal N glycosylation site

conjugated

GlycoP

HOMOLOGY

interspecies

ortholog to head inducer in Xenopus laevis,secreted inducer of the Speeman's organizer

Homologene

FAMILY

dickkopf family

CATEGORY

regulatory , RNA associated

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
text	mesenchymal tissue

basic FUNCTION	potent inhibitor of Wnt signaling pathway and involved in embryonic development through its inhibition of the WNT signaling pathway
	regulating the spatial patterning/morphogenesis of the mammalian central nervous system
	mediating interactions between epithelial and mesenchymal cells
	may be able to antagonize Wnt signaling and exert its tumor suppressive effects through beta-catenin-independent non-canonical pathways (i.e., the Wnt/JNK pathway)
	required for the development of ischemic neuronal death
	plays a key role in the remodeling of joints by two mechanisms: impairing local bone formation, which is particularly deleterious in rheumatoid arthritis, and low levels of DKK1 appear to be crucial for the emergence of osteophytes
	antagonizes WNT signaling and plays essential roles in vertebrate embryogenesis including head induction, skeletal development, and limb patterning
	playing a role in modulating movements of internalization and rostral progression of the mesendoderm
	regulates gastrulation movement through interaction with LRP5/6 and coordinated modulations of Wnt/beta catenin and Wnt/planar cell polarity pathways
	with WNT3A, shunt LRP6 to distinct internalization pathways in order to activate and inhibit the beta-catenin signaling, respectively
	reduced the distribution of LRP6 in the lipid raft fraction where caveolin is associated
	contributes to the pathophysiology of ischemic neuronal damage
	induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling)
	potentially controls kidney papilla development coordinated by WNT7B signalling
	during eye development itself, retinal DKK1 activation is depending on cilia mediated GLI3 regulation
	distinct functions of DKK1 and DKK2 in controlling angiogenesis
	important roles for PROK1 and DKK1 during endometrial receptivity and early pregnancy, which include regulation of endometrial cell proliferation and decidualization
	potent inhibitor of Wnt/BETA-catenin signaling, and controls post-natal mandibular molar dentin formation either directly or indirectly via the inhibition of Wnt signaling
	functions as an inhibitor of Wnt signaling, which affects expression of numerous target genes that modulate ECM degradation, proliferation, apoptosis, transcription, and cell signaling
	plays an important role on skeletal development and bone remodeling
	blocks pericyte activation and transition to myofibroblasts and reverses myofibroblast activation, inhibiting fibrogenesis, capillary rarefaction, and inflammation
	DKK1 and DKK2 have differential roles in normalization and functionality of tumor blood vessels, in addition to angiogenesis

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

signal transduction

Wnt-beta catenin signaling pathway

a component

INTERACTION

DNA

RNA

small molecule

protein	binding KREMEN1, KREMEN2 (may not be essential for DKK1-mediated Wnt antagonism and may only play a role when cells express a high level of LRP5/6)
	WNT proteins
	binding by its C terminus and inducing removal of LRP6 from the plasma membrane, interaction inhibited by the N terminus of DKK1
	binds to LRP5/6 and induces its endocytosis, leading to inhibition of the canonical WNT pathway
	direct transcriptional target of RUNX2 in tooth development (stimulation by BMP4 before the formation of the ossification center, and necessary for bone formation)
	high affinity antagonistic ligand for LRP6 (inhibition of LRP6 is independent of LRP6 internalization and degradation)
	interacting with SFRP4 (DKK1 and SFRP4 perform an important function in adipogenesis in adipose tissue-derived mesenchymal stem cells)
	interact with LRP5 and LRP6 to modulate canonical Wnt signaling during development, and are known to be expressed in the developing heart
	interacting with ACVR1 (ACVR1 negatively regulates bone mass by suppressing Wnt signaling through SOST and DKK1)
	regulatory mechanism of DNAJB6-mediated DKK1 transcriptional up-regulation that can influence EMT (epithelial-mesenchymal transition)
	KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation, respectively
	is antifibrotic and anti-inflammatory by inhibiting multiple signaling pathways in pericytes and myofibroblasts through binding to the cell-surface receptors LRP-5/-6, which in turn act as coreceptors for multiple signaling pathways
	BMP2 decreases periosteal cell proliferation and induces apoptosis via the activation of Wnt inhibitors DKK1 and SOST
	DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment
	inhibition of MMP13 expression through GDF5 stimulation is mediated by DKK1
	WNT10B/DKK1 can modulate hair follicle size during hair regeneration
	OTX2 can interact with the H1 regulatory region of DKK1 to activate its expression
	KAT2A regulated DKK1 expression by acetylation of Histone H3 lysine 9 (H3K9) and Histone H3 lysine 14 (H3K14) at its promoter region
	AFF1 regulates the expression of DKK1 via binding to its promoter region
	ZBTB38 could repress cell migration and proliferation in prostate cancer via promoting DKK1 expression

cell & other

REGULATION

activated by

transiently in the early stages of adipogenesis

induced by

rapidly induced in neurons after induction of focal brain ischemia

Other

target of TP53

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in prostate carcinoma tumoral     --over   in bone marrow plasma and peripheral blood is associated with the presence of osteolytic bone lesions in multiple myeloma tumoral     --low   in colon cancer constitutional     --over   in arthritis is mediated by TNF-induced activation of MAPK14 signaling tumoral         in placental choriocarcinoma tumoral       loss of function contribute to epithelial ovarian cancer progression, metastasis, and chemoresistance

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer reproductive placenta target in treatment of placental choriocarcinomas cardiovascular     DKK1 antagonists or drugs that rescue the Wnt pathway might be neuroprotective in stroke cancer hemopathy   potentially important antigen for immunotherapy in multiple myeloma osteoarticular bone ostéoporosis sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair

ANIMAL & CELL MODELS

Dkk1-null mutant embryos display severe defects in head induction