Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene. [5]
Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene. [5]
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] DKK1 was also demonstrated to antagonize the Wnt/β-catenin pathway via a reduction in β-catenin and an increase in OCT4 expression. [9] This inhibition plays a key role in heart, head and forelimb development during anterior morphogenesis of the embryo. [5] [10]
DKK1 has been shown to interact with LRP6 [11] and is a high affinity ligand of Kremen proteins. [12]
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. [13] [14] [15]
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.
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. [16] DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate. [17]
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. [18] The Wnt signaling pathway is crucial for brain development processes, which include neuron proliferation and differentiation as well as neuroblast migration and axon guidance. [19] Downregulation of this signaling has been shown in those with Alzheimer's as a result of high levels of DKK1. [19] Because of the hyperphosphorylation induced by DKK1, tau cannot interact with neuronal microtubules consequently compromising axonal transport resulting in synaptic loss and neuronal apoptosis. [18] 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. [19]
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors.
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the CTNNB1 gene.
Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the GSK3B gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased susceptibility towards bipolar disorder.
Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. It's a member of T cell factor/lymphoid enhancer factor (TCF/LEF) family.
Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the WNT1 gene.
Frizzled-5(Fz-5) is a protein that in humans is encoded by the FZD5 gene.
Frizzled-7(Fd-7) is a protein that in humans is encoded by the FZD7 gene.
Frizzled-8(Fz-8) is a protein that in humans is encoded by the FZD8 gene.
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.
Dickkopf-related protein 3 is a protein in the Dickkopf family that in humans is encoded by the DKK3 gene.
Protein Wnt-7a is a protein that in humans is encoded by the WNT7A gene.
Wnt inhibitory factor 1 is a protein that in humans is encoded by the WIF1 gene. WIF1 is a lipid-binding protein that binds to Wnt proteins and prevents them from triggering signalling.
Dickkopf-related protein 2 is a protein in the Dickkopf family that in humans is encoded by the DKK2 gene.
R-spondin-1 is a secreted protein that in humans is encoded by the Rspo1 gene, found on chromosome 1. In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal. Furthermore, it promotes canonical WNT/β catenin signaling.
Kremen protein 1 is a protein that in humans is encoded by the KREMEN1 gene. Kremen1 is conserved in chordates including amphioxus and most vertebrate species. The protein is a type I transmembrane receptor of ligands Dickkopf1, Dickkopf2, Dickkopf3, Dickkopf4, EpCAM and Rspondin1.
Wingless-type MMTV integration site family, member 2, also known as WNT2, is a human gene.
Dickkopf (DKK) is a family of proteins consisting of five members as of 2020. The most well-studied is Dickkopf-related protein 1 (DKK1). 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. DKK proteins have important roles in the development of vertebrates.