粘菌、ショウジョウバエからヒトまで、進化上良く保存され、形態形成や生体の組織の維持、幹細胞の自己複製など、様々な生命現象に関わる。Wntシグナル伝達経路の異常はがんを含む様々な疾患の原因となる。ショウジョウバエwinglessとマウス乳癌ウイルスの挿入が高頻度に起こる遺伝子領域int-1が相同なことからWntと名づけられた。（ウイングレスシグナル伝達経路＿
20種類以上のファミリーからなる分泌タンパク質。受容体はFrizzledと呼ばれる。
Wntシグナルによりβカテニンが安定化し、核内に移行して転写因子と複合体を形成し、標的遺伝子の転写活性化を引き起こす。（カノニカル経路）
βカテニンはAPC, Axin, グリコーゲンシンターゼキナーゼ3β、カゼインキナーゼ１の複合体によりリン酸化され、ユビキチン化を受けて分解される。βカテニンの分解経路の異常はがん化の原因となる。
Proto-oncogene Wnt-1
Alternative name(s):
Proto-oncogene Int-1 homolog
Gene names
Name: WNT1
Synonyms: INT1
Function
Ligand for members of the frizzled family of seven transmembrane receptors. In some developmental processes, is also a ligand for the coreceptor RYK, thus triggering Wnt signaling. Probable developmental protein. May be a signaling molecule important in CNS development. Is likely to signal over only few cell diameters. Has a role in osteoblast function and bone development. Ref.6
Subunit structure
Interacts with PORCN. Interacts with RSPO1, RSPO2 and RSPO3 By similarity. Interacts with WLS By similarity.
Subcellular location
Secreted › extracellular space › extracellular matrix.
Post-translational modification
Palmitoylation at Ser-224 is required for efficient binding to frizzled receptors. It is also required for subsequent palmitoylation at Cys-93. Palmitoylation is necessary for proper trafficking to cell surface. Ref.5
Polymorphism
Genetic variations in WNT1 define the bone mineral density quantitative trait locus 16 (BMND16) [MIM:615221]. Variance in bone mineral density influences bone mass, contributes to size determination in the general population, and is a susceptibility factor for osteoporotic fractures.
Involvement in disease
Osteoporosis (OSTEOP) [MIM:166710]: A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.6 Ref.7
Osteogenesis imperfecta 15 (OI15) [MIM:615220]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI15 is characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclerae. Tooth development and hearing are normal. Learning and developmental delays and brain anomalies have been observed in some patients.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6 Ref.7 Ref.8 Ref.9
Sequence similarities
Belongs to the Wnt family.
Frizzled-4
Short name=Fz-4
Short name=hFz4
Alternative name(s):
FzE4
CD_antigen=CD344
Gene names
Name: FZD4
Function
Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.
Subunit structure
Interacts with MAGI3 and norrin (NDP). Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP) By similarity.
Subcellular location
Membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein By similarity.
Tissue specificity
Almost ubiquitous. Largely expressed in adult heart, skeletal muscle, ovary, and fetal kidney. Moderate amounts in adult liver, kidney, pancreas, spleen, and fetal lung, and small amounts in placenta, adult lung, prostate, testis, colon, fetal brain and liver.
Domain
Lys-Thr-X-X-X-Trp motif interacts with the PDZ doman of Dvl (Disheveled) family members and is involved in the activation of the Wnt/beta-catenin signaling pathway By similarity.
The FZ domain is involved in binding with Wnt ligands By similarity.
Post-translational modification
Ubiquitinated by ZNRF3, leading to its degradation by the proteasome. Ref.7
Involvement in disease
Vitreoretinopathy, exudative 1 (EVR1) [MIM:133780]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. In many ways the disease resembles retinopathy of prematurity but there is no evidence of prematurity or small birth weight in the patient history.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.18 Ref.19 Ref.20 Ref.21
Sequence similarities
Belongs to the G-protein coupled receptor Fz/Smo family.
Contains 1 FZ (frizzled) domain.
Segment polarity protein dishevelled homolog DVL-2
Short name=Dishevelled-2
Alternative name(s):
DSH homolog 2
Gene names
Name: DVL2
Function
Participates in Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors. Promotes internalization and degradation of frizzled proteins upon Wnt signaling. Plays a role both in canonical and non-canonical Wnt signaling. Plays a role in the signal transduction pathways mediated by multiple Wnt genes By similarity. Ref.13
Subunit structure
Interacts through its PDZ domain with the C-terminal regions of VANGL1 and VANGL2. Interacts with Rac. Interacts with ARRB1; the interaction is enhanced by phosphorylation of DVL1 By similarity. Can form large oligomers (via DIX domain). Interacts (via DIX domain) with DIXDC1 (via DIX domain). Interacts (via DEP domain) with AP2M1 and the AP-2 complex By similarity. Interacts with DACT1 and FAM105B/otulin. Ref.5 Ref.6 Ref.11 Ref.12
Subcellular location
Cell membrane; Peripheral membrane protein; Cytoplasmic side By similarity. Cytoplasm › cytosol By similarity. Cytoplasmic vesicle By similarity. Note: Localizes at the cell membrane upon interaction with frizzled family members and promotes their internalization. Localizes to cytoplasmic puncta By similarity. Ref.1
Domain
The DIX domain mediates homooligomerization By similarity.
Post-translational modification
Phosphorylated by CSNK1D. Ref.1 Ref.9
Sequence similarities
Belongs to the DSH family.
Contains 1 DEP domain.
Contains 1 DIX domain.
Contains 1 PDZ (DHR) domain.
