Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Frizzled-4

Gene

FZD4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, G-protein coupled receptor, Receptor, Transducer
Biological processWnt signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-373080 Class B/2 (Secretin family receptors)
R-HSA-4086398 Ca2+ pathway
R-HSA-4608870 Asymmetric localization of PCP proteins
R-HSA-4641263 Regulation of FZD by ubiquitination
R-HSA-5099900 WNT5A-dependent internalization of FZD4
R-HSA-5340588 RNF mutants show enhanced WNT signaling and proliferation
R-HSA-8856825 Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828 Clathrin-mediated endocytosis
SignaLinkiQ9ULV1
SIGNORiQ9ULV1

Names & Taxonomyi

Protein namesi
Recommended name:
Frizzled-4
Short name:
Fz-4
Short name:
hFz4
Alternative name(s):
FzE4
CD_antigen: CD344
Gene namesi
Name:FZD4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000174804.3
HGNCiHGNC:4042 FZD4
MIMi604579 gene
neXtProtiNX_Q9ULV1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini37 – 222ExtracellularSequence analysisAdd BLAST186
Transmembranei223 – 243Helical; Name=1Sequence analysisAdd BLAST21
Topological domaini244 – 254CytoplasmicSequence analysisAdd BLAST11
Transmembranei255 – 275Helical; Name=2Sequence analysisAdd BLAST21
Topological domaini276 – 302ExtracellularSequence analysisAdd BLAST27
Transmembranei303 – 323Helical; Name=3Sequence analysisAdd BLAST21
Topological domaini324 – 344CytoplasmicSequence analysisAdd BLAST21
Transmembranei345 – 365Helical; Name=4Sequence analysisAdd BLAST21
Topological domaini366 – 389ExtracellularSequence analysisAdd BLAST24
Transmembranei390 – 410Helical; Name=5Sequence analysisAdd BLAST21
Topological domaini411 – 436CytoplasmicSequence analysisAdd BLAST26
Transmembranei437 – 457Helical; Name=6Sequence analysisAdd BLAST21
Topological domaini458 – 477ExtracellularSequence analysisAdd BLAST20
Transmembranei478 – 498Helical; Name=7Sequence analysisAdd BLAST21
Topological domaini499 – 537CytoplasmicSequence analysisAdd BLAST39

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Vitreoretinopathy, exudative 1 (EVR1)13 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:133780
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06392033P → S in EVR1; unknown pathological significance. 3 PublicationsCorresponds to variant dbSNP:rs61735304EnsemblClinVar.1
Natural variantiVAR_06392136G → D in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358281Ensembl.1
Natural variantiVAR_06392240E → Q in EVR1. 1 PublicationCorresponds to variant dbSNP:rs139401671EnsemblClinVar.1
Natural variantiVAR_06392369H → Y in EVR1; minor reduction of its wild-type activity. 4 PublicationsCorresponds to variant dbSNP:rs80358282EnsemblClinVar.1
Natural variantiVAR_063924105M → T in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358285Ensembl.1
Natural variantiVAR_038947105M → V in EVR1; loss of function. 4 PublicationsCorresponds to variant dbSNP:rs80358284EnsemblClinVar.1
Natural variantiVAR_063925114I → T in EVR1. 1 Publication1
Natural variantiVAR_038948157M → V in EVR1; loss of function. 2 PublicationsCorresponds to variant dbSNP:rs80358286Ensembl.1
Natural variantiVAR_063927181C → R in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358287Ensembl.1
Natural variantiVAR_063929204C → R in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358288Ensembl.1
Natural variantiVAR_063930204C → Y in EVR1. 1 PublicationCorresponds to variant dbSNP:rs1064794064Ensembl.1
Natural variantiVAR_063931223M → K in EVR1. 1 Publication1
Natural variantiVAR_063932256I → V in EVR1. 1 PublicationCorresponds to variant dbSNP:rs104894223EnsemblClinVar.1
Natural variantiVAR_063933335W → C in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358292EnsemblClinVar.1
Natural variantiVAR_063934342M → V in EVR1. 2 PublicationsCorresponds to variant dbSNP:rs80358293EnsemblClinVar.1
Natural variantiVAR_063936417R → Q in EVR1; 48% loss of its wild-type activity; associated in a EVR4 patient with mutation CYS-444 in LPR5. 3 PublicationsCorresponds to variant dbSNP:rs80358294EnsemblClinVar.1
Natural variantiVAR_063937445T → P in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358297Ensembl.1
Natural variantiVAR_063938488G → D in EVR1. 2 PublicationsCorresponds to variant dbSNP:rs80358298Ensembl.1
Natural variantiVAR_017777493 – 494Missing in EVR1; loss of function. 3 Publications2
Natural variantiVAR_063939497S → F in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358300Ensembl.1
Natural variantiVAR_063940525G → R in EVR1. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi8322
GeneReviewsiFZD4
MalaCardsiFZD4
MIMi133780 phenotype
OpenTargetsiENSG00000174804
Orphaneti891 Familial exudative vitreoretinopathy
91495 Persistent hyperplastic primary vitreous
90050 Retinopathy of prematurity
PharmGKBiPA28459

Polymorphism and mutation databases

BioMutaiFZD4
DMDMi62298045

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 36Sequence analysisAdd BLAST36
ChainiPRO_000001298537 – 537Frizzled-4Add BLAST501

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi45 ↔ 106PROSITE-ProRule annotation
Disulfide bondi53 ↔ 99PROSITE-ProRule annotation
Glycosylationi59N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi90 ↔ 128PROSITE-ProRule annotation
Disulfide bondi117 ↔ 158PROSITE-ProRule annotation
Disulfide bondi121 ↔ 145PROSITE-ProRule annotation
Glycosylationi144N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ9ULV1
PaxDbiQ9ULV1
PeptideAtlasiQ9ULV1
PRIDEiQ9ULV1
ProteomicsDBi85129

PTM databases

iPTMnetiQ9ULV1
PhosphoSitePlusiQ9ULV1

Expressioni

Tissue specificityi

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.

Gene expression databases

BgeeiENSG00000174804 Expressed in 213 organ(s), highest expression level in adipose tissue of abdominal region
CleanExiHS_FZD4
GenevisibleiQ9ULV1 HS

Organism-specific databases

HPAiHPA042328
HPA074833

Interactioni

Subunit structurei

Interacts with MAGI3 and NDP. Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP). Interacts (via FZ domain) with TSKU.By similarity

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi113918, 12 interactors
IntActiQ9ULV1, 7 interactors
MINTiQ9ULV1
STRINGi9606.ENSP00000434034

Structurei

Secondary structure

1537
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9ULV1
SMRiQ9ULV1
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini40 – 161FZPROSITE-ProRule annotationAdd BLAST122

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi499 – 504Lys-Thr-X-X-X-Trp motif, mediates interaction with the PDZ domain of Dvl family membersBy similarity6
Motifi535 – 537PDZ-binding3

Domaini

Lys-Thr-X-X-X-Trp motif interacts with the PDZ domain 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

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3577 Eukaryota
ENOG410XRC8 LUCA
GeneTreeiENSGT00760000118864
HOGENOMiHOG000233236
HOVERGENiHBG006977
InParanoidiQ9ULV1
KOiK02354
OMAiSMCLSVK
OrthoDBiEOG091G0N5M
PhylomeDBiQ9ULV1
TreeFamiTF317907

Family and domain databases

Gene3Di1.10.2000.10, 1 hit
InterProiView protein in InterPro
IPR015526 Frizzled/SFRP
IPR000539 Frizzled/Smoothened_TM
IPR020067 Frizzled_dom
IPR036790 Frizzled_dom_sf
IPR026551 FZD4
IPR017981 GPCR_2-like
PANTHERiPTHR11309 PTHR11309, 1 hit
PTHR11309:SF23 PTHR11309:SF23, 1 hit
PfamiView protein in Pfam
PF01534 Frizzled, 1 hit
PF01392 Fz, 1 hit
PRINTSiPR00489 FRIZZLED
SMARTiView protein in SMART
SM00063 FRI, 1 hit
SM01330 Frizzled, 1 hit
SUPFAMiSSF63501 SSF63501, 1 hit
PROSITEiView protein in PROSITE
PS50038 FZ, 1 hit
PS50261 G_PROTEIN_RECEP_F2_4, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9ULV1-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MAWRGAGPSV PGAPGGVGLS LGLLLQLLLL LGPARGFGDE EERRCDPIRI
60 70 80 90 100
SMCQNLGYNV TKMPNLVGHE LQTDAELQLT TFTPLIQYGC SSQLQFFLCS
110 120 130 140 150
VYVPMCTEKI NIPIGPCGGM CLSVKRRCEP VLKEFGFAWP ESLNCSKFPP
160 170 180 190 200
QNDHNHMCME GPGDEEVPLP HKTPIQPGEE CHSVGTNSDQ YIWVKRSLNC
210 220 230 240 250
VLKCGYDAGL YSRSAKEFTD IWMAVWASLC FISTAFTVLT FLIDSSRFSY
260 270 280 290 300
PERPIIFLSM CYNIYSIAYI VRLTVGRERI SCDFEEAAEP VLIQEGLKNT
310 320 330 340 350
GCAIIFLLMY FFGMASSIWW VILTLTWFLA AGLKWGHEAI EMHSSYFHIA
360 370 380 390 400
AWAIPAVKTI VILIMRLVDA DELTGLCYVG NQNLDALTGF VVAPLFTYLV
410 420 430 440 450
IGTLFIAAGL VALFKIRSNL QKDGTKTDKL ERLMVKIGVF SVLYTVPATC
460 470 480 490 500
VIACYFYEIS NWALFRYSAD DSNMAVEMLK IFMSLLVGIT SGMWIWSAKT
510 520 530
LHTWQKCSNR LVNSGKVKRE KRGNGWVKPG KGSETVV
Length:537
Mass (Da):59,881
Last modified:March 29, 2005 - v2
Checksum:iE0A83ECEC560A381
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti481I → T in BAA86286 (PubMed:10544037).Curated1
Sequence conflicti500T → S in BAA86286 (PubMed:10544037).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06392033P → S in EVR1; unknown pathological significance. 3 PublicationsCorresponds to variant dbSNP:rs61735304EnsemblClinVar.1
Natural variantiVAR_06392136G → D in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358281Ensembl.1
Natural variantiVAR_06392240E → Q in EVR1. 1 PublicationCorresponds to variant dbSNP:rs139401671EnsemblClinVar.1
Natural variantiVAR_06392369H → Y in EVR1; minor reduction of its wild-type activity. 4 PublicationsCorresponds to variant dbSNP:rs80358282EnsemblClinVar.1
Natural variantiVAR_063924105M → T in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358285Ensembl.1
Natural variantiVAR_038947105M → V in EVR1; loss of function. 4 PublicationsCorresponds to variant dbSNP:rs80358284EnsemblClinVar.1
Natural variantiVAR_063925114I → T in EVR1. 1 Publication1
Natural variantiVAR_038948157M → V in EVR1; loss of function. 2 PublicationsCorresponds to variant dbSNP:rs80358286Ensembl.1
Natural variantiVAR_063926168P → S3 PublicationsCorresponds to variant dbSNP:rs61735303EnsemblClinVar.1
Natural variantiVAR_063927181C → R in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358287Ensembl.1
Natural variantiVAR_063928203K → N in retinopathy of prematurity. 1 Publication1
Natural variantiVAR_063929204C → R in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358288Ensembl.1
Natural variantiVAR_063930204C → Y in EVR1. 1 PublicationCorresponds to variant dbSNP:rs1064794064Ensembl.1
Natural variantiVAR_063931223M → K in EVR1. 1 Publication1
Natural variantiVAR_063932256I → V in EVR1. 1 PublicationCorresponds to variant dbSNP:rs104894223EnsemblClinVar.1
Natural variantiVAR_063933335W → C in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358292EnsemblClinVar.1
Natural variantiVAR_063934342M → V in EVR1. 2 PublicationsCorresponds to variant dbSNP:rs80358293EnsemblClinVar.1
Natural variantiVAR_063935370A → G in retinopathy of prematurity. 1 Publication1
Natural variantiVAR_063936417R → Q in EVR1; 48% loss of its wild-type activity; associated in a EVR4 patient with mutation CYS-444 in LPR5. 3 PublicationsCorresponds to variant dbSNP:rs80358294EnsemblClinVar.1
Natural variantiVAR_036413436K → T in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_063937445T → P in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358297Ensembl.1
Natural variantiVAR_063938488G → D in EVR1. 2 PublicationsCorresponds to variant dbSNP:rs80358298Ensembl.1
Natural variantiVAR_017777493 – 494Missing in EVR1; loss of function. 3 Publications2
Natural variantiVAR_063939497S → F in EVR1. 1 PublicationCorresponds to variant dbSNP:rs80358300Ensembl.1
Natural variantiVAR_063940525G → R in EVR1. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB032417 mRNA Translation: BAA86286.1
AY462097 mRNA Translation: AAR23924.1
AK292768 mRNA Translation: BAF85457.1
AP001528 Genomic DNA No translation available.
BC114527 mRNA Translation: AAI14528.1
BC114622 mRNA Translation: AAI14623.1
CCDSiCCDS8279.1
PIRiJC7127
RefSeqiNP_036325.2, NM_012193.3
UniGeneiHs.591968

Genome annotation databases

EnsembliENST00000531380; ENSP00000434034; ENSG00000174804
GeneIDi8322
KEGGihsa:8322
UCSCiuc001pce.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiFZD4_HUMAN
AccessioniPrimary (citable) accession number: Q9ULV1
Secondary accession number(s): A8K9Q3, Q14C97, Q6S9E4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 5, 2001
Last sequence update: March 29, 2005
Last modified: September 12, 2018
This is version 175 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again