Q61088 (FZD4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Frizzled-4
Short name=Fz-4
Short name=mFz4

Alternative name(s):
CD_antigen=CD344

Gene names

Name:

Fzd4

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	537 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

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. Activation by Wnt5A stimulates PKC activity via a G-protein-dependent mechanism. Ref.4 Ref.7
Subunit structure	Interacts with MAGI3 and NDP. Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP). Ref.5 Ref.6 Ref.7
Subcellular location	Membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein Ref.4.
Tissue specificity	Expressed in chondrocytes.
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 By similarity.
Disruption phenotype	Defects in retinal vascularization. Ref.5
Sequence similarities	Belongs to the G-protein coupled receptor Fz/Smo family. Contains 1 FZ (frizzled) domain.

Ontologies

Keywords
Biological process	Wnt signaling pathway
Cellular component	Cell membrane Membrane
Domain	Signal Transmembrane Transmembrane helix
Molecular function	Developmental protein G-protein coupled receptor Receptor Transducer
PTM	Disulfide bond Glycoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway, calcium modulating pathway Inferred from electronic annotation. Source: Compara canonical Wnt receptor signaling pathway Inferred from direct assay Ref.5. Source: BHF-UCL cerebellum vasculature morphogenesis Inferred from mutant phenotype Ref.5. Source: BHF-UCL embryo development Inferred from Biological aspect of Ancestor. Source: RefGenome extracellular matrix-cell signaling Inferred from direct assay Ref.5. Source: BHF-UCL locomotion involved in locomotory behavior Inferred from mutant phenotype PubMed 11425903. Source: MGI negative regulation of cell-substrate adhesion Inferred from mutant phenotype PubMed 18156211. Source: BHF-UCL positive regulation of JUN kinase activity Inferred from genetic interaction Ref.6. Source: MGI positive regulation of sequence-specific DNA binding transcription factor activity Inferred from direct assay Ref.5. Source: BHF-UCL positive regulation of transcription, DNA-dependent Inferred from direct assay Ref.5. Source: BHF-UCL progesterone secretion Inferred from mutant phenotype PubMed 16093361. Source: MGI regulation of transcription from RNA polymerase II promoter Inferred from Biological aspect of Ancestor. Source: RefGenome regulation of vascular endothelial growth factor receptor signaling pathway Inferred from mutant phenotype PubMed 16093361. Source: MGI retinal blood vessel morphogenesis Inferred from mutant phenotype Ref.5. Source: BHF-UCL sensory perception of sound Inferred from mutant phenotype PubMed 11425903. Source: MGI substrate adhesion-dependent cell spreading Inferred from mutant phenotype PubMed 18156211. Source: MGI vasculogenesis Inferred from mutant phenotype PubMed 16093361. Source: MGI
Cellular_component	cell projection Inferred from Biological aspect of Ancestor. Source: RefGenome cell surface Inferred from electronic annotation. Source: Compara cell-cell junction Inferred from direct assay Ref.6. Source: MGI cytoplasm Inferred from Biological aspect of Ancestor. Source: RefGenome integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from direct assay Ref.5. Source: BHF-UCL
Molecular_function	G-protein coupled receptor activity Inferred from electronic annotation. Source: UniProtKB-KW PDZ domain binding Inferred from Biological aspect of Ancestor. Source: RefGenome Wnt-activated receptor activity Inferred from physical interaction PubMed 16163358. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 36	36	Potential
	Chain	37 – 537	501	Frizzled-4		PRO_0000012986
Regions
	Topological domain	37 – 222	186	Extracellular Potential
	Transmembrane	223 – 243	21	Helical; Name=1; Potential
	Topological domain	244 – 254	11	Cytoplasmic Potential
	Transmembrane	255 – 275	21	Helical; Name=2; Potential
	Topological domain	276 – 302	27	Extracellular Potential
	Transmembrane	303 – 323	21	Helical; Name=3; Potential
	Topological domain	324 – 344	21	Cytoplasmic Potential
	Transmembrane	345 – 365	21	Helical; Name=4; Potential
	Topological domain	366 – 389	24	Extracellular Potential
	Transmembrane	390 – 410	21	Helical; Name=5; Potential
	Topological domain	411 – 436	26	Cytoplasmic Potential
	Transmembrane	437 – 457	21	Helical; Name=6; Potential
	Topological domain	458 – 477	20	Extracellular Potential
	Transmembrane	478 – 498	21	Helical; Name=7; Potential
	Topological domain	499 – 537	39	Cytoplasmic Potential
	Domain	40 – 161	122	FZ
	Motif	499 – 504	6	Lys-Thr-X-X-X-Trp motif, mediates interaction with the PDZ domain of Dvl family members By similarity
	Motif	535 – 537	3	PDZ-binding
Amino acid modifications
	Glycosylation	59	1	N-linked (GlcNAc...) Potential
	Glycosylation	144	1	N-linked (GlcNAc...) Potential
	Disulfide bond	45 ↔ 106		By similarity
	Disulfide bond	53 ↔ 99		By similarity
	Disulfide bond	90 ↔ 128		By similarity
	Disulfide bond	117 ↔ 158		By similarity
	Disulfide bond	121 ↔ 145		By similarity
Experimental info
	Sequence conflict	27	1	F → L in AAH15256. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q61088 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 6641996E6960BCD8	FASTA	537	60,143
	10 20 30 40 50 60 MAWPGTGPSS RGAPGGVGLR LGLLLQFLLL LRPTLGFGDE EERRCDPIRI AMCQNLGYNV 70 80 90 100 110 120 TKMPNLVGHE LQTDAELQLT TFTPLIQYGC SSQLQFFLCS VYVPMCTEKI NIPIGPCGGM 130 140 150 160 170 180 CLSVKRRCEP VLREFGFAWP DTLNCSKFPP QNDHNHMCME GPGDEEVPLP HKTPIQPGEE 190 200 210 220 230 240 CHSVGSNSDQ YIWVKRSLNC VLKCGYDAGL YSRSAKEFTD IWMAVWASLC FISTTFTVLT 250 260 270 280 290 300 FLIDSSRFSY PERPIIFLSM CYNIYSIAYI VRLTVGRERI SCDFEEAAEP VLIQEGLKNT 310 320 330 340 350 360 GCAIIFLLMY FFGMASSIWW VILTLTWFLA AGLKWGHEAI EMHSSYFHIA AWAIPAVKTI 370 380 390 400 410 420 VILIMRLVDA DELTGLCYVG NQNLDALTGF VVAPLFTYLV IGTLFIAAGL VALFKIRSNL 430 440 450 460 470 480 QKDGTKTDKL ERLMVKIGVF SVLYTVPATC VIACYFYEIS NWALFRYSAD DSNMAVEMLK 490 500 510 520 530 IFMSLLVGIT SGMWIWSAKT LHTWQKCSNR LVNSGKVKRE KRGNGWVKPG KGNETVV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled." Wang Y., Macke J.P., Abella B.S., Andreasson K., Worley P., Gilbert D.J., Copeland N.G., Jenkins N.A., Nathans J. J. Biol. Chem. 271:4468-4476(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.
[3]	"Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner." Sheldahl L.C., Park M., Malbon C.C., Moon R.T. Curr. Biol. 9:695-698(1999) [PubMed] [Europe PMC] [Abstract] Cited for: WNT-MEDIATED PKC ACTIVATION.
[4]	"Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein." Hsieh J.C., Rattner A., Smallwood P.M., Nathans J. Proc. Natl. Acad. Sci. U.S.A. 96:3546-3551(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[5]	"Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair." Xu Q., Wang Y., Dabdoub A., Smallwood P.M., Williams J., Woods C., Kelley M.W., Jiang L., Tasman W., Zhang K., Nathans J. Cell 116:883-895(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NDP, DISRUPTION PHENOTYPE.
[6]	"MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap." Yao R., Natsume Y., Noda T. Oncogene 23:6023-6030(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MAGI3.
[7]	"TSPAN12 regulates retinal vascular development by promoting Norrin-but not Wnt-induced FZD4/beta-catenin signaling." Junge H.J., Yang S., Burton J.B., Paes K., Shu X., French D.M., Costa M., Rice D.S., Ye W. Cell 139:299-311(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, IDENTIFICATION IN A COMPLEX WITH NDP AND TSPAN12.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U43317 mRNA. Translation: AAC52430.1. BC015256 mRNA. Translation: AAH15256.1.
IPI	IPI00117094.
RefSeq	NP_032081.3. NM_008055.4.
UniGene	Mm.86755.
3D structure databases
ProteinModelPortal	Q61088.
SMR	Q61088. Positions 45-161.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-41623N.
MINT	MINT-1779328.
Protein family/group databases
GPCRDB	Search...
PTM databases
PhosphoSite	Q61088.
Proteomic databases
PaxDb	Q61088.
PRIDE	Q61088.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000058755; ENSMUSP00000049852; ENSMUSG00000049791.
GeneID	14366.
KEGG	mmu:14366.
Organism-specific databases
CTD	8322.
MGI	MGI:108520. Fzd4.
Phylogenomic databases
eggNOG	NOG284049.
GeneTree	ENSGT00660000095421.
HOGENOM	HOG000233236.
HOVERGEN	HBG006977.
InParanoid	Q61088.
KO	K02354.
OMA	SMCLSVK.
OrthoDB	EOG4KPT9H.
Gene expression databases
ArrayExpress	Q61088.
Bgee	Q61088.
CleanEx	MM_FZD4.
Genevestigator	Q61088.
GermOnline	ENSMUSG00000049791. Mus musculus.
Family and domain databases
Gene3D	1.10.2000.10. 1 hit.
InterPro	IPR000539. Frizzled. IPR015526. Frizzled/SFRP. IPR020067. Frizzled_dom. IPR026551. FZD4. IPR017981. GPCR_2-like. [Graphical view]
PANTHER	PTHR11309. PTHR11309. 1 hit. PTHR11309:SF23. PTHR11309:SF23. 1 hit.
Pfam	PF01534. Frizzled. 1 hit. PF01392. Fz. 1 hit. [Graphical view]
PRINTS	PR00489. FRIZZLED.
SMART	SM00063. FRI. 1 hit. [Graphical view]
SUPFAM	SSF63501. Frizzled_Cys-rich. 1 hit.
PROSITE	PS50038. FZ. 1 hit. PS50261. G_PROTEIN_RECEP_F2_4. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	285835.
SOURCE	Search...

Entry information

Entry name

FZD4_MOUSE

Accession

Primary (citable) accession number: Q61088

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 5, 2001
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 115 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program