{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9ULV1","secondaryAccessions":["A8K9Q3","Q14C97","Q6S9E4"],"uniProtkbId":"FZD4_HUMAN","entryAudit":{"firstPublicDate":"2001-12-05","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2005-03-29","entryVersion":218,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Frizzled-4"},"shortNames":[{"value":"Fz-4"},{"value":"hFz4"}]},"alternativeNames":[{"fullName":{"value":"FzE4"}}],"cdAntigenNames":[{"value":"CD344"}],"flag":"Precursor"},"genes":[{"geneName":{"value":"FZD4"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q61088"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30135577"}],"value":"Receptor for Wnt proteins (PubMed:30135577). Most 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 (PubMed:30135577). Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP) (By similarity). In retina, it can be activated by Wnt protein-binding and also by Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs (By similarity). 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"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q61088"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24496449"}],"value":"Interacts with MAGI3 and NDP (By similarity). Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP) (By similarity). Interacts (via FZ domain) with TSKU; TSKU competes with WNT2B for binding to FZD4, inhibiting Wnt signaling and repressing peripheral eye development (By similarity). Interacts with glypican GPC3 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Largely expressed in adult heart, skeletal muscle, ovary, and fetal kidney (PubMed:10544037). 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 (PubMed:10544037)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"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"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The FZ domain is involved in binding with Wnt ligands"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22575959"}],"value":"Ubiquitinated by ZNRF3, leading to its degradation by the proteasome"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Vitreoretinopathy, exudative 1","diseaseAccession":"DI-01126","acronym":"EVR1","description":"An autosomal dominant 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 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