Pathway Human Homo sapiens

Regulation of FZD by ubiquitination

R-HSA-4641263 in Reactome release 97: under TCF dependent signaling in response to WNT, with 21 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-4641263 (mouse), R-RNO-4641263 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-4641263.4
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2014-03-12
Last updated: 2016-12-21
Events inside: 6, counted from the record

WNT responsiveness is influenced by expression levels of FZD and LRP proteins. Levels of these receptors at the cell surface are regulated in part by endocytosis, but the mechanisms are not fully elucidated (Garliardi et al, 2008). A number of recent studies have identified a role for ubiquitination in the localization and turnover of WNT receptors at the plasma membrane. ZNRF3 and RNF43 are E3 ligases that have been shown to ubiquitinate FZD proteins and promote their lysosomal degradation, while the deubiquitinating enzyme USP8 promotes recycling of the receptor back to the plasma membrane (Hao et al, 2012; Mukai et al, 2010). This balance of ubiquitination and deubiquitination is in turn regulated by the R-spondin (RSPO) proteins, agonists of WNT signaling which appear to act by downregulating ZNRF3 and RNF43, thus potentiating both canonical and non-canonical pathways (Hao et al, 2012; reviewed in Abo and Clevers, 2012; Fearon and Spence, 2012, Papartriantafyllou, 2012).

Literature Reactome attaches

ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive mannerNature, 2012, vol. 485, p. 195-200PubMed 22575959
Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/WntEMBO J., 2010, vol. 29, p. 2114-25PubMed 20495530
Endocytosis: a positive or a negative influence on Wnt signalling?Traffic, 2008, vol. 9, p. 1-9PubMed 17908284
Modulating WNT receptor turnover for tissue repairNat. Biotechnol., 2012, vol. 30, p. 835-6PubMed 22965053
Cancer biology: a new RING to Wnt signalingCurr. Biol., 2012, vol. 22, p. R849-51PubMed 23058807
Preventing WNT signallingNat. Rev. Mol. Cell Biol., 2012, vol. 13, p. 342PubMed 22617469

Reactome's record lists 8 orthologous events, R-RNO-4641263 (Rattus norvegicus), R-MMU-4641263 (Mus musculus) among the species this site serves, and 6 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"Regulation of FZD by ubiquitination". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-4641263 with StableID: R-HSA-4641263.4 (accessed 2026-10-01 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 21 genes in this human pathway; showing 1 to 21, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneFZD4	AuthorityHGNC:4042	Mapping file id8322 NCBI file	EvidenceTAS
GeneFZD5	AuthorityHGNC:4043	Mapping file id7855 NCBI file	EvidenceTAS
GeneFZD6	AuthorityHGNC:4044	Mapping file id8323 NCBI file	EvidenceTAS
GeneFZD8	AuthorityHGNC:4046	Mapping file id8325 NCBI file	EvidenceTAS
GeneLGR4	AuthorityHGNC:13299	Mapping file id55366 NCBI file	EvidenceTAS
GeneLGR5	AuthorityHGNC:4504	Mapping file id8549 NCBI file	EvidenceTAS
GeneLGR6	AuthorityHGNC:19719	Mapping file id59352 NCBI file	EvidenceTAS
GeneLRP5	AuthorityHGNC:6697	Mapping file id4041 NCBI file	EvidenceTAS
GeneLRP6	AuthorityHGNC:6698	Mapping file id4040 NCBI file	EvidenceTAS
GeneRNF43	AuthorityHGNC:18505	Mapping file id54894 NCBI file	EvidenceTAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneRSPO1	AuthorityHGNC:21679	Mapping file id284654 NCBI file	EvidenceTAS
GeneRSPO2	AuthorityHGNC:28583	Mapping file id340419 NCBI file	EvidenceTAS
GeneRSPO3	AuthorityHGNC:20866	Mapping file id84870 NCBI file	EvidenceTAS
GeneRSPO4	AuthorityHGNC:16175	Mapping file id343637 NCBI file	EvidenceTAS
GeneUBA52	AuthorityHGNC:12458	Mapping file id7311 NCBI file	EvidenceTAS
GeneUBB	AuthorityHGNC:12463	Mapping file id7314 NCBI file	EvidenceTAS
GeneUBC	AuthorityHGNC:12468	Mapping file id7316 NCBI file	EvidenceTAS
GeneUSP8	AuthorityHGNC:12631	Mapping file id9101 NCBI file	EvidenceTAS
GeneWNT3A	AuthorityHGNC:15983	Mapping file id89780 NCBI file	EvidenceTAS
GeneZNRF3	AuthorityHGNC:18126	Mapping file id84133 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

TCF dependent signaling in response to WNTR-HSA-201681222 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.