Reactome | Regulation of FZD by ubiquitination

Regulation of FZD by ubiquitination

Stable Identifier

R-HSA-4641263

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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 References

PubMed ID	Title	Journal	Year
17908284	Endocytosis: a positive or a negative influence on Wnt signalling? Gagliardi, M, Piddini, E, Vincent, JP	Traffic	2008
22575959	ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner Hao, HX, Xie, Y, Zhang, Y, Charlat, O, Oster, E, Avello, M, Lei, H, Mickanin, C, Liu, D, Ruffner, H, Mao, X, Ma, Q, Zamponi, R, Bouwmeester, T, Finan, PM, Kirschner, MW, Porter, JA, Serluca, FC, Cong, F	Nature	2012
20495530	Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt Mukai, A, Yamamoto-Hino, M, Awano, W, Watanabe, W, Komada, M, Goto, S	EMBO J.	2010
23058807	Cancer biology: a new RING to Wnt signaling Fearon, ER, Spence, JR	Curr. Biol.	2012
22965053	Modulating WNT receptor turnover for tissue repair Abo, A, Clevers, HC	Nat. Biotechnol.	2012
22617469	Preventing WNT signalling Papatriantafyllou, M	Nat. Rev. Mol. Cell Biol.	2012