Regulation of FZD by ubiquitination

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R-HSA-4641263
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Pathway
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Homo sapiens
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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
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
17908284 Endocytosis: a positive or a negative influence on Wnt signalling?

Gagliardi, M, Piddini, E, Vincent, JP

Traffic 2008
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
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