Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt

Mukai, Akiko; Yamamoto-Hino, Miki; Awano, Wakae; Watanabe, Wakako; Komada, Masayuki; Goto, Satoshi

doi:10.1038/emboj.2010.100

Cited by 125 publications

(158 citation statements)

References 48 publications

(81 reference statements)

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“…One contributing factor to such defective EGFR trafficking is that USP8 controls the stability of ESCRT-0 components, Hrs and STAM in cells and in conditional knockout mice (185,219). However, for Frizzled receptor (Fz) and Smoothened (Smo), key components of Wingless (Wnt) and Hedgehog signaling pathways, respectively, USP8 plays a negative regulatory role with regard to receptor degradation more akin to that originally proposed for AMSH (153,180,281).…”

Section: B Escrt Dubsmentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

359

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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Section: B Escrt Dubsmentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

359

384

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“…Recently, a somatic mutational hotspot was found in the gene encoding ubiquitin-specific protease 8 (USP8) in 30-60% of sporadic corticotrophinomas (28,29). The USP8 protein product controls the lysosomal trafficking and abundance of cell surface receptors, such as the epidermal growth factor receptor (EGFR), and enables their signaling (30,31).…”

Section: Genetic Events In CDmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

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“…Conversely, the ER chaperone Boca/Mesd facilitates Wnt signaling by preventing aggregation of Arrow/LRP5/6 and permitting transport from the ER to the plasma membrane (Culi and Mann, 2003;Hsieh et al, 2003). Whereas Shisa and Boca/Mesd influence Wnt receptor transport to the surface, balanced ubiquitylation and deubiquitylation control Frizzled levels maintained at the surface (Mukai et al, 2010). Recently, the mammalian cell-surface transmembrane E3 ubiquitin ligases RNF43 and ZNRF3 were shown to downregulate the response to Wnts by inducing endocytosis of Frizzled and LRP6 (Hao et al, 2012;Koo et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans

et al. 2014

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Wnts control a wide range of essential developmental processes, including cell fate specification, axon guidance and anteroposterior neuronal polarization. We identified a conserved transmembrane RING finger protein, PLR-1, that governs the response to Wnts by lowering cell-surface levels of the Frizzled family of Wnt receptors in Caenorhabditis elegans. Loss of PLR-1 activity in the neuron AVG causes its anteroposterior polarity to be symmetric or reversed because signaling by the Wnts CWN-1 and CWN-2 are inappropriately activated, whereas ectopic PLR-1 expression blocks Wnt signaling and target gene expression. Frizzleds are enriched at the cell surface; however, when PLR-1 and Frizzled are coexpressed, Frizzled is not detected at the surface but instead is colocalized with PLR-1 in endosomes. The Frizzled cysteine-rich domain (CRD) and invariant second intracellular loop lysine are crucial for PLR-1 downregulation. The PLR-1 RING finger and protease-associated (PA) domain are essential for activity. In a Frizzled-dependent manner, PLR-1 reduces surface levels of the Wnt receptors CAM-1/Ror and LIN-18/Ryk. PLR-1 is a homolog of the mammalian transmembrane E3 ubiquitin ligases RNF43 and ZNRF3, which control Frizzled surface levels in an R-spondin-sensitive manner. We propose that PLR-1 downregulates Wnt receptor surface levels via lysine ubiquitylation of Frizzled to coordinate spatial and temporal responses to Wnts during neuronal development.

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Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt

Cited by 125 publications

References 48 publications

Deubiquitylases From Genes to Organism

Deubiquitylases From Genes to Organism

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans

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