Post‐translational Wnt receptor regulation: Is the fog slowly clearing?

Tsukiyama, Tadasuke; Koo, Bon‐Kyoung; Hatakeyama, Susumi

doi:10.1002/bies.202000297

Cited by 13 publications

(15 citation statements)

References 97 publications

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“…In line with these findings, the amino acid sequence of the TMD is poorly conserved between RNF43 and ZNRF3 (Fig. 3H) (Tsukiyama et al, 2021). Regulation of FZD activity was shown previously to depend on TMD-mediated interactions.…”

Section: Relation Between Tissue Distribution Of Rnf43 and Znrf3 Canc...supporting

confidence: 86%

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E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled family members

Bugter,

van Kerkhof,

Janssen

et al. 2023

Preprint

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The transmembrane E3 ligases RNF43 and ZNRF3 perform key tumour suppressor roles by depleting members of the Frizzled (FZD) family, the primary receptors for WNTs, from the cell surface. Mutational inactivation ofRNF43orZNRF3is a frequent event in cancer, which has been linked to FZD stabilisation and a WNT hypersensitive growth state. Strikingly, inactivating mutations in eitherRNF43orZNRF3display a substantial level of tissue specificity across cancer types, thus raising the question to what extent both ligases are functionally redundant. In this study, we investigate the efficacy of RNF43 and ZNRF3 to remove various FZDs from the cell surface. Our results reveal that RNF43 preferentially downregulates FZD1, FZD5 and FZD7, while ZNRF3 displays improved efficacy towards FZD6 and FZD10. Mechanistically, we show that the RNF43 transmembrane domain (TMD) is a key molecular determinant for cell surface removal of FZD5. Moreover, we find that a TMD swap between RNF43 and ZNRF3 is sufficient to re-direct their preference for downregulation of either FZD5 or FZD6. In summary, we uncover that RNF43 and ZNRF3 preferentially downregulate specific FZDs by a mechanism that involves their TMDs. In line with these observations, FZD homologue expression occurs in tissue-specific patterns that correlate with the incidence ofRNF43orZNRF3mutations in cancers arising from those tissues. Consequently, our data point to druggable vulnerabilities of specific FZD receptors inRNF43-orZNRF3-mutant human cancers.

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Section: Relation Between Tissue Distribution Of Rnf43 and Znrf3 Canc...supporting

confidence: 86%

“…3H). By contrast, the PA domain displays 46/100 (46%) and the RING domain 31/45 (69%) overlap in amino acids for both proteins (Tsukiyama et al, 2021). Regulation of FZD activity was shown previously to depend on TMD-mediated interactions.…”

Section: Resultsmentioning

confidence: 99%

E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled family members

Bugter,

van Kerkhof,

Janssen

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…The protease-associated (PA) domain is the only conservative part between the extracellular fragments of ZNRF3 and RNF43 (Tsukiyama et al , 2021). Therefore, we tested whether this domain is necessary for the interaction between ZNRF3/RNF43 with EGFR.…”

Section: Resultsmentioning

confidence: 99%

“…6B). EGF and EGFR signaling are also critical for the culture and maintenance of organoids derived from Apc- deficient mouse intestinal adenomas (Sato et al , 2011), which exhibits constitutively canonical WNT signaling that is no longer modulated by the RSPO-ZNRF3/RNF43 control at the membrane receptor level (Tsukiyama et al ., 2021; Tsukiyama et al , 2020). Therefore, we established intestinal tumor organoids using the intestinal polyps from the Apc min mice (Evans et al , 1992) and supplemented RSPO1 in the organoid culture medium to investigate the effect of ZNRF3/RNF43 deactivation on organoid growth and EGFR.…”

Section: Resultsmentioning

confidence: 99%

Loss of ZNRF3/RNF43 Unleashes EGFR in Cancer

Yue,

Ku,

Stevens

et al. 2024

Preprint

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ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the most negatively correlated protein withZNRF3/RNF43mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression ofZNRF3reduces EGFR levels and suppresses cancer cell growthin vitroandin vivo, whereas knockout ofZNRF3/RNF43stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data highlight ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptor, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer.

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“…ZNRF3 is a cell surface ubiquitin ligase that regulates Wnt-β-catenin signaling by ubiquitinating and degrading the Wnt protein receptors Frizzled and LRP6 [ 77 ]. When ZNRF3 loses its activity due to mutation, Wnt-β-catenin signaling is not regulated and β-catenin activity is increased [ 17 , 71 ] ( Figure 8 ).…”

Section: The Pathogenesis and Molecular Mechanisms In Adrenocortical Carcinoma (Acc)mentioning

confidence: 99%

Molecular Mechanisms of Functional Adrenocortical Adenoma and Carcinoma: Genetic Characterization and Intracellular Signaling Pathway

et al. 2021

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The adrenal cortex produces steroid hormones as adrenocortical hormones in the body, secreting mineralocorticoids, glucocorticoids, and adrenal androgens, which are all considered essential for life. Adrenocortical tumors harbor divergent hormonal activity, frequently with steroid excess, and disrupt homeostasis of the body. Aldosterone-producing adenomas (APAs) cause primary aldosteronism (PA), and cortisol-producing adenomas (CPAs) are the primary cause of Cushing’s syndrome. In addition, adrenocortical carcinoma (ACC) is a highly malignant cancer harboring poor prognosis. Various genetic abnormalities have been reported, which are associated with possible pathogenesis by the alteration of intracellular signaling and activation of transcription factors. In particular, somatic mutations in APAs have been detected in genes encoding membrane proteins, especially ion channels, resulting in hypersecretion of aldosterone due to activation of intracellular calcium signaling. In addition, somatic mutations have been detected in those encoding cAMP-PKA signaling-related factors, resulting in hypersecretion of cortisol due to its driven status in CPAs. In ACC, mutations in tumor suppressor genes and Wnt-β-catenin signaling-related factors have been implicated in its pathogenesis. In this article, we review recent findings on the genetic characteristics and regulation of intracellular signaling and transcription factors in individual tumors.

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Post‐translational Wnt receptor regulation: Is the fog slowly clearing?

Cited by 13 publications

References 97 publications

E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled family members

E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled family members

Loss of ZNRF3/RNF43 Unleashes EGFR in Cancer

Molecular Mechanisms of Functional Adrenocortical Adenoma and Carcinoma: Genetic Characterization and Intracellular Signaling Pathway

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