WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition

Lee, Yu-Ru; Yehia, Lamis; Kishikawa, Takahiro; Ni, Ying; Heald, Brandie; Zhang, Jinfang; Panch, Nivedita; Liu, Jing; Wei, Wenyi; Eng, Charis; Pandolfi, Pier Paolo

doi:10.1056/nejmoa1914919

Cited by 61 publications

(64 citation statements)

References 28 publications

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“…Each of the three variants was present in two patients, and 3 out of the six patients carrying any of these variants died (Table 1, Supplementary Table 1). Interestingly, WWP1 has a known binding activity with the protein S of the virus, and the N745S missense variant previously characterized by Lee et al 31 , leads to aberrant WWP1 enzymatic activation with subsequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.…”

Section: Hect Germline Allelic Variants In Critical/life-threatening Covid-19 Patientsmentioning

confidence: 99%

Inhibition of HECT E3 ligases as potential therapy for COVID-19

et al. 2021

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SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

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Section: Hect Germline Allelic Variants In Critical/life-threatening Covid-19 Patientsmentioning

confidence: 99%

Inhibition of HECT E3 ligases as potential therapy for COVID-19

et al. 2021

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“…To predict the potential impact of the identified variants on the protein we used different tools (PolyPhen2, Mutation Taster, SIFT, MetaLR_pred, and MetaSVM_pred). The recurrent N745S variant has been previously reported by Lee et al 5 : it is in the HECT domain and is expected to decrease its binding to the N-terminal domain. Analogously, R86H (C2 domain) was also described by Lee et al 5 .…”

mentioning

confidence: 84%

“…The recurrent N745S variant has been previously reported by Lee et al 5 : it is in the HECT domain and is expected to decrease its binding to the N-terminal domain. Analogously, R86H (C2 domain) was also described by Lee et al 5 . This variant is functionally relevant since it induces a gain-of-function effect in triggering PTEN polyubiquitination 5 .…”

mentioning

confidence: 84%

“…Analogously, R86H (C2 domain) was also described by Lee et al 5 . This variant is functionally relevant since it induces a gain-of-function effect in triggering PTEN polyubiquitination 5 . With regards to the other five coding variants observed in our ASD cases, one is predicted by in silico analysis to be deleterious (R528H), while the others gave conflicting results.…”

mentioning

confidence: 95%

“…In addition, germline PTEN mutations have been identified in 2-5% of all ASD patients and~10% of macrocephalic ASD 4 . Recently, Lee et al 5 identified germline variants within the E3 ubiquitin ligase WWP1 (MIM: 602307) gene in PTEN mutation negative individuals with neoplastic phenotypes found in PHTS (MIM: 158350).…”

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confidence: 99%

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WWP1 germline variants are associated with normocephalic autism spectrum disorder

Novelli

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et al. 2020

Cell Death Dis

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Systemic depletion of WWP1 improves insulin sensitivity and lowers triglyceride content in the liver of obese mice

et al. 2023

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Obesity is a metabolic disorder associated with many diseases. WW domain‐containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT‐type E3 ubiquitin ligase involved in several diseases. Recently, we found that the level of WWP1 is increased in white adipose tissue in a mouse model of obesity and that obese Wwp1 knockout (KO) mice exhibit improved whole‐body glucose metabolism. Here, to determine which insulin‐sensitive tissues contribute to this phenotype, we investigated the levels of several insulin signaling markers in white adipose tissue, liver, and skeletal muscle of Wwp1 KO mice, which were fed a normal or high‐fat diet and transiently treated with insulin. In obese Wwp1 KO mice, phosphorylated Akt levels were increased in the liver but not in white adipose tissue or skeletal muscle. Moreover, the weight and triglyceride content of the liver of obese Wwp1 KO mice were decreased. These results suggest that systemic deletion of WWP1 improves glucose metabolism via enhanced hepatic insulin signaling and suppressed hepatic fat accumulation. In summary, WWP1 participates in obesity‐related metabolic dysfunction and pathologies related to hepatic steatosis via suppressed insulin signaling.

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WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition

Cited by 61 publications

References 28 publications

Inhibition of HECT E3 ligases as potential therapy for COVID-19

Inhibition of HECT E3 ligases as potential therapy for COVID-19

WWP1 germline variants are associated with normocephalic autism spectrum disorder

Systemic depletion of WWP1 improves insulin sensitivity and lowers triglyceride content in the liver of obese mice

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